Perry Davis' "VEGETABLE PAIN KILLER"

"PAIN KILLER" was patented by Perry Davis in 1845. It is believed to be the first nationally advertised remedy specifically for pain - as distinct from a particular disorder. "Pain Killer"

was distributed by Christian missionaries around the world. In its heyday, Perry Davis' "vegetable elixir" was widely regarded as a wonderdrug. Its ingredients, mainly opiates and ethyl alcohol, were entirely natural. The concoction was created Perry Davis in 1840. Since

"Perry Davis Pain Killer" was a registered trade brand name, there was no legal requirement to make its ingredients public on the bottle.

FUTURE  OPIOIDS

"If we could sniff or swallow something that would, for five or six hours each day, abolish our solitude as individuals, atone us with our fellows in a glowing exaltation of affection and

make life in all its aspects seem not only worth living, but divinely beautiful and significant, and if this heavenly, world-transfiguring drug were of such a kind that we could wake up

next morning with a clear head and an undamaged constitution - then, it seems to me, all our problems (and not merely the one small problem of discovering a novel pleasure) would

be wholly solved and earth would become paradise."

ALDOUS HUXLEY1894 - 1963

THE BIRTH OF A NEW GENERATION

A significant minority of the population only feel truly well on opioids. In effect, they self-medicate, taking responsibility for their own mental health in defiance of medical orthodoxy.

        It would indeed be extraordinary if - alone among the neurotransmitter systems of the brain - the endogenous opioid families were immune from dysfunction. Enkephalins are critical to "basal hedonic tone" i.e. whether we naturally feel happy or sad. Yet the therapeutic implications of a recognition that dysfunctional endogenous opioid systems underlie a spectrum of anxiety-disorders and depression are too radical - at present - for the medical establishment to contemplate. In consequence, the use of opioid-based pharmacotherapies for "psychological" pain is officially taboo. The unique efficacy of opioids in banishing mental distress is neglected. Their unrivalled efficacy in treating "physical" nociceptive pain is grudgingly accepted.

        Later this century and beyond, however, the development of highly selective, site-specific designer drugs and innovative gene-therapies may enhance our native opioid function and revolutionise mental health. Therapeutic intervention targeted on the opioid pathways will potentially enrich the quality of life of even the nominally "well", not least

because - by the more enlightened health standards of posterity - we may all be reckoned mentally ill.

        Today, by contrast, immense energy is devoted by the authorities into persecuting "illicit" narcotic users. Many drug-"abusers" feel well thanks only to the "non-therapeutic" use of opioids. They are stigmatised, pilloried and criminalised in a futile War Against Drugs. In the "Inquisition against pleasure", victims of medically-sanctioned human-rights abuses - e.g. the hundreds of thousands of drug "offenders" incarcerated in the Amerikan gulag - are officially supposed to believe their malaise-ridden drug-naïve states were "normal", "natural" and mentally healthy. In the course of our ill-conceived Drug War, vast resources are dissipated by the state-apparatus in an effort to choke off narcotic production and supply. When these efforts are temporarily successful, drug-deprivation makes the habitual opioid user feel ill; [s]he "cold-turkeys" with characteristic irritability, anhedonia, depression, sickness behaviour and sometimes raw physical pain. The ill-effects felt from involuntary deprivation of opioids are taken to demonstrate the likely ill-effects of legalised access, a paradox that might be thought laboured were its human costs not so tragic.

        When caught up in the criminal justice system, users may be pressured into taking opioid antagonists like naltrexone (Trexan). Such drugs can induce dysphoria and suicidal despair. At best, their use subtly diminishes the victim's capacity ever to feel well. Meanwhile Chinese military surgeons have developed (2003) a new treatment weapon against narcotic users: surgical destruction of the pleasure centres. Western doctors are said to be following these procedures with interest, but are more likely to achieve their functional equivalent by non-surgical means.

        Even where it is acknowledged that many opioid users have a pre-existing anxiety or depressive disorder in urgent need of relief, those so afflicted are fobbed off with often third-rate psychotropics instead. For a start, the monoamine hypothesis of depression - and the new classes of drug it has spawned (SSRIs, NARIs, SNRIs, NaSSAs, RIMAs etc to complement the dirty old tricyclics and irreversible unselective MAOIs) - is radically incomplete. A minority of people, admittedly, find such drugs effective. Often taking a licensed antidepressant is better than nothing at all - perhaps in part because of their positive effects on endogenous opioid peptide release. Yet even in the context of controlled clinical trials with relatively high dosage-regimens and artificially good rates of patient-compliance, it's rare for response-rates to reach more than 70%. Rates of full remission of depressive symptoms are far lower, perhaps 25-30%. Out "in the field", the picture is worse still. Adverse side-effects are common. Response may take weeks. Withdrawal reactions can be unpleasant.

        A recognition of the crucial role of dopamine, and selective dopamine reuptake blockers, in sub-types of depressive mood-disorders might push response and remission rates higher. The mesolimbic dopamine system is critical to vitality, motivation, libido and a capacity to anticipate reward. Dopaminergics can also act as analgesics. They can also reverse the apathetic sedation induced by some antidepressants and opioid agonists. Yet the FDA stymies the licensing of effective dopamine reuptake-blocking mood-brighteners at home; and applies pressure to deny access to them abroad. This is because of worries about their (sometimes) faster efficacy - and mild psychostimulant effect - raise the spectre of "abuse-potential"; and proscription, persecution and indiction are favoured over consumer education. For Big Brother knows best.

        More controversially, adding customised opioids, enkephalinase-inhibitors and kappa-antagonists to our therapeutic armamentarium may prove critical to boosting response- and remission-rates towards 100% in the decades ahead. Crudely, whereas dopamine mediates "wanting", mu opioid agonists mediate "liking". Both systems can be fruitfully enhanced.

Depressive and dysthymic people often suffer from a dysfunctional opioid system and anhedonia - an incapacity to experience pleasure. Sometimes orthodox "antidepressants" may even make them feel worse. Yet controlled clinical trials of designer narcotics for refractory and/or melancholic depression, let alone their use by "normal" people with "ordinary" mood-disorders, are not imminent.

        So what is to be done? Even in the context of today's crude agents, would some of us be better off as legalised junkies?

        No, usually not, at least in contemporary society. Self-medicating users with enough resources to maintain a regular supply may indeed find they can function as well as, or better than, their drug-naïve state. Popular mythology aside, users don't seek to escalate dosage indefinitely: both humans and laboratory monkeys with unlimited access tend slowly to increase injection-frequency until eventually they self-administer a stable and subjectively optimal amount of the drug. Most users take heroin, not primarily to stave off the abstinence syndrome, but because they find life on heroin better than their pain-ridden life without it. Yet the existence of a typical heroin addict in prohibitionist society can still be exceedingly unpleasant at times. Contemporary opioid drugs, natural and synthetic alike, are flawed. The problem is not the euphoric well-being they can induce - an ill-named "adverse side-effect" - but their tendency to induce a financially ruinous tolerance; perhaps insidiously to dull the intellect; trigger nausea; slow digestive processes; and sometimes induce a parodoxical hyperalgesia. Most seriously, when taken in acute excess, today's opioids can cause respiratory depression. This is a consequence of their stimulation of the mu-2 receptors in the medullary respiratory centres of the brain. These problems are exacerbated a thousandfold, however, by the illegal status of narcotics in contemporary society. Dosage, purity and regularity of supply cannot be guaranteed; prices are inflated; quality-control is negligible; good hygiene is difficult. Pharmacological education is non-existent, whereas it ought to be part of the core curriculum. Opioid users are frequently forced into crime to pay for pharmacotherapies that should be cheaply and safely available; and damned for seeking a state of mind which will one day be their birthright: invincible happiness.

        To promote emotional superhealth both durably and effectively, designer-opioids must be synthesised that are also subjectively nicer, richer and cleaner than today's product-line. For one of our three major endogenous opioid families is implicated in profoundly dysphoric psychological effects: a cruel negative-feedback system exists between the mu and kappa systems that "corrects" any "excess" tendency to well-being. Thus dynorphin activity at the kappa receptors tonically inhibits the release of dopamine from the mesolimbic terminals. By contrast, the mu-opioid receptor selective endomorphins, especially endomorphin 1, are potent antidepressants: they enhance mu opioid receptor-mediated dopamine release in the nucleus accumbens. If our well-being is to be sustainably enhanced, the balance between the two opposing opioid systems must be shifted.

        The role of the mu receptors appears to be crucial in another respect. Today, people vary hugely in their sensitivity to pain. This sensitivity is genetically regulated. Pain perception - and, conversely, emotional well-being - is closely linked to the number of neuronal mu receptors. This number is controlled by a single gene, the mu opioid receptor gene. Pain-sensitivity is diminished when the receptors are present in relative abundance. When the receptors are reduced in number or missing altogether, relatively minor noxious stimuli may be perceived as painful.

        In the short-to-medium term, then, we need better-targeted opioids, safer and more site-specific than the present crop. Smarter opioids can potentially be combined with cholecystokinin antagonists (e.g. proglumide); nitric oxide (NO) synthase inhibitors; peroxynitrite-blockers; and also, perhaps, better-designed NMDA receptor antagonists - co-

analgesics with potential antidepressant efficacy that inhibit the onset of tolerance. Although mu receptor agonists are the best analgesics and euphoriants, selective delta receptor agonists and enkephalinase inhibitors may prove clinically valuable antidepressants. The development of centrally active and more selective kappa antagonists - which block the endogenous excess production and reuptake of dynorphin underlying many depressive and anxiety disorders - is also a priority. Orally active JDTic, a potent, exceedingly long-acting selective kappa antagonist, is currently undergoing preclinical testing. Kappa Therapeutics, the world's first conference dedicated to the kappa opioid receptor, was held in Seattle July 2011. In the meantime, Buprenorphine (Buprenex, Temgesic, Subutex), for instance, is certainly no panacea; but it would probably benefit a far wider section of the population than its current restriction to use in "detoxifying" heroin-addicts. Its role as a mixed mu agonist reduces buprenorphine's addictive potential as a euphoriant while increasing its safety in overdose. Buprenorphine's kappa receptor antagonism may contribute to its superior efficacy as an antidepressant. Even the humble codeine analogue tramadol (Ultram), a selective partial mu agonist analgesic with noradrenaline and serotonin reuptake inhibiting properties, can serve as a useful mood-brightening stopgap. Weak but non-negligible kappa agonism limits its therapeutic benefit. But contemporary medico-legal opiophobia ensures such usage remains strictly off-label.

THE QUEST FOR A DRUG-FREE SOCIETY

        In the longer-run, however, irrespective of how clever our pharmacological interventions may one day be, we'd arguably be better off taking no drugs at all. For if there were nothing fundamentally wrong with our default-state of consciousness, then we wouldn't now try so hard to change it. Thus our sophisticated descendants may opt instead to rewrite the vertebrate genome and allow themselves life-long genetically pre-programmed bliss. They may "naturally" be animated by gradients of well-being beyond the bounds of normal human experience as an everyday part of mental health.

        Wouldn't lifelong happiness make us stagnate? No. In our genetically-enhanced post-human successors, the functional analogues of aversive experience can potentially perform an analogous functional role to mental and physical pain in our Darwinian past, but without its textures of phenomenal nastiness. Our descendants' enriched dopamine function will enhance their drive, energy and will-power, not just hedonic capacity. Thus outright abolitionism is not technically infeasible - just ideologically problematic.

        Tomorrow's bioscientists face another challenge. Taken in excess, opioid-based drugs of today tend to dull consciousness, inducing a dreamy warm contentment. The name "narcotic" derives from the Greek word for stupor. Indeed smacked-out bliss is typically used as the archetype of what any drug-or-gene-underwritten chemical utopia would be like. Most notably, soma in Aldous Huxley's Brave New World is depicted as a cross between a non-addictive opioid and a hangover-less tranquilliser. Thus Huxley's utopians enjoy only an empty imbecilic happiness, not life-enriching peak experiences. Unlike dopaminergics, soma doesn't increase incentive-motivation, nor does it heighten the felt intensity of experience. You can use soma to drift off to sleep.

        Yet this negative stereotype of synthetic bliss is profoundly misleading. Addictive tranquillity is only one option among many. It reflects a poverty in our conception of the range of options for paradise-engineering that biotechnology puts on offer. In reality, the quality of our consciousness can be intensified, sharpened and radically diversified by creative psychopharmacology. Intellect and empathy, and not just mood, can be

prodigiously enhanced when the ideology of Better Living Through Chemistry finally enters mainstream culture.

        Better still, when a wholesale genomic rewrite - and not just piecemeal genetic tinkering - unfolds in the millennium ahead, then any chemical manipulation of our descendants' emotionally- and intellectually-enriched superminds may be redundant. At most, lifestyle drugs will offer an optional fine-tuning for the parameters of their well-being - set against a backdrop of native-born bliss. In the wake of any such Post-Darwinian Transition, a wide variety of social interactions will "naturally" trigger a far richer endogenous opioid release than occurs today; and do so from a much higher baseline of emotional well-being.

        However, our present restrictive definitions of mental illness, and the technical challenges posed by large-scale genetic-rewrites, make germline gene-therapy seem a pipe-dream for now. In the present era, lifetime pure dysthymia afflicts far too many people; and periods of "mild" anxiety, malaise and depressive episodes blight the lives of hundreds of millions more. Meanwhile countless victims of chronic pain-disorders are condemned to a life of needless suffering by institutionalized opiophobia. Victims of the most unspeakable, spirit-crushing neuropathic or central pain are liable to be fobbed off with pain-management courses - "helping you to manage your pain" - rather than given the potent pain-relief they deserve. For with a bit of creative psychopharmacology, both the tolerance and adverse side-effects of chronic opioid use are manageable even with today's crude agents. Thanks to tomorrow's biotechnology, the real obstacles to curing the nasty side of life are set to become doctrinal, not technical. Suffering of any kind is due to become optional. It remains to be seen how quickly the ideological baggage of the past can be overcome.

The Plant Of Joy

"God's Own Medicine"Sir William Osler

Opium is an extract of the exudate derived from seedpods of the opium poppy, Papaver somniferum. The poppy plant was cultivated in the ancient civilisations of Persia, Egypt and Mesopotamia. Archaeological evidence and fossilised poppy seeds suggest that Neanderthals may have used the opium poppy over thirty thousand years ago. Less controversially, the first known written reference to the poppy appears in a Sumerian text dated around 4,000 BC. The flower was known as hul gil, plant of joy. The Egyptian Eber papyrus of some 3500 years ago advises use of condensed juice of the unripe seed pod "to prevent the excessive crying of children". Papaver somniferum is the only species of Papaver used to produce opium. It is believed to have evolved through centuries of breeding and cultivation from a Mediterranean-growing wild strain, Papaver setigerum.

        Homer conveys its effects in The Odyssey. In one episode, Telemachus is depressed after failing to find his father Odysseus. But then Helen...

"...had a happy thought. Into the bowl in which their wine was mixed, she slipped a drug that had the power of robbing grief and anger of their sting and banishing all painful memories. No one who swallowed this dissolved in their wine could shed a single tear that day, even for the death of his mother or father, or if they put his brother or his own son to the sword and he were there to see it done..."

In some parts of the contemporary Middle East, chilled glasses of poppy tea are served to mourners at funerals to ease their grief.

        Papaver somniferum has long been popular in Europe. Fossil remains of poppy-seed cake and poppy-pods have been found in Neolithic Swiss lake-dwellings dating from over 4,000 years ago. Poppy images appear in Egyptian pictography and Roman sculpture. Representations of the Greek and Roman gods of sleep, Hypnos and Somnos, show them wearing or carrying poppies. Throughout Egyptian civilisation, priest-physicians promoted the household use of opium preparations. Such remedies were called "thebacium" after the highly potent poppies grown near the capital city of Thebes. Egyptian pharaohs were entombed with opium artefacts by their side. Opium could also readily be bought on the street-markets of Rome. Emperor Marcus Aurelius (161-180), author of the philosophical

classic Meditations, regularly enjoyed opium; it may have contributed to his celebrated stoicism. By the eighth century AD, opium use had spread to Arabia, India and China. The Arabs both used opium and organised its trade. For the Prophet had prohibited the use of alcohol, not hashish or opiates.

        Classical Greek physicians either ground the whole plant or used opium extract. Galen lists its medical indications, noting how opium...

"...resists poison and venomous bites, cures chronic headache, vertigo, deafness, epilepsy, apoplexy, dimness of sight, loss of voice, asthma, coughs of all kinds, spitting of blood, tightness of breath, colic, the lilac poison, jaundice, hardness of the spleen stone, urinary complaints, fever, dropsies, leprosies, the trouble to which women are subject, melancholy and all pestilences."

Later authorities were scarcely less enthusiastic. Physicians commonly believed that the poppy plant was of divine origin; opium was variously called the Sacred Anchor Of Life, Milk Of Paradise, the Hand Of God, and Destroyer Of Grief. Medical pioneer Thomas Sydenham (1624-1689), sometimes known as 'the English Hippocrates' and 'the Shakespeare of medicine', writes....

"Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium."

This may be overstating God's benevolence; but by relieving emotional as well as physical pain, opiates have been understandably popular. Robert Burton (1577-1640), scholar, priest and author of Anatomy of Melancholy, commended laudanum - essentially opium dissolved in wine - for those who were insomniacs... "...by reason of their continual cares, fears, sorrows, dry brains [which] is a symptom that much crucifies melancholy men..."Indeed opium was probably the world's first authentic antidepressant. Unlike other pain-relieving agents such as ethyl alcohol, ether or the barbiturates, opium doesn't impair sensory perception, the intellect or motor co-ordination. Pain ceases to be threatening, intrusive and distressing; but it can still be sensed and avoided. In low doses, opium may sometimes be pleasantly stimulating rather than soporific. In the East, opium was typically treated as a social drug; and opium-smoking was a tool for conviviality. Nowadays a life of habitual opioid use evokes images of stupor and mindless oblivion, yet ironically Coleridge coined the word intensify to describe opium's effects on consciousness.

        A significant advance in opium-processing occurred in the sixteenth century. In freebase form, the alkaloids found in opium are significantly less soluble in water than in alcohol. Philippus Aureolus Theophrastus Bombastus von Hohenheim (1490-1541), better known as Paracelsus, claimed: "I possess a secret remedy which I call laudanum and which is superior to all other heroic remedies". He concocted laudanum [literally: "something to be praised"] by extracting opium into brandy, thus producing, in effect, tincture of morphine. His original witches' brew contained extra ingredients such as crushed pearls, henbane and frog-spawn. It was steeped in alchemical mumbo-jumbo: Paracelsus called opium itself "the stone of immortality". Thomas Sydenham, however, went on to standardise laudanum in the now classic formulation: 2 ounces of opium; 1 ounce of saffron; a drachm of cinnamon and cloves - all dissolved in a pint of Canary wine.

        Laudanum can be habit-forming. Yet the sometimes spectacular ill-effects noted by early modern writers when coming off laudanum probably owed more to its ethyl alcohol content than its opium. As their opioid tolerance increased, so did users' consumption of tinctures: De Quincey's florid withdrawal signs on abstaining...

"I was stared at, hooted at, grinned at, chattered at, by monkeys, by paroquets, by cockatoos. I ran into pagodas, and was fixed, for centuries, at the summit, or in secret rooms: I was the idol; I was the priest; I was worshipped; I was sacrificed. I fled from the wrath of Brama through all the forests of Asia: Vishnu hated me; Seva laid wait for me. I came suddenly upon Isis and Osiris: I had done a deed, they said, which the ibis and the crocodile trembled at. I was buried for a thousand years, in stone coffins, with mummies and sphinxes, in narrow chambers at the heart of eternal pyramids. I was kissed, with cancerous kisses, by crocodiles; and laid, confounded with all unuttemble slimy things, amongst reeds and Nilotic mud..."

...suggest an alcoholic's delirium tremens rather than a junky's cold-turkey.

        By the nineteenth century, vials of laudanum and raw opium were freely available at any English pharmacy or grocery store. One nineteenth-century author declared: "[Laudanum] Drops, you are darling! If I love nothing else, I love you." Another user, the English gentleman quoted in Jim Hogshire's Opium for the Masses (1994), enthused that opium felt akin to a gentle and constant orgasm.

        British opium imports rose from a brisk 91,000lb in 1830 to an astonishing 280,000lb in 1860. Despite British control of Indian production, most domestic imports came from Turkey. This was because of the superior morphine content - 10-13% - of Turkish opium; opium's varying potency depends on its particular growing conditions. For obscure reasons, opium was most popular among the rural peasantry of the Fens. The British Medical Association estimated that sparsely populated Cambridgeshire and its environs consumed around half of Britain's annual opium imports. This consumption was topped up by generous use of poppy-tea brewed from homegrown poppies.

        Youngsters were introduced to the pleasures of opiates at their mothers' breast. Harassed baby-minders - and overworked parents - found opium-based preparations were a dependable way to keep their kids happy and docile; this was an era before Ritalin. Sales of Godfrey's Cordial, a soothing syrup of opium tincture effective against colic, were prodigious. But Godfrey's Cordial had its competitors: Street's Infants' Quietness, Atkinson's Infants' Preservative, and Mrs Winslow's Soothing Syrup.

        Opium was viewed as a medicine, not a drug of abuse. Contemporary medical theory didn't allow that one could become addicted to a cure. However, the chemists and physicians most actively investigating the properties of opium were also its dedicated consumers; and this may conceivably have coloured their judgement.

        Writers of distinction certainly consumed opium in copious quantities. Samuel Taylor Coleridge (1772-1834) wrote Kubla Khan in a dream-like trance while under its spell; opium promotes vivid dreams and rich visual imagery as well as gentle euphoria...

"In Xanadu did Kubla KhanA stately pleasure-dome decreeWhere Alph, the sacred river, ranDown to a sunless sea...I would build that dome in air, That sunny dome, those caves of ice!And all who heard should see them there, And all should cry, Beware! Beware!His flashing eyes, his floating hair!Weave a circle round him thrice,

And close your eyes with holy dread,For he on honey-dew hath fed,And drunk the milk of Paradise."

Fellow English author Thomas de Quincey (1785-1859) writes of "the marvellous agency of opium, whether for pleasure or for pain". De Quincey seems to have treated opium as a mood-brightening smart-drug. The author of Confessions of an English Opium-Eater (1821) draws invidious comparisons with alcohol. He attributes a heightening of his mental powers to opium use..."Whereas wine disorders the mental faculties, opium introduces amongst them the most exquisite order, legislation and harmony. Wine robs a man of self-possession; opium greatly invigorates it....Wine constantly leads a man to the brink of absurdity and extravagance; and, beyond a certain point, it is sure to volatilize and disperse the intellectual energies; whereas opium seems to compose what has been agitated, and to concentrate what had been distracted. ...A man who is inebriated...is often...brutal; but the opium eater...feels that the diviner part of his nature is paramount; that is, the moral affections are in a state of cloudless serenity; and over all is the great light of majestic intellect...."        De Quincey states that not he himself, but opium, should be regarded as the true hero of his essay. Opium was his "Divine Poppy-juice, as indispensable as breathing". By reputation, opium users have dull wits, idle lives and diminished sensibility. This was not de Quincey's verdict. He made a habit of going to the opera under its influence - and found his experience of music delightfully enhanced... "Now opium, by greatly increasing the activity of the mind, generally increases, of necessity, that particular mode of its activity by which we are able to construct out of the raw material of organic sound an elaborate intellectual pleasure...It is sufficient to say, that a chorus, etc of elaborate harmony displayed before me, as in a piece of arras work, the whole of my past life - not as if recalled by an act of memory, but as if present and incarnated in the music; no longer painful to dwell upon, but the detail of its incidents removed...and its passions exalted, spiritualized, and sublimed..." Opium induces gentle, subtle, dream-like hallucinations very different from the fierce and unpredictable weirdness of LSD. Charles Baudelaire (1821-1867) likens opium to a woman friend, "...an old and terrible friend, and, alas! like them all, full of caresses and deceptions." Across the Atlantic, in 1842, William Blair describes his experiences with opium in a New York magazine... "While I was sitting at tea, I felt a strange sensation, totally unlike any thing I had ever felt before; a gradual creeping thrill, which in a few minutes occupied every part of my body, lulling to sleep the before-mentioned racking pain, producing a pleasing glow from head to foot, and inducing a sensation of dreamy exhilaration (if the phrase be intelligible to others as it is to me) similar in nature but not in degree to the drowsiness caused by wine, though not inclining me to sleep; in fact far from it, that I longed to engage in some active exercise; to sing, dance, or leap...so vividly did I feel my vitality - for in this state of delicious exhilaration even mere excitement seemed absolute elysium - that I could not resist the tendency to break out in the strangest vagaries, until my companions thought me deranged...After I had been seated [at the play I was attending] a few minutes, the nature of the excitement changed, and a 'waking sleep' succeeded. The actors on the stage vanished; the stage itself lost its reality; and before my entranced sight magnificent halls stretched out in endless succession with galley above gallery, while the roof was blazing with gems, like stars whose rays alone illumined the whole building, which was tinged with strange, gigantic figures, like the wild possessors of lost globe...I will not attempt farther to describe the magnificent vision which a little pill of 'brown gum' had conjured up from the realm of ideal being. No words that I can command would do justice to its Titanian splendour and immensity..."        Opium was also well known in Chinese antiquity. One 10th century poem celebrates how the opium poppy can be made into a drink "fit for Buddha". Ancient peoples either ate parts of the flower or converted them into liquids to drink. But by the 7th century, the Turkish and Islamic cultures of western Asia had discovered that the most powerful

medicinal effects could be obtained by igniting and smoking the poppy's congealed juices; and the habit spread. The widespread use of opium in China dates to tobacco-smoking in pipes introduced by the Dutch from Java via the island of Formosa in the 17th century. Whereas Indians ordinarily ate opium, the Chinese smoked it. The Chinese mixed Indian opium with tobacco, two products traded by the Dutch. Pipe-smoking was adopted throughout the region. Predictably enough, this resulted in increased opium-smoking, both with and without tobacco. Old encrusted opium-pipes were still valuable because they contained a residue of charcoal and raw opium known as "dross". Dross could be recycled with tobacco plus various adulterants and sold to the poor. Styles of opium pipe reflected the relative wealth or poverty of their owners. Pipes ranged from bejewelled, elaborately ornamented works of art to simple constructions of clay or bamboo.

        By the late-1700s, the British East India Company controlled the prime Indian poppy-growing areas on the Ganges plain between Patna and Benares. The company dominated the Asian opium trade; but they did not create it. "Take your opium" was a standard greeting in some Indian cities even before the Europeans arrived. By 1800, however, the British East India Company had a virtual monopoly, controlling supply and setting prices. Dealers, merchants and users alike lovingly assessed the quality and potency of their merchandise with the ardour of a wine connoisseur. According to The Chinese Repository, discerning purchasers of the raw product looked for opium of...

"...moderately firm texture, capable of receiving an impression from the finger; of a dark yellow color when held in the light, but nearly black in the mass, with a strong smell, and free from grittiness..."

        Opium was already heavily used in China as a recreational drug. The Imperial Chinese court had banned its use and importation, but large quantities were still being smuggled into the country. In 1839, the Qing Emperor, Tao Kwang, ordered his minister Lin Tse-hsü to take action. Lin petitioned Queen Victoria for help; but he was ignored. In reaction, the Emperor instructed the confiscation of 20,000 barrels of opium and detained some foreign traders. The British retaliated by attacking the port-city of Canton.

        Thus began the First Opium War, launched by the biggest, richest and perhaps most aggressive drug cartel the world has ever known, the British Empire. The Chinese were defeated. They were forced to sign the Treaty of Nanjing in 1842. The British required that the opium trade be allowed to continue; that the Chinese pay a large settlement and open five new ports to foreign trade; and that China cede Hong Kong to Britain.

        Peace didn't last. The Second Opium War began and ended in 1856 over western demands that opium markets be expanded. The Chinese were again defeated. In 1858, by the Treaty of Tientsin, opium importation to China was formally legalised. God-fearing British traders claimed that the hard-working Chinese were entitled to "a harmless luxury"; the opium trade in less respectable hands would be taken over by "desperadoes, pirates and marauders". Soon opium poured into China in unprecedented quantities. By the end of the nineteenth century, it has been estimated that over a quarter of the adult male Chinese population were addicted.

        In 1893, a Royal Commission on Opium was established to investigate the use of opium in the British Indian Empire. Many Protestants had begun to demonise opium; and Britain's Liberal Party hoped to see the drug banned for non-medical use. The Commission held seventy days of public hearings and called hundreds of witnesses. Its final Report ran to seven volumes totalling some 2500 pages. The Commission concluded that the use of opium in India was not a cause of "extensive moral or physical degradation." Opium was no worse than alcohol. The medical and non-medical use of opium were impossible to distinguish in practice. An effective ban would be infeasible. The Report was welcomed by an editorial

published in the British medical journal The Lancet in April 1895. The Report's findings "dealt a crushing blow to the anti-opium faddists". Prohibitionist claims were "...either ridiculously exaggerated or even altogether unfounded."

        In North America, the initial history of Papaver somniferum was somewhat more peaceful than in Asia. During the first few centuries of European settlement, opium poppies were widely cultivated. Early settlers dissolved the resin in whisky to relieve coughs, aches and pains.

        The plant had further uses. Papaver somniferum produces lots of small black seeds. Poppy-seeds are an ingredient of typical bird-seed and a common garnish on rolls. Poppy-seeds can also be ground into flour; used in salad-dressings; added to sauces as flavouring or thickening-agents; and the oil can be expressed and used in cooking. Poppy-heads are infused to make a traditional sedative drink.

        Many distinguished early Americans grew Papaver somniferum. Rightly or wrongly, they would today be treated as felons. Thomas Jefferson cultivated opium poppies at his garden in Monticello. The seeds from its plants, including the poppies, were sold at the gift-shop of Thomas Jefferson Center for Historic Plants until 1991 - when a drug-bust at the nearby University of Virginia panicked the Board of Directors into ripping up the plants and burning the seeds. The cultivation of Papaver somniferum is banned in the USA under the Opium Poppy Control Act of 1942. Amateur horticulturists, however, continue to value the beautiful red, yellow and white flowers as an adornment to their gardens.

        Until the nineteenth century, the only opioids used medicinally or recreationally took the form of crude opium. Opium is a complex chemical cocktail containing sugars, proteins, fats, water, meconic acid, plant wax, latex, gums, ammonia, sulphuric and lactic acids, and numerous alkaloids, most notably morphine (10%-15%), codeine (1%-3%), noscapine (4%-8%), papaverine (1%-3%), and thebaine (1%-2%). All of the latter, apart from thebaine, are used medicinally as analgesics. The opioid analgesics are of inestimable value because they reduce or abolish pain without causing a loss of consciousness. They also relieve coughs, spasms, fevers and diarrhea.

        Even thebaine, though without analgesic effect, is of immense pharmaceutical worth. This is because it can be used to produce semi-synthetic opioid morphine analogues such as oxycodone (Percodan), dihydromorphenone (Dilaudid), hydrocodone (Vicodin) and etorphine (Immobilon). Classes of morphine analogue include the diphenylpropylamines (e.g. methadone), the 4-phenylpiperidines (e.g. meperidine), the morphinans (e.g. levorphanol) and 6,7-benzomorphans (e.g. metazocine). Although seemingly structurally diverse, all these compounds either possess a piperidine ring or contain the critical part of its ring structure. Etorphine, for instance, is a very potent analogue of morphine. On one occasion a team of researchers, working in the 1960s under Professor Bentley of Macfarlan Smith and Co, drank mid-morning tea that had been stirred with a contaminated rod. They were soon laid out. The scientists had unwittingly drunk a drug later developed as etorphine. Etorphine is over 1000 times more powerful than morphine; it is used in dart-guns as Immobilon to subdue elephants and rhinos. Fortunately the scientists recovered.

        Morphine was first isolated from opium in 1805 by a German pharmacist, Wilhelm Sertürner (1783-1841). Sertürner described it as the Principium Somniferum. He named it morphium - after Morpheus, the Greek god of dreams. Today morphine is isolated from opium in substantially larger quantities - over 1000 tons per year - although most commercial opium is converted into codeine by methylation. On the illicit market, opium gum is filtered into morphine base and then synthesized into heroin.

        Doctors had long hunted for effective ways to administer drugs without ingesting them. Taken orally, opium is liable to cause unpleasant gastric side-effects. The development of the hypodermic syringe in the mid-nineteenth century allowed the injection of pure morphine. Both in Europe and America, members of high society and middle-class professionals alike would jack up daily; poor folk couldn't afford to inject drugs. Morphinism became rampant in the USA after its extensive use by injured soldiers on both sides of the Civil War. In late nineteenth-century America, opiates were cheap, legal and abundant. In the judgement of one historian, America became "a dope fiend's paradise". Moreover it was believed that injecting morphine wasn't addictive. Quitting habitual opium use can cause malaise, flu-like symptoms, and depression; morphine seemed an excellent cure. In China, for instance, early twentieth century missionaries handed out anti-opium remedies in such profusion that the pills became known as "Jesus Opium"; their active ingredient was morphine.

         Soldiers, missionaries and patent-medicine salesmen were not alone in eulogising its properties. A leading American medical textbook (1868) revealed that opiates...

"...cause a feeling of delicious ease and comfort, with an elevation of the whole moral and intellectual nature...There is not the same uncontrollable excitement as from alcohol, but an exaltation of our better mental qualities, a warmer glow of benevolence, a disposition to do great things, but nobly and beneficently, a higher devotional spirit, and withal a stronger self-reliance, and consciousness of power. Nor is this consciousness altogether mistaken. For the intellectual and imaginative faculties are raised to the highest point compatible with individual capacity...Opium seems to make the individual, for a time, a better and greater man...."

        Early optimism about morphine's non-addictive nature proved sadly misplaced. Women in particular came to be seen as especially vulnerable to opiate dependence. The most likely candidate for addiction, according to American doctor R Batholow, was... "...a delicate female, having light blue eyes and flaxen hair, [who] possesses, according to my observations, the maximum susceptibility..." Racist stereotypes, rampant xenophobia and lurid images of white slave-traders abounded too. In the 1850s and 1860s, tens of thousands of Chinese had emigrated to the USA to help build the western railroads and work the California mines. Opium-smoking was an integral part of Chinese culture; and its effects offered a merciful relief from dirty and backbreaking work. But the medical tide was turning. Dr Hamilton Wright, newly appointed US opium commissioner, blamed "the Chinese vice" for corrupting the nation's youth.... "One of the most unfortunate phases of the habit of smoking opium in this country [was] the large number of women who have become involved and were living as common-law wives or cohabiting with Chinese in the Chinatowns of our various cities..."Meanwhile Dr John Witherspoon, later President of the American Medical Association, exhorted the medical community to... "...save our people from the clutches of this hydra-headed monster which stalks abroad through the civilized world, wrecking lives and happy homes, filling our jails and lunatic asylums, and taking from these unfortunates, the precious promise of eternal life..."         So the search began for a powerful non-addictive alternative to opium and morphine. In 1874, English pharmacist C.R. Alder Wright (1844-1894) had boiled morphine and acetic acid to produce diacetylmorphine, C17H17NO (C2H3O2)2. Diacetylmorphine was synthesized and marketed commercially by the German pharmaceutical giant, Bayer. In 1898, Bayer launched the best-selling drug-brand of all time, Heroin.

Deadly Short Cuts

"It's so good. Don't even try it once."intravenous heroin user

Heroin is named after the German word for powerful, heroic, heroisch. According to popular legend, its substitute, methadone, was initially christened Dolophine in honour of Adolf Hitler. In reality, the name comes from the Latin dolor, meaning "pain", and fin, meaning "end": hence "end of pain".

        The consumption of heroin is marked by a euphoric rush, a warm feeling of relaxation, a sense of security and protection, and a dissipation of pain, fear, hunger, tension and anxiety. When heroin is snorted or smoked, the rush is intense and orgasmic. Subjectively, time may slow down. Any sense of anger, frustration or aggression disappears. Users enjoy the feeling of "being wrapped in God's warmest blanket".

        Heroin is the most fast-acting of all the opiates. When injected, it reaches the brain in 15-30 seconds; smoked heroin reaches the brain in around 7 seconds. The peak experience via this route lasts at most a few minutes. The surge of pleasure seems to start in the abdomen; a delicious warmth then spreads throughout the body, or at least the somatosensory cortex. After the intense euphoria, a period of tranquillity ("on the nod") follows, lasting up to an hour. Experienced users will inject between 2-4 times per day. After taking heroin, some people feel cocooned and emotionally self-contained. Others feel stimulated and sociable. Either way, there is a profound sense of control and well-being. The euphoria gradually subsides into a dreamy and relaxed state of contentment. Higher doses of heroin normally make a person feel sleepy. At higher doses still, the user will nod off into a semi-conscious state. The effects usually wear off in 3-5 hours, depending on the dose. Heroin is not inherently toxic to the organ systems of the body. Whereas a 200-400mg dose of heroin could kill a novice, a chronic user may take 1800mg without ill-effects. But in prohibitionist society the mortality of street users is high.

        Diacetylmorphine, or heroin, was first synthesized from morphine in 1874. It is formed simply by adding two acetyl groups. Heroin is around three times more potent than morphine. Its increased lipid solubility allows heroin to cross the blood-brain barrier more quickly. The drug is reconverted back to morphine before it binds to brain-tissue receptors. Pure heroin is a white, odourless powder with a bitter taste. Most illicit heroin, however, varies in color from white, pink/beige to dark brown. This is because of impurities left from the manufacturing process or the presence of additives.

        In the late nineteenth century, it was fondly believed that if only one could filter out the "addictive" properties of opium, then one would capture its therapeutic essence. Heinrich Dreser, in charge of drug development at Bayer, tested the new semi-synthetic drug on

animals, humans, and most notably himself. Dreser was impressed. He pronounced heroin an effective treatment for a variety of respiratory ailments, especially bronchitis, asthma and tuberculosis.

        Commercial production of heroin began in 1898. Heroin was advertised under its well-known trademark by German manufacturers Bayer as "the sedative for coughs". The new wonderdrug enjoyed widespread acceptance in the medical profession. This was because heroin induces a serene, un-manic euphoria with minimal interference with sensation, motor skills or intellect - though chronic opioid use typically diminishes the inclination to abstract thought.

        Bayer was soon enthusiastically selling heroin to dozens of countries. Free samples were handed out to physicians. The medical profession remained largely unaware of the potential risk of addiction for years. Eventually news filtered out. Doctors noticed that some of their patients were consuming inordinate quantities of heroin-based cough remedies. It transpired that heroin was not the miracle-cure for morphinism that some of its early boosters had supposed. In 1913, Bayer halted production. They wrote the drug out of their official company history, and focused instead on marketing their second blockbuster drug, aspirin.

        Comprehensive control of opiates in the United States was first established in 1914 with the Harrison Narcotic Act. In 1924, federal law made any use of heroin illegal. Within a decade, the Bureau of Narcotics had arrested some 50,000 users and 25,000 physicians. Most of the problems suffered by contemporary users derive, directly or indirectly, from the criminalisation of heroin use and the draconian penalties inflicted on those who take it. Likewise, most of the needless pain suffered by the physically ill today derives, directly or indirectly, from the demonisation of opioid drugs and from the reluctance of physicians to prescribe stigmatised remedies for pain that really work.

        During World War One, newspaper editors, police forces, politicians and "patriots" whipped up a climate of hysteria against seditious "dope fiends" enslaved by "the German invention". Heroin use was associated with anarchy, violence, foreigners and Bolshevism. Prohibition led inexorably to control of the heroin business by organised crime. Jewish gangsters such as Meyer Lansky dominated distribution in the 1920s. In the 1930s, they were superseded by the Mafia: this was the era of "Lucky" Luciano, the celebrated Sicilian mobster.

        Drug law was widely flouted. In explaining the failure of decades of prohibitionist legislation, former chief of police of the USA, Joseph D McNamara, wrote in National Review...

"It's the money, stupid. After 33 years as a police officer in three of the country's largest cities, that is my message to the righteous politicians who obstinately proclaim that a war on drugs will lead to a drug-free America. About $500 of heroin or cocaine in a source country will bring in as much as $100,000 on the streets of an American city. All the cops, armies, prisons and executions in the world cannot impede a market with that kind of tax-free profit-margin. It is the illegality that permits the obscene mark-up, enriching drug-traffickers, distributors, dealers, crooked cops, lawyers, judges, politicians, bankers, businessmen..."

Choking off the supply of narcotics at source isn't a realistic prospect either. Myles Ambrose, one of President Nixon's closest advisers in the War on Drugs, was scathing in his judgement of some of his fellow drug-warriors... "...The basic fact that eluded these great geniuses was that it takes only ten square miles of poppy to feed the entire American heroin market, and they grow everywhere...."

        Traditionally, the purity of heroin in a bag has ranged from 1% to 10%; more recently, heroin purity has ranged from 1% to 98%, with a US national average of 35 percent. Pure heroin is rarely sold on the street. A bag may contain 100 mg of powder, only a portion of which is heroin; the remainder could be sugars, starch, powdered milk, or quinine. Until recently, heroin in the United States was almost exclusively injected, either intravenously, subcutaneously ("skin-popping"), or intramuscularly. Injection is the most practical and efficient way to administer low-purity heroin. The availability of higher-purity heroin, however, allows users to snort or smoke ("chasing the dragon"). Snorting is most widespread in those areas where high-purity heroin is easy to obtain.

        When injected, heroin provides an extremely powerful rush. After 4 to 8 hours, the effects start to wear off. Tolerance develops to the respiratory depressant, sedative, analgesic, emetic and euphorigenic effect. So users tend to increase their daily dose - sometimes as much as a hundredfold or more - if financial resources permit. Financial resources frequently don't: the term "junkie" derives from addicts who stole junk metal to support their habit.

        Injecting drugs can be a risky business in prohibitionist society. This is because hygiene is difficult, education is minimal, and fluctuations in quality can lead to accidental overdose. US opposition to needle-exchange programs at home and abroad has massively promoted the spread of HIV and hepatitis in users - and non-users - alike. Noxious tobacco-smoking aside, the Supreme Court of the United States has never been sympathetic to a drug-based lifestyle....

"To be a confirmed drug addict is to be one of the walking dead....The teeth have rotted out, the appetite is lost, and the stomach and intestines don't function properly. The gall bladder becomes inflamed; eyes and skin turn a bilious yellow; in some cases membranes of the nose turn a flaming red; the partition separating the nostrils is eaten away-breathing is difficult. Oxygen in the blood decreases; bronchitis and tuberculosis develop. Good traits of character disappear and bad ones emerge. Sex organs become affected. Veins collapse and livid purplish scars remain. Boils and abscesses plague the skin; gnawing pain racks the body. Nerves snap; vicious twitching develops. Imaginary and fantastic fears blight the mind and sometimes complete insanity results. Often times, too, death comes-much too early in life....Such is the torment of being a drug addict; such is the plague of being one of the walking dead..." (1962)

        Heroin is sometimes smoked with crack cocaine. This combination delivers an even more intensely rewarding experience than taking either drug alone. "Speedballs" are hugely addictive and ruinously expensive. Yet in a clinical setting and among the terminally ill, the simultaneous use of cocaine, methylphenidate or amphetamines with heroin or morphine can augment the opioid's analgesic and anxiolytic effect while allowing its dosage to be lowered. The risks of respiratory depression are thus diminished.

        Why do we like opium and its derivatives so much?

        Heroin mimics the action of natural chemicals, endorphins, produced by the body in response to pain. Endorphins are small-chain peptides that activate our endogenous opioid receptors. Opioid receptors are proteins embedded in the cell membrane; opioid agonists bind to the receptors to initiate their effects. The highest density of opioid receptors is found in the limbic system. Their activation produces feelings of happiness, relaxation, fearlessness and tolerance to pain. Endorphins are hundreds or even thousands of times more potent than morphine on a molar basis. Their potency means their concentrations in vivo are low. Endorphins are also involved in respiration, nausea, vomiting, pain modulation, hormonal regulation and itching.

        Opioid drugs also act in these limbic brain regions. Yet except at very high doses, the opioids don't block the pain messages themselves. Rather, they change the subjective experience of the pain. This is why people receiving morphine for pain-relief may say that they still feel the pain - but that it doesn't bother them any more. Many users self-medicate: opioids are powerful antidepressants and antianxiety agents. Response and remission rates are high; but so are tolerance, dependence and addiction.

Endogenous Opioids

"I'll die young, but it's like kissing God"Lenny Bruce

We are all naturally dependent on opioids for our emotional health. Both narcotics and internally generated endorphins exert their action on the body by interacting with specific membrane receptor-proteins on our nerve cells.

        The body produces three large pro-compounds: proenkephalin, prodynorphin, and pro-opiomelanocortin. Endorphins can further decompose to small fragments, oligomers, which are still active. Oligomers pass the blood-brain barrier more readily. Enzymatic degradation of small-chain endorphins is accomplished by dipeptidyl carboxypeptidase, enkephalinases, angiotensinases, and other enzymes. This limits their lifetime in the unbound state.

        Opioid receptors presynaptically inhibit transmission of excitatory pathways. These pathways include acetylcholine, the catecholamines, serotonin, and substance P. Substance P is a neuropeptide active in neurons that mediate our sense of pain; antagonists of substance P are currently under investigation as clinical antidepressants. Endorphins are also involved in glucose regulation. Opioid receptors are functionally designated as mu, delta, kappa, etc. These categories can be further sub-classified by function or structure. Decoding the human genome has allowed the genetic switching-mechanisms that control the expression of each opioid receptor to be determined at the transcriptional and post-transcriptional level.

        All classes of opioid receptor share key similarities. Opioid-driven inhibition of neuronal excitability is mediated by the activation of a variety of potassium channels in the plasma membrane. The disparate subjective and behavioural effects evoked by activation of the different categories of opioid receptor are typically not the outcome of different cellular responses, but reflect the different anatomical distributions of each receptor. Unlike kappa opioid receptors, however, both mu and delta opioid receptors internalise on exposure to agonists. Activation of any type of opioid receptor inhibits adenylate cyclase, resulting in a fall in intracellular cAMP and diminished action potential firing. This causes a reduced flow of nociceptive information to the brain. Conversely, opioid addicts undergoing withdrawal suffer elevated cAMP levels and enhanced protein kinase A activity, resulting in increased neurotransmitter release.

        The opioid receptors all have a common general structure. They are characteristically G protein-linked receptors embedded in the plasma membrane of neurons. Once the receptors are bound, a portion of the G protein is activated, allowing it to diffuse within the plasma membrane. The G protein moves within the membrane until it reaches its target - either an enzyme or an ion channel. These targets normally alter protein phosphorylation and/or gene

transcription. Whereas protein phosphorylation alters short-term neuronal activity, gene transcription acts over a longer timescale.

        Two new classes of opioid neuropeptide have recently been identified. These are nociceptin and the endomorphins.

        Nociceptin (also known as orphanin) was first identified in 1995. It is the endogenous ligand of the opioid receptor-like 1 receptor. Depending dosage and site, nociceptin has subjectively extremely nasty hyperalgesic effects. Nociceptin receptor antagonists are candidate antidepressants and analgesics.

        Endomorphin1 and endomorphin2 are newly-discovered ligands with the highest affinity and selectivity for the mu opioid receptor of all the endogenous opioids. Critically, endomorphin1 increases dopamine efflux in the nucleus accumbens via mu-1 opioid receptors. In the absence of selective endogenous mu-opioid receptor agonists, our vulnerability to pain and suffering would be even worse. Several novel, peripherally administered endomorphin1 analogues are under investigation that are more resistant to enzymatic hydrolysis. They should offer new opportunities for euphoric well-being, enriched mental health and more effective pain-relief.

        Morphine itself is produced naturally by the human body and brain, albeit in much lower concentrations than in the opium poppy Papaver somniferum. Morphine is synthesised in human neuroblastoma cells via a biosynthetic route similar to that of the opium poppy. It is also present in healthy neurons, where it undergoes Ca2+-dependent release suggestive of a neurotransmitter or neuromodulator role. But the physiological role of endogenous morphine is still obscure.

        Opioidergic neurons are particularly concentrated in the ventral tegmental area. The VTA is an important nerve tract in the limbic system. The VTA passes messages to clusters of nerve cells in the nucleus accumbens and the frontal cortex. This forms the brain's primary reward pathway, the mesolimbic dopamine system. Its neurons are called dopaminergic because dopamine is manufactured, transported down the length of the neuron, and packaged for release into the synapses.

        GABA normally plays a braking role on the dopaminergic cells. Opioids and endogenous opioid neurotransmitters activate the presynaptic opioid receptors on GABA neurons. This inhibits the release of GABA in the ventral tegmental area. Inhibiting GABA allows the dopaminergic neurons to fire more vigorously. The release of extra dopamine in the nucleus accumbens is intensely pleasurable.

        Both delta opioid agonists and inhibitors of enkephalin catabolism have anxiolytic and antidepressant activity. Kappa opioid receptor antagonists have antidepressant activity; the first orally active selective kappa receptor antagonist is the investigational drug JDTic. Mu receptor activation is crucial to the rewarding, analgesic and addictive properties of opioids. Government researchers and pharmaceutical companies are searching for powerful analgesics that won't make the user feel happy ["high"] too.

        Mu-receptors are found mainly in the brainstem and the medial thalamus. There are two primary sub-types: mu-1 and mu-2. More than 100 polymorphisms have been identified in the human mu opioid peptide receptor gene. Stimulation of the mu-1 receptors is primarily responsible for the beautiful sense of euphoria, serenity and analgesia induced by a potent and selective mu opioid agonist. Receptor activation by mu opioid agonists increases cell firing in the ventral tegmental area. This triggers dopamine release in the nucleus accumbens by reducing GABA's tonic inhibitory control of the dopaminergic

neurons. By contrast, at the height of the opioid withdrawal syndrome, typical firing rates and burst firings of VTA-nucleus accumbens neurons are reduced to around 30% of normal. The withdrawal syndrome can be quickly remedied by the administration of a potent mu agonist such as morphine. Care is needed: stimulation of the mu-2 opioid receptors helps modulate respiratory depression. For obvious reasons, this is potentially dangerous. The endogenous ligands for the mu opioid receptors have recently been discovered. They are endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2).

        Unfortunately, we still lack clinically available opioids specific to the mu-1 receptor. Their advent will (potentially) be a tremendous boon to mental and physical health.

0 : 1 : 2 : 3

REFERENCESand further reading

Heroin OnlineOpium PeopleOpium ImagesDesigner DrugsOpium TimelineThe Plant of JoyOpioids GlossaryOpioid ReceptorsDiacetylmorphineJust For ChemistsOff-Shore PharmaciesThe Afghan ConnectionThe Pleasure and the PainCultivation and ManufactureHeroin: A Drug Fit For Heroes?Confessions of an English Opium-Eater

E-mail info@opioids.com

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Empathogens.comThe Good Drug Guide

Utopian PharmacologyThe Abolitionist Project

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Just For Chemists

(3R,4S,beta-S)-13-fluoro ohmefentanyl Alfentanil (Alfenta) Buprenorphine (Temgesic, Subutex) Carfentanil (Carfenta) Codeine Diacetylmorphine (Heroin) Dihydrocodeine (DF118) Dihydroetorphine Diprenorphine Etorphine (Immobilon) Fentanyl (Sublimaze) 'Heroin' Hydrocodone (Vicodin) Hydromorphone (Dilaudid, Palladone) LAAM (Orlaam) Levorphanol (Levo-Dromoran) Lofentanil Meperidine (Demerol) Methadone (Dolophine) Morphine Naloxone (Narcan) Naltrexone (Trexan) Beta-hydroxy 3-methylfentanyl N-methylnaltrexone Oxycodone (Oxycontin, Percodan) Oxymorphone (Numorphan) Propoxyphene (Darvon) Remifentanil (Ultiva) Sufentanil (Sufenta) Tilidine (Valeron) Tramadol (Ultram)

Just for Chemists (1)(mood-brighteners and antidepressants)

A BRIEFHISTORY

OF OPIUM

"Opium teaches only one thing, which is that asidefrom physical suffering, there is nothing real."

André MalrauxMAN'S FATE

Opium Timeline

c.3400 B.C. The opium poppy is cultivated in lower Mesopotamia. The Sumerians refer to it as Hul Gil, the 'joy plant.' The Sumerians would soon pass along the plant and its euphoric effects to the Assyrians. The art of opium poppy-culling would continue from the Assyrians to the Babylonians who in turn would pass their knowledge onto the Egyptians.

c.1300 B.C.In the capital city of Thebes, Egyptians begin cultivation of opium thebaicum, grown in their famous poppy fields. The opium trade flourishes during the reign of Thutmose IV, Akhenaton and King Tutankhamen. The trade route included the Phoenicians and Minoans who move the profitable item across the Mediterranean Sea into Greece, Carthage, and Europe.

c.1100 B.C. On the island of Cyprus, the "Peoples of the Sea" craft surgical-quality culling knives to harvest opium, which they would cultivate, trade and smoke before the fall of Troy.

c. 460 B.C. Hippocrates, "the father of medicine", dismisses the magical attributes of opium but acknowledges its usefulness as a narcotic and styptic in treating internal diseases, diseases of women and epidemics.

330 B.C. Alexander the Great introduces opium to the people of Persia and India.

A.D. 400 Opium thebaicum, from the Egyptian fields at Thebes, is first introduced to China by Arab traders.

1020Avicenna of Persia teaches that opium is "the most powerful of stupefacients."

A.D. 1200Ancient Indian medical treatises The Shodal Gadanigrah and Sharangdhar Samahita describe the use of opium for diarrohea and sexual debility. The Dhanvantri Nighantu also describes the medical properties of opium.

1300s Opium disappears for two hundred years from European historical record. Opium had become a taboo subject for those in circles of learning during the Holy Inquisition. In the eyes of the Inquisition, anything from the East was linked to the Devil.

1500 The Portuguese, while trading along the East China Sea, initiate the smoking of opium. The effects were instantaneous as they discovered but it was a practice the Chinese considered barbaric and subversive.

1527 During the height of the Reformation, opium is reintroduced into European medical literature by Paracelsus as laudanum. These black pills or "Stones of Immortality" were made of opium thebaicum, citrus juice and quintessence of gold and prescribed as painkillers.

1600s Residents of Persia and India begin eating and drinking opium mixtures for recreational use. Portuguese merchants carrying cargoes of Indian opium through Macao direct its trade flow into China.

1601 Ships chartered by Elizabeth I are instructed to purchase the finest Indian opium and transport it back to England.

1620s -1670sRajput troops fighting for the Mughals introduce the habit of taking opium to Assam. Opium is given daily to Rajput soldiers. From 1637 onwards Opium becomes the main commodity of British trade with China.

1680 English apothecary, Thomas Sydenham, introduces Sydenham's Laudanum, a compound of opium, sherry wine and herbs. His pills along with others of the time become popular remedies for numerous ailments.

1700 The Dutch export shipments of Indian opium to China and the islands of Southeast Asia; the Dutch introduce the practice of smoking opium in a tobacco pipe to the Chinese.

1729 Chinese emperor, Yung Cheng, issues an edict prohibiting the smoking of opium and its domestic sale, except under license for use as medicine.

1750 The British East India Company assumes control of Bengal and Bihar, opium-growing districts of India. British shipping dominates the opium trade out of Calcutta to China.

1753 Linnaeus, the father of botany, first classifies the poppy, Papaver somniferum - 'sleep-inducing', in his book Genera Plantarum.

1767 The British East India Company's import of opium to China reaches a staggering two thousand chests of opium per year.

1773East India Company assumes monopoly over all the opium produced in Bengal, Bihar and Orissa. Warren Hastings introduces system of contracts. Contracts for dealing in opium were awarded through auction.

1793 The British East India Company establishes a monopoly on the opium trade. All poppy growers in India were forbidden to sell opium to competitor trading companies.

1796The import of opium into China becomes a contraband trade. Silver was smuggled out to pay for smuggling opium in.

1797East India Company introduced Bengal Regulation IV to enable appointment of Opium Agents for purchase of opium from cultivators and its processing at factories owned by the company at Patna and Ghazipur

1799 China's emperor, Kia King, bans opium completely, making trade and poppy cultivation illegal.

1800 The British Levant Company purchases nearly half of all of the opium coming out of Smyrna, Turkey strictly for importation to Europe and the United States.

1803 Friedrich Sertürner of Paderborn, Germany discovers the active ingredient of opium by dissolving it in acid then neutralizing it with ammonia. The result: alkaloids - Principium somniferum or morphine. Physicians believe that opium had finally been perfected and tamed. Morphine is lauded as "God's own medicine" for its reliability, long-lasting effects and safety.

1805 A smuggler from Boston, Massachusetts, Charles Cabot, attempts to purchase opium from the British, then smuggle it into China under the auspices of British smugglers.

1812 American John Cushing, under the employ of his uncles' business, James and Thomas H. Perkins Company of Boston, acquires his wealth from smuggling Turkish opium to Canton.

1816 John Jacob Astor of New York City joins the opium smuggling trade. His American Fur Company purchases ten tons of Turkish opium then ships the contraband item to Canton on the Macedonian. Astor would later leave the China opium trade and sell solely to England.

1819 Writer John Keats and other English literary personalities experiment with opium intended for strict recreational use - simply for the high and taken at extended, non-addictive intervals

1821 Thomas De Quincey publishes his autobiographical account of opium addiction, Confessions of an English Opium-eater.

1827 E. Merck & Company of Darmstadt, Germany, begins commercial manufacturing of morphine.

1830 The British dependence on opium for medicinal and recreational use reaches an all time high as 22,000 pounds of opium is imported from Turkey and India. Jardine-Matheson & Company of London inherit India and its opium from the British East India Company once the mandate to rule and dictate the trade policies of British India are no longer in effect.

1837 Elizabeth Barrett Browning falls under the spell of morphine. This, however, does not impede her ability to write "poetical paragraphs."

March 18, 1839 Lin Tse-Hsu, imperial Chinese commissioner in charge of suppressing the opium traffic, orders all foreign traders to surrender their opium. In response, the British send expeditionary warships to the coast of China, beginning The First Opium War.

1840 New Englanders bring 24,000 pounds of opium into the United States. This catches the attention of U.S. Customs which promptly puts a duty fee on the import.

1841 The Chinese are defeated by the British in the First Opium War. Along with paying a large indemnity, Hong Kong is ceded to the British.

1842 The Treaty of Nanking between the Queen of Great Britain and the Emperor of China.

1843 Dr. Alexander Wood of Edinburgh discovers a new technique of administering morphine, injection with a syringe. He finds the effects of morphine on his patients instantaneous and three times more potent.

1852 The British arrive in lower Burma, importing large quantities of opium from India and selling it through a government-controlled opium monopoly.

1856 The British and French renew their hostilities against China in the Second Opium War. In the aftermath of the struggle, China is forced to pay another indemnity. The importation of opium is legalized. Opium production increases along the highlands of Southeast Asia.

1874 English researcher, C.R. Wright first synthesizes heroin, or diacetylmorphine, by boiling morphine over a stove. In San Francisco, smoking opium in the city limits is banned and is confined to neighboring Chinatowns and their opium dens.

1878 Britain passes the Opium Act with hopes of reducing opium consumption. Under the new regulation, the selling of opium is restricted to registered Chinese opium smokers and Indian opium eaters while the Burmese are strictly prohibited from smoking opium.

1886 The British acquire Burma's northeast region, the Shan state. Production and smuggling of opium along the lower region of Burma thrives despite British efforts to maintain a strict monopoly on the opium trade.

1890U.S. Congress, in its earliest law-enforcement legislation on narcotics, imposes a tax on opium and morphine. Tabloids owned by William Randolph Hearst publish stories of white women being seduced by Chinese men and their opium to invoke fear of the 'Yellow Peril', disguised as an "anti-drug" campaign.

1895 Heinrich Dreser working for The Bayer Company of Elberfeld, Germany, finds that diluting morphine with acetyls produces a drug without the common morphine side effects. Bayer begins production of diacetylmorphine and coins the name "heroin." Heroin would not be introduced commercially for another three years.

Early 1900s The philanthropic Saint James Society in the U.S. mounts a campaign to supply free samples of heroin through the mail to morphine addicts who are trying give up their habits. Efforts by the British and French to control opium production in Southeast Asia are successful. Nevertheless, this Southeast region, referred to as the 'Golden Triangle', eventually becomes a major player in the profitable opium trade during the 1940s.

1902 In various medical journals, physicians discuss the side effects of using heroin as a morphine step-down cure. Several physicians would argue that their patients suffered from heroin withdrawal symptoms equal to morphine addiction.

1903 Heroin addiction rises to alarming rates.

1905 U.S. Congress bans opium.

1906China and England finally enact a treaty restricting the Sino-Indian opium trade. Several physicians experiment with treatments for heroin addiction. Dr. Alexander Lambert and Charles B. Towns tout their popular cure as the most "advanced, effective and compassionate cure" for heroin addiction. The cure consisted of a 7 day regimen, which included a five day purge of heroin from the addict's system with doses of belladonna delirium. U.S. Congress passes the Pure Food and Drug Act requiring contents labeling on patent medicines by pharmaceutical companies. As a result, the availability of opiates and opiate consumers significantly declines.

1909 The first federal drug prohibition passes in the U.S. outlawing the importation of opium. It

was passed in preparation for the Shanghai Conference, at which the US presses for legislation aimed at suppressing the sale of opium to China.

February 1, 1909 The International Opium Commission convenes in Shanghai. Heading the U.S. delegation are Dr. Hamilton Wright and Episcopal Bishop Henry Brent. Both would try to convince the international delegation of the immoral and evil effects of opium.

1910 After 150 years of failed attempts to rid the country of opium, the Chinese are finally successful in convincing the British to dismantle the India-China opium trade.

Dec. 17, 1914 The passage of Harrison Narcotics Act which aims to curb drug (especially cocaine but also heroin) abuse and addiction. It requires doctors, pharmacists and others who prescribed narcotics to register and pay a tax.

1923 The U.S. Treasury Department's Narcotics Division (the first federal drug agency) bans all legal narcotics sales. With the prohibition of legal venues to purchase heroin, addicts are forced to buy from illegal street dealers.

1925 In the wake of the first federal ban on opium, a thriving black market opens up in New York's Chinatown.

1930s The majority of illegal heroin smuggled into the U.S. comes from China and is refined in Shanghai and Tietsin.

Early 1940s During World War II, opium trade routes are blocked and the flow of opium from India and Persia is cut off. Fearful of losing their opium monopoly, the French encourage Hmong farmers to expand their opium production.

1945-1947 Burma gains its independence from Britain at the end of World War II. Opium cultivation and trade flourishes in the Shan states.

1948-1972 Corsican gangsters dominate the U.S. heroin market through their connection with Mafia drug distributors. After refining the raw Turkish opium in Marseilles laboratories, the heroin is made easily available for purchase by junkies on New York City streets.

1950s U.S. efforts to contain the spread of Communism in Asia involves forging alliances with tribes and warlords inhabiting the areas of the Golden Triangle, (an expanse covering Laos, Thailand and Burma), thus providing accessibility and protection along the southeast border of China. In order to maintain their relationship with the warlords while continuing to fund the struggle against communism, the U.S. and France supply the drug warlords and their armies with ammunition, arms and air transport for the production and sale of opium. The result: an explosion in the availability and illegal flow of heroin into the United States and into the hands of drug dealers and addicts.

1962 Burma outlaws opium.

1965-1970 U.S. involvement in Vietnam is blamed for the surge in illegal heroin being smuggled into the States. To aid U.S. allies, the Central Intelligence Agency (CIA) sets up a charter airline, Air America, to transport raw opium from Burma and Laos. As well, some of the opium would be transported to Marseilles by Corsican gangsters to be refined into heroin and shipped to the U.S via the French connection. The number of heroin addicts in the U.S. reaches an estimated 750,000.

October 1970 Legendary singer, Janis Joplin, is found dead at Hollywood's Landmark Hotel, a victim of an "accidental heroin overdose."

1972Heroin exportation from Southeast Asia's Golden Triangle, controlled by Shan warlord, Khun Sa, becomes a major source for raw opium in the profitable drug trade. Solomon Snyder and Candace Pert discover opiate receptor in the brain.

July 1, 1973 President Nixon creates the DEA (Drug Enforcement Administration) under the Justice Dept. to consolidate virtually all federal powers of drug enforcement in a single agency.

Mid-1970s Saigon falls. The heroin epidemic subsides. The search for a new source of raw opium yields Mexico's Sierra Madre. "Mexican Mud" would temporarily replace "China White" heroin until 1978.

1975Hans Kosterlitz and his colleagues isolate and purify an endogenous opioid in the brain, enkephalin.

1978 The U.S. and Mexican governments find a means to eliminate the source of raw opium - by spraying poppy fields with Agent Orange. The eradication plan is termed a success as the amount of "Mexican Mud" in the U.S. drug market declines. In response to the decrease in availability of "Mexican Mud", another source of heroin is found in the Golden Crescent area - Iran, Afghanistan and Pakistan, creating a dramatic upsurge in the production and trade of illegal heroin.

1982 Comedian John Belushi of Animal House fame, dies of a heroin-cocaine - "speedball" overdose.

Sept. 13, 1984 U.S. State Department officials conclude, after more than a decade of crop substitution programs for Third World growers of marijuana, coca or opium poppies, that the tactic cannot work without eradication of the plants and criminal enforcement. Poor results are reported from eradication programs in Burma, Pakistan, Mexico and Peru.

1988 Opium production in Burma increases under the rule of the State Law and Order Restoration Council (SLORC), the Burmese junta regime. The single largest heroin seizure is made in Bangkok. The U.S. suspects that the 2,400-pound shipment of heroin, en route to New York City, originated from the Golden Triangle region, controlled by drug warlord, Khun Sa.

1990 A U.S. Court indicts Khun Sa, leader of the Shan United Army and reputed drug warlord, on heroin trafficking charges. The U.S. Attorney General's office charges Khun Sa with importing 3,500 pounds of heroin into New York City over the course of eighteen months, as well as holding him responsible for the source of the heroin seized in Bangkok.

1992 Colombia's drug lords are said to be introducing a high-grade form of heroin into the United States.

1993 The Thai army with support from the U.S. Drug Enforcement Agency (DEA) launches its operation to destroy thousands of acres of opium poppies from the fields of the Golden Triangle region.

January 1994 Efforts to eradicate opium at its source remains unsuccessful. The Clinton Administration orders a shift in policy away from the anti- drug campaigns of previous administrations. Instead the focus includes "institution building" with the hope that by "strengthening democratic governments abroad, [it] will foster law-abiding behavior and promote legitimate economic opportunity."

1995 The Golden Triangle region of Southeast Asia is now the leader in opium production,

yielding 2,500 tons annually. According to U.S. drug experts, there are new drug trafficking routes from Burma through Laos, to southern China, Cambodia and Vietnam.

January 1996 Khun Sa, one of Shan state's most powerful drug warlords, "surrenders" to SLORC. The U.S. is suspicious and fears that this agreement between the ruling junta regime and Khun Sa includes a deal allowing "the opium king" to retain control of his opium trade but in exchange end his 30-year-old revolutionary war against the government.

November 1996 International drug trafficking organizations, including China, Nigeria, Colombia and Mexico are said to be "aggressively marketing heroin in the United States and Europe."

1999Bumper opium crop of 4,600 tons in Afghanistan. UN Drug Control Program estimates around 75% of world's heroin production is of Afghan origin.

2000Taliban leader Mullah Omar bans poppy cultivation in Afghanistan; United Nations Drug Control Program confirms opium production eradicated.

July 2001Portugal decriminalizes all drugs for personal consumption.

Autumn 2001War in Afghanistan; heroin floods the Pakistan market. Taleban regime overthrown.

October 2002U.N. Drug Control and Crime Prevention Agency announces Afghanistan has regained its position as the world's largest opium producer.

December 2002UK Government health plan will make heroin available free on National Health Service "to all those with a clinical need for it". Consumers are sceptical.

April 2003State sponsored heroin trafficking: Korea's attempt to penetrate the Australian heroin market hits rocky waters.

October 2003US Food and Drug Administration (FDA) and Drug Enforcement Administration (DEA) launch special task force to curb surge in Net-based sales of narcotics from online pharmacies.

January 2004Consumer groups file a lawsuit against Oxycontin maker Purdue Pharma. The company is alleged to have used fraudulent patents and deceptive trade practices to block the prescription of cheap generic medications for patients in pain.

September 2004Singapore announces plans to execute a self-medicating heroin user, Chew Seow Leng. Under Singapore law, chronic heroin users with a high physiological tolerance to the drug are deemed to be "traffickers". Consumers face a mandatory death sentence if they take more than 15 grams (0.5 ounces) of heroin a day.

September 2004A Tasmanian company publishes details of its genetically-engineered opium poppies. Top1 [thebaine oripavine poppy 1] mutants do not produce morphine or codeine. Tasmania is the source of some 40% of the world's legal opiates; its native crop of poppies is already being re-engineered with the mutant stain. Conversely, some investigators expect that the development of genetically-engineered plants and microorganisms to manufacture potent psychoactive compounds will become widespread later in the 21st century. Research into transgenic psychotropic botanicals and microbes is controversial; genes from mutants have a habit of spreading into the wild population by accident as well as design.

September 2004

The FDA grants a product license to Purdue's pain medication Palladone: high dose, extended-release hydromorphone capsules. Palladone is designed to provide "around-the-clock" pain-relief for opioid-tolerant users.

October 2004Unannounced withdrawal of newly-issued DEA guidelines to pain specialists. The guidelines had pledged that physicians wouldn't be arrested for providing adequate pain-relief to their patients. DEA drug-diversion chief Patricia Good earlier stated that the new rules were meant to eliminate an "aura of fear" that stopped doctors treating pain aggressively.

December 2004McLean pain-treatment specialist Dr William E. Hurwitz is sent to prison for allegedly "excessive" prescription of opioid painkillers to chronic pain patients. Testifying in court, Dr Hurwitz describes the abrupt stoppage of prescriptions as "tantamount to torture".

May 2005Researchers at Ernest Gallo Clinic and Research Center in Emeryville, California, inhibit expression of the AGS3 gene in the core of nucleus accumbens. Experimentally blocking the AGS3 gene curbs the desire for heroin in addicted rodents. By contrast, activation of the reward centres of the nucleus accumbens is immensely pleasurable and addictive. The possible effects of overexpression and gene amplification of AGS3 remain unexplored.

December 2005Neuroscientists close in on the (hypothetical) final common pathway of pleasure in the brain. The "hedonic hotspot" is activated by agonists of the mu opioid receptor. In rats, at least, the hedonic hotspot is located in a single cubic millimeter of tissue: the substrates of pure bliss may lie in medium spiny neurons in the rostrodorsal region of the medial shell of the nucleus accumbens.

May 2006In Mexico, Congress passes a bill legalising the private personal use of all drugs, including opium and all opiate-based drugs. President Vicente Fox promises to to sign the measure, but buckles a day later under US government pressure. The bill is referred back to Congress for changes. "We welcome the idea of Mexico reviewing the legislation to avoid the perception that drug use would be tolerated in Mexico," says the U.S. Embassy in Mexico City.

June 2006University of Southern California neuroscientist Irving Biederman publishes in the American Scientist a theory of knowledge-acquisition likening all human beings to "junkies". On this hypothesis, knowledge junkies are driven to learn more information by a craving for the brain's own natural opium-like substances.

September 2006The head of the United Nations Office on Drugs and Crime reports that Afghanistan's harvest in 2006 will be around 6,100 metric tons of opium - a world record. This figure amounts to some 92% of global opium supply.

November 2006Senior UK police officer Howard Roberts advocates legalisation of heroin and its availability without charge on National Health Service (NHS) prescription.

August 2007Afghanistan's poppy production rises an estimated 15 percent over 2006. Afghanistan now accounts for 95 percent of the world's opium poppy crop, a 3 percentage point increase over last year. The US State Department's top counternarcotics official Tom Schweich claims that Afghanistan is now "providing close to 95 percent of the world's heroin".

October 2007Death of Golden Triangle opium lord and former Shan separatist leader Khun Sa (1933-2007). At its peak, Khun Sa's narcotics empire controlled production of an estimated quarter of the world's heroin supply.

March 2008A report by The Pew Centre, a Washington think tank, reveals that over one in 100 adults in the USA is now in jail: some 2,300,000 prisoners, triple the rate in the 1980s. American prisons now hold around a quarter of the world's inmates. Nearly half of US federal prisoners are imprisoned for non-violent, drug-related "crimes". Law professor Paul Cassell of the University of Utah comments on the size of the US prison population: "it's the price of living in the most free society in the world.”

November 2008Swiss voters overwhelmingly endorse a permanent and comprehensive legalized heroin program.

February 2009FDA announces plans further to restrict access to opioid-based pain-relievers by American citizens and their doctors.

March 2009According to the World Health Organization, around 80% of the world’s population does not have adequate access to pain relief. The international organisation Human Rights Watch (HRW) blames a failure of leadership, inadequate training of health care workers, and “over-zealous drug control efforts”.

May 2010Research published in Proceedings of the National Academy of Sciences confirms that mice (and humans?) can synthesise their own morphine.

July 2011Seattle hosts Kappa Therapeutics, the world's first conference dedicated to kappa opioids and antagonists. The kappa receptor is the "nasty" opioid receptor, bound by dynorphin. Selective, orally active kappa opioid antagonists, notably JDTic and the shorter-acting zyklophin, are subjectively enjoyable and relaxing; but they (probably) lack significant "abuse potential". Investigators hope that selective kappa opioid antagonists can be used therapeutically to treat anxiety disorders, clinical depression, anhedonia, eating disorders, alcoholism and a variety of substance abuse disorders.

Opium: A History. by Martin Booth

Simon & Schuster, Ltd., 1996.

Opium People

SNAPSHOTS

Marcus Aurelius (AD 121 - 180) Charles Baudelaire (1821-1867) Elizabeth Barrett Browning (1806 - 1861) William S Burroughs (1917 - 1997) Robert Clive (1725 -1774) Samuel Taylor Coleridge (1772 - 1834) Wilkie Collins (1824 - 1889) George Crabbe (1754 - 1832) Hector Berlioz (1803 - 1869) Heinrich Dreser (1860 - 1924) Galen (AD 131 - 200)

William Stewart Halsted (1852 - 1922) Hippocrates (c.460 - c.377 BC) John Keats (1795 - 1821) Hans Kosterlitz (1903 - 1996) Linnaeus (1707 - 1778) André Malraux (1901 - 1976) Paracelsus (1490 - 1541) Candace Pert (1946 - ) Edgar Allan Poe (1809 - 1849) Thomas de Quincey (1785 - 1859) Wilhelm Sertürner (1783 - 1841) Solomon Snyder Thomas Sydenham (1624 - 1689) Warren Hastings (1732 - 1818) William Wilberforce (1759 - 1833)

Opium People

1. Marcus Aurelius(AD 121 - 180)

Bust of the Stoic philosopher and illustrious opium-eater Emperor Marcus Aurelius (reigned AD 161 - 180). The Emperor ruled during "...the period in the history of the world, during which the condition of the human race was most happy and prosperous..." (Gibbon). Marcus Aurelius wrote Meditations (AD 167). Meditations explains how the moral life leads to tranquillity. Marcus stresses the virtues of wisdom, justice, fortitude, and moderation. He recommended opium-eating for headache, dizziness, epilepsy, asthma, fever, leprosy and other ills of the flesh.

2. Charles BaudelaireBaudelaire compares opium to a woman friend, "...an old and terrible friend, and, alas! like them all, full of caresses and deceptions""Common sense tells us that the things of the earth exist only a little, and that true reality is only in dreams. "Les Paradis artificiels, dedication (1860).Charles Baudelaire(1821-1867)

3. Elizabeth Barrett Browning(1806-1861)

The English Victorian poet Elizabeth Barrett Browning initially took laudanum to treat her childhood spinal tuberculosis. She became a lifelong addict. However, for her opium was a source of poetic inspiration; and letters between Elizabeth and her husband Robert Browning abound with images of scarlet poppies.

4. William S. Burroughs(1917 - 1997)

"Junk is the ideal product . . . the ultimate merchandise. No sales talk necessary. The client will crawl through a sewer and beg to buy. . . . The junk merchant does not sell his product to the consumer, he sells the consumer to his product. He does not improve and simplify his merchandise. He degrades and simplifies the client. He pays his staff in junk."

William S. Burroughs was the wealthy grandson of the founder of the Burroughs Adding Machine company. He was a regular heroin user for over a decade, and dependent on opioids almost continually from his first habit in the forties until his death. During the mid-eighties, Burroughs got on methadone maintenance. He remained so until he died. He took many 'cures' but relapsed quickly each time - his opioid

abstinent periods were very brief. Most famously, Burroughs wrote Junkie (1953) and Naked Lunch (1959). In the preface of Junkie, Burroughs writes "I have never regretted my experience with drugs." However, his account of narcotic addiction is unlikely to tempt the drug-naive reader into self-experimentation.

5. Robert Clive(1725 -1774)

Robert Clive, victor of the battle of Plassey (1757) and an opium addict. The decline of the Mughal Empire in the eighteenth century allowed The Honourable East India Company to consolidate a vast drug empire in India. Under the terms of its charter, the Company was permitted to acquire territory; exercise civil and criminal jurisdiction; raise and command armies; wage war; conclude treaties; and to issue its own currency. Many respectable British fortunes have their origin in the trade of Indian opium for Chinese tea.

6. Samuel Taylor Coleridge(1772-1834)

"In Xanadu did Kubla KhanA stately pleasure-dome decreeWhere Alph, the sacred river, ranDown to a sunless sea...I would build that dome in air, That sunny dome, those caves of ice!And all who heard should see them there, And all should cry, Beware! Beware!His flashing eyes, his floating hair!Weave a circle round him thrice, And close your eyes with holy dread,For he on honey-dew hath fed,And drunk the milk of Paradise."

Samuel Taylor Coleridge(1772-1834)KUBLA KHAN

"Laudanum gave me repose, not sleep ; but you, I believe, know how devine that repose is, what a spot of enchantment, a green spot of fountain and flowers and trees in ther very heart of a waste of sands!" George Coleridge (1772-1834)

7. Wilkie Collins(1824 - 1889)

"Laudanum - divine laudanum - was his only friend"

"who was the man who invented laudenaum ? I thank him from the bottom of my heart. whoever he was .... I have had six delicious hiours of oblivion ; I have woek up with myu mind comoposed ; O have written s perfect little letter ; I have drunk my cup of tea with a real relish of it ; and I have dawdles over my morning toilet with an excquiste sense of relief -- and all trhough the modest little bottle of drops which I see on my bedroom chimney-piece at the moment. Drops, you are a darling ! If I love nothing else, I love you !"

Wilkie Collins (1824 - 1889)Note made on a spring morning (1864)

Wilkie Collins had a prodigious opium habit. He is famous for writing one of the first detective-novels in British fiction, The Moonstone (1868). Opium is central to the plot. The moonstone of the title is a sacred Hindu diamond "‘growing and lessening in lustre with the waxing and waning of the moon". The gem is stolen by a laudanum-intoxicated thief who later remembers nothing of the crime.

8. George Crabbe(1754-1832)

Respectable British citizens like the parson and poet George Crabbe took opium for 40 years or more without discernible ill-effects. For in the era of the Romantic poets "most doctors and patients still thought of opium not as a dangerous addictive drug but mainly as a useful analgesic and tranquillizer of which every household should have a supply, for minor ailments and nervous crises of all kinds, much as aspirin is used today" (Alethea Hayter Alethea Hayter, Opium and the Romantic Imagination (London, 1968)

9. Hector Berlioz(1803-1869)

French Romantic composer Hector Berlioz was an habitual opium user. He is most famous for his orchestral work Symphonie fantastique. Symphonie fantastique is an "opera without words". It was first performed in 1830. Each movement is designed to evoke the different stages of the opium experience. A sublimation of his own unrequited love for actress Harriet Smithson, Berlioz's masterpiece is about a tormented lovesick artist who takes an overdose of opium. Instead of killing him, the opium induces astonishing dream imagery.

10.Professor Heinrich Dreser(1860 - 1924)

Enjoying the delights of Heroin made Heinrich Dreser and his fellow chemists at Bayer feel "heroic" (heroisch).

11.Galen(AD 131-200)

Galen of Pergamum writes about the juice of the poppy "which physicians are in the habit of calling opium". He commended its use as a cure for headaches, deafness, epilepsy, asthma, coughs, colic, fevers, women's problems and melancholy.

12.William Stewart Halsted(1852-1922)

The "father of American surgery" took morphine for the last thirty years of his extremely successful life. From 1889, William Stewart Halsted was first chief of the Department of Surgery at Johns Hopkins Hospital. In 1892 he was promoted to Professor of Surgery. Halsted's drug habit was revealed in William Osler's posthumously published The Inner History of Johns Hopkins Hospital. Few of Halsted's colleagues had any idea that their brilliant mentor was addicted to morphine.

Halsted had ready access to inexpensive, high-grade morphine. So he did not encounter some of the problems common to users of street narcotics in prohibitionist society.

13.Hippocrates

The Greek physician Hippocrates (c460 - c377 BC) discounts belief in the literally magical attributes of opium, an indication perhaps of the high reputation of the opium poppy in classical antiquity. Like his successor Galen of Pergamum, Hippocrates readily acknowledges the benefits of opium poppy juice as a narcotic and styptic in treating internal diseases, diseases of women and epidemics. Hippocrates also notes the excellent nutritive properties of the poppy seed. Opium poppy seeds are very popular with birds, though their effects on avian consciousness are unknown.

14. John Keats (1795-1821)

"The blissful cloud of summer-indolenceBenumb'd my eyes; my pulse grew less and less;Pain had no string, and pleasure's wreath no flower:O, why did ye not melt, and leave my sense Unhaunted quite of all but-nothingness?"

from "Ode on Indolence," May 1819 by John Keats (1795-1821)

15. Hans Kosterlitz(1903 - 1996)

After Candace Pert, together with Solomon Snyder and colleagues, first identified opioid receptors in the brain in 1972, in 1975 Hans Kosterlitz and his colleagues reported the existence of an endogenous morphine-like substance. Later, they purified their discovery after a two year investigation of pig-brain materials. They named it enkephalin for "in the head". Enkephalins, endorphins, and dynophins bind to specific receptor sites in the brain. The anatomy of pleasure is still not fully understood. But mu opioid receptor agonists disinhibit the pathways that modulate the dopamininergic neurons projecting from the ventral tegmental area to the nuclear accumbens. This causes extra dopamine to be released into the synapses. Mesolimbic dopamine mediates our sense of pleasurable anticipation: "At a purely chemical level, every experience humans find enjoyable - whether listening to music, embracing a lover, or savoring chocolate - amounts to little more than an explosion of dopamine in the nucleus accumbens as exhilarating and ephemeral as a firecracker." (J Madelaine Nash)

16. Carolus Linnaeus(1707-1778)

The opium poppy was first classified by Carolus Linnaeus as Papaver somniferum - 'sleep-inducing' - in his book Genera Plantarum.

17.André Malraux(1901-1976)

"Il faut toujours s'intoxiquer : ce pays a l'opium,l'Islam le haschich, l'Occident la femme..."

18. Philippus Aureolus Theophrastus Bombastus von Hohenheim:"Paracelsus" - (1490-1541)

Contemporary print of Paracelus. Part quack, part physician of genius, Paracelsus claimed "...I possess a secret remedy which I call laudanum and which is superior to all other heroic remedies."

19.Candace Pert (1946 - )

Candace Pert, together with Solomon Snyder and colleagues, played a key role in discovering the brain's long-suspected but elusive opioid receptors in 1972. She is author of the controversial Molecules of Emotion (1997).

20.Edgar Allan Poe

"All that we see or seemIs but a dream within a dream"Edgar Allan Poe ( 1809-1849 ) A Dream within a Dream

21. Thomas de Quincey

The Pleasures of Opium

(1821; revised edition 1856)"I took it, and in an hour, Oh Heavans ! What a revulsion ! What an upheaving, from its lowest depths, of the inner spirit 1 What an apocalypse of the world within me. What had opened before me -- an abyss of divine enjoyment suddenly revealed. Here was a panacea for all human woes. Here was the secret of happiness, about which philosophers had disputed for so many ages, at once discovered".

Thomas de Quincey (1785-1859)(Essay, 1849)

22. Friedrich Wilhelm Sertürner(1783-1841)

Morphine was first isolated from opium by Friedrich Wilhelm Sertürner in 1805. Sertürner named the bitter white crystalline alkaloid after Morpheus, the Greek god of dreams.

23. Solomon Snyder

"The godfather of synaptic chemistry", Solomon Snyder, is an expert on the molecular basis of psychiatric disorders. With his student, Candace Pert, Professor Snyder located the elusive neural opioid receptor in 1972. John Hughes and Hans Kosterlitz in Aberdeen then went on to discover and purify an endogenous morphine-like compound, enkephalin. Work in Professor Synder’s laboratory at John Hopkins University has shown the role of the reactive gas nitric oxide in the regulation of brain-function and blood-flow; and that D-serine may be an important modulator of learning and memory in the brain. Professor Snyder is the author of Drugs and the Brain (1986; revised edition 1996)

24. Thomas Sydenham (1624-1689)"the Shakespeare of Medicine"

The Shakespeare of Medicine was happy to pay tribute to Providence: "Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium."

25. Warren Hastings(1732 - 1818)

Warren Hastings joined the British East India Company in 1750 as a clerk. He served as the first governor-general of British India from 1773 to 1786. Hastings was accused by anti-opium campaigners of a cynical willingness to poison foreigners for commercial advantage. Some of his comments lend weight to this charge: "Opium is not a necessity of life, but a pernicious article of luxury, which ought not to be permitted but for the purpose of foreign commerce only, and which the wisdom of the Government should carefully restrain consumption".

26. William Wilberforce(1759 - 1833)

Slave-trade abolitionist William Wilberforce took opium before addressing Parliament. "To that", he said, "I owe my success as a public speaker."

THE  PLEASURES  OF  OPIUM

fromConfessions of an English Opium-Eater

byThomas de Quincey

(1785-1859)

It is so long since I first took opium, that if it had been a trifling incident in my life, I might have forgotten its date: but cardinal events are not to be forgotten; and from circumstances connected with it, I remember that it must be referred to the autumn of 1804. During that season I was in London, having come thither for the first time since my entrance at college. And my introduction to opium arose in the following way. From an early age I had been accustomed to wash my head in cold water at least once a day: being suddenly seized with toothache, I attributed it to some relaxation caused by an accidental intermission of that practice; jumped out of bed; plunged my head into a bason of cold water; and with hair thus wetted went to sleep. The next morning, as I need hardly say, I awoke with excruciating rheumatic pains of the head and face, from which I had hardly any respite for about twenty days. On the twenty-first day, I think it was, and on a Sunday, that I went out into the streets; rather to run away, if possible, from my torments, than with any distinct purpose. By accident I met a college acquaintance who recommended opium. Opium! dread agent of unimaginable pleasure and pain! I had heard of it as I had of manna or of Ambrosia, but no further: how unmeaning a sound was it at that time! what solemn chords does it now strike upon my heart! what heart-quaking vibrations of sad and happy remembrances! Reverting for a moment to these, I feel a mystic importance attached to the minutest circumstances connected with the place and the time, and the man (if man he was) that first laid open to me the Paradise of Opium-eaters. It was a Sunday afternoon, wet and cheerless: and a duller spectacle this earth of ours has not to show than a rainy Sunday in London. My road homewards lay through Oxford-street; and near "the stately Pantheon," (as Mr. Wordsworth has obligingly called it) I saw a druggist's shop. The druggist -- unconscious minister of celestial pleasures! -- as if in sympathy with the rainy Sunday, looked dull and stupid, just as any mortal druggist might be expected to look on a Sunday; and, when I asked for the tincture of opium, he gave it to me as any other man might do: and furthermore, out of my shilling, returned me what seemed to be real copper halfpence, taken out of a real wooden drawer. Nevertheless, in spite of such indications of humanity, he has ever since existed in my mind as the beatific vision of an immortal druggist, sent down to earth on a special mission to myself. And it confirms me in this way of considering him, that, when I next came up to London, I sought him near the stately Pantheon, and found him not: and thus to me,

who knew not his name (if indeed he had one) he seemed rather to have vanished from Oxford-street than to have removed in any bodily fashion. The reader may choose to think of him as, possibly, no more than a sublunary druggist: it may be so: but my faith is better: I believe him to have evanesced,[1] or evaporated. So unwillingly would I connect any mortal remembrances with that hour, and place, and creature, that first brought me acquainted with the celestial drug.

        Arrived at my lodgings, it may be supposed that I lost not a moment in taking the quantity prescribed. I was necessarily ignorant of the whole art and mystery of opium-taking: and, what I took, I took under every disadvantage. But I took it: -- and in an hour, oh! Heavens! what a revulsion! what an upheaving, from its lowest depths, of the inner spirit! what an apocalypse of the world within me! That my pains had vanished, was now a trifle in my eyes: -- this negative effect was swallowed up in the immensity of those positive effects which had opened before me -- in the abyss of divine enjoyment thus suddenly revealed. Here was a panacea -- a [pharmakon nepenthez] for all human woes: here was the secret of happiness, about which philosophers had disputed for so many ages, at once discovered: happiness might now be bought for a penny, and carried in the waistcoat pocket: portable ecstasies might be had corked up in a pint bottle: and peace of mind could be sent down in gallons by the mail coach. But, if I talk in this way, the reader will think I am laughing: and I can assure him, that nobody will laugh long who deals much with opium: its pleasures even are of a grave and solemn complexion; and in his happiest state, the opium-eater cannot present himself in the character of Il Allegro: even then, he speaks and thinks as becomes Il Penseroso. Nevertheless, I have a very reprehensible way of jesting at times in the midst of my own misery: and, unless when I am checked by some more powerful feelings, I am afraid I shall be guilty of this indecent practice even in these annals of suffering or enjoyment. The reader must allow a little to my infirm nature in this respect: and with a few indulgences of that sort, I shall endeavour to be as grave, if not drowsy, as fits a theme like opium, so anti-mercurial as it really is, and so drowsy as it is falsely reputed.

        And, first, one word with respect to its bodily effects: for upon all that has been hitherto written on the subject of opium, whether by travellers in Turkey (who may plead their privilege of lying as an old immemorial right), or by professors of medicine, writing ex cathedra, -- I have but one emphatic criticism to pronounce -- Lies! lies! lies! I remember once, in passing a book-stall, to have caught these words from a page of some satiric author: -- "By this time I became convinced that the London newspapers spoke truth at least twice a week, viz. on Tuesday and Saturday, and might safely be depended upon for -- the list of bankrupts." In like manner, I do by no means deny that some truths have been delivered to the world in regard to opium: thus it has been repeatedly affirmed by the learned, that opium is a dusky brown in colour; and this, take notice, I grant: secondly, that it is rather dear; which I also grant: for in my time, East-India opium has been three guineas a pound, and Turkey eight: and, thirdly, that if you eat a good deal of it, most probably you must -- do what is particularly disagreeable to any man of regular habits, viz. die.[2] These weighty propositions are, all and singular, true: I cannot gainsay them: and truth ever was, and will be, commendable. But in these three theorems, I believe we have exhausted the stock of knowledge as yet accumulated by man on the subject of opium. And therefore, worthy doctors, as there seems to be room for further discoveries, stand aside, and allow me to come forward and lecture on this matter.

        First, then, it is not so much affirmed as taken for granted, by all who ever mention opium, formally or incidentally, that it does, or can, produce intoxication. Now reader, assure yourself, meo periculo, that no quantity of opium ever did, or could intoxicate. As to the tincture of opium (commonly called laudanum) that might certainly intoxicate if a man could bear to take enough of it; but why? because it contains so much proof spirit, and not because it contains so much opium. But crude opium, I affirm peremptorily, is incapable of producing any state of body at all resembling that which is produced by alcohol; and not in

degree only incapable, but even in kind: it is not in the quantity of its effects merely, but in the quality, that it differs altogether. The pleasure given by wine is always mounting, and tending to a crisis, after which it declines: that from opium, when once generated, is stationary for eight or ten hours: the first, to borrow a technical distinction from medicine, is a case of acute -- the second, of chronic pleasure: the one is a flame, the other a steady and equable glow. But the main distinction lies in this, that whereas wine disorders the mental faculties, opium, on the contrary (if taken in a proper manner), introduces amongst them the most exquisite order, legislation, and harmony. Wine robs a man of his self possession: opium greatly invigorates it. Wine unsettles and clouds the judgment, and gives a preternatural brightness, and a vivid exaltation to the contempts and the admirations, the loves and the hatreds, of the drinker: opium, on the contrary, communicates serenity and equipoise to all the faculties, active or passive: and with respect to the temper and moral feelings in general, it gives simply that sort of vital warmth which is approved by the judgment, and which would probably always accompany a bodily constitution of primeval or antediluvian health. Thus, for instance, opium, like wine, gives an expansion to the heart and the benevolent affections: but then, with this remarkable difference, that in the sudden development of kind-heartedness which accompanies inebriation, there is always more or less of a maudlin character, which exposes it to the contempt of the by-stander. Men shake hands, swear eternal friendship, and shed tears -- no mortal knows why: and the sensual creature is clearly uppermost. But the expansion of the benigner feelings, incident to opium, is no febrile access, but a healthy restoration to that state which the mind would naturally recover upon the removal of any deep- seated irritation of pain that had disturbed and quarrelled with the impulses of a heard originally just and good. True it is, that even wine, up to a certain point, and with certain men, rather tends to exalt and to steady the intellect: I myself, who have never been a great wine-drinker, used to find that half a dozen glasses of wine advantageously affected the faculties -- brightened and intensified the consciousness -- and gave to the mind a feeling of being "ponderibus librata suis"; and certainly it is most absurdly said, in popular language, of any man, that he is disguised in liquor: for, on the contrary, most men are disguised by sobriety; and it is when they are drinking (as some old gentleman says in Athenaeus), that men [eantonz emfanixondin oitinez eidin]. -- display themselves in their true complexion of character; which surely is not disguising themselves. But still, wine constantly leads a man to the brink of absurdity and extravagance; and, beyond a certain point, it is sure to volatilize and to disperse the intellectual energies: whereas opium always seems to compose what had been agitated, and to concentrate what had been distracted. In short, to sum up all in one word, a man who is inebriated, or tending to inebriation, is, and feels that he is, in a condition which calls up into supremacy the merely human, too often the brutal, part of his nature: but the opium-eater (I speak of him who is not suffering from any disease, or other remote effects of opium) feels that the diviner part of his nature is paramount; that is, the moral affections are in a state of cloudless serenity; and over all is the great light of the majestic intellect.

        This is the doctrine of the true church on the subject of opium: of which church I acknowledge myself to be the only member -- the alpha and the omega: but then it is to be recollected, that I speak from the ground of a large and profound personal experience: whereas most of the unscientific[3] authors who have at all treated of opium, and even of those who have written expressly on the materia medica, make it evident, from the horror they express of it, that their experimental knowledge of its action is none at all. I will, however, candidly acknowledge that I have met with one person who bore evidence to its intoxicating power, such as staggered my own incredulity: for he was a surgeon, and had himself taken opium largely. I happened to say to him, that his enemies (as I had heard) charged him with talking nonsense on politics, and that his friends apologized for him, by suggesting that he was constantly in a state of intoxication from opium. Now the accusation, said I, is not prima facie, and of necessity, an absurd one: but the defence is. To my surprise, however, he insisted that both his enemies and his friends were in the right: "I will maintain," said he, "that I do talk nonsense; and secondly, I will maintain that I do not talk

nonsense upon principle, or with any view to profit, but solely and simply, said he, solely and simply, -- solely and simply (repeating it three times over), because I am drunk with opium; and that daily." I replied that, as to the allegation of his enemies, as it seemed to be established upon such respectable testimony, seeing that the three parties concerned all agreed in it, it did not become me to question it; but the defence set up I must demur to. He proceeded to discuss the matter, and to lay down his reasons: but it seemed to me so impolite to pursue an argument which must have presumed a man mistaken in a point belonging to his own profession, that I did not press him even when his course of argument seemed open to objection: not to mention that a man who talks nonsense, even though "with no view to profit," is not altogether the most agreeable partner in a dispute, whether as opponent or respondent. I confess, however, that the authority of a surgeon, and one who was reputed a good one, may seem a weighty one to my prejudice: but still I must plead my experience, which was greater than his greatest by 7000 drops a day; and, though it was not possible to suppose a medical man unacquainted with the characteristic symptoms of vinous intoxication, it yet struck me that he might proceed on a logical error of using the word intoxication with too great latitude, and extending it generically to all modes of nervous excitement, connected with certain diagnostics. Some people have maintained, in my hearing, that they had been drunk on green tea: and a medical student in London, for whose knowledge in his profession I have reason to feel great respect, assured me, the other day, that a patient, in recovering from an illness, had got drunk on a beef-steak.

        Having dwelt so much on this first and leading error, in respect t opium, I shall notice very briefly a second and a third; which are, that the elevation of spirits produced by opium is necessarily followed by a proportionate depression, and that the natural and even immediate consequence of opium is torpor and stagnation, animal and mental. The first of these errors I shall content myself with simply denying; assuring my reader, that for ten years, during which I took opium at intervals, the day succeeding to that on which I allowed myself this luxury was always a day of unusually good spirits.

        With respect to the torpor supposed to follow, or rather (if we were to credit the numerous pictures of Turkish opium-eaters) to accompany the practice of opium-eating, I deny that also. Certainly, opium is classed under the head of narcotics; and some such effect it may produce in the end: but the primary effects of opium are always, and in the highest degree, to excite and stimulate the system: this first stage of its action always lasted with me, during my noviciate, for upwards of eight hours; so that it must be the fault of the opium-eater himself if he does not so time his exhibition of the dose (to speak medically) as that the whole weight of its narcotic influence may descend upon his sleep. Turkish opium-eaters, it seems, are absurd enough to sit, like so many equestrian statues, on logs of wood as stupid as themselves. But that the reader may judge of the degree in which opium is likely to stupify the faculties of an Englishman, I shall (by way of treating the question illustratively, rather than argumentively) describe the way in which I myself often passed an opium evening in London, during the period between 1804-1812. It will be seen, that at least opium did not move me to seek solitude, and much less to seek inactivity, or the torpid state of self- involution ascribed to the Turks. I give this account at the risk of being pronounced a crazy enthusiast or visionary: but I regard that little: I must desire my reader to bear in mind, that I was a hard student, and at severe studies for all the rest of my time: and certainly had a right occasionally to relaxations as well as the other people: these, however, I allowed myself but seldom.

        The late Duke of Norfolk used to say, "Next Friday, by the blessing of Heaven, I purpose to be drunk:" and in like manner I used to fix beforehand how often, within a given time, and when, I would commit a debauch of opium. This was seldom more than once in three weeks: for at that time I could no have ventured to call every day (as I did afterwards) for "a glass of laudanum negus, warm, and without sugar." No: as I have said, I seldom drank laudanum, at that time, more than once in three weeks: this was usually on a Tuesday or a Saturday

night; my reason for which was this. In those days Grassini sang at the Opera: and her voice was delightful to me beyond all that I had ever heard. I know not what may be the state of the Opera- house now, having never been within its walls for seven or eight years, but at that time it was by much the most pleasant place of public resort in London for passing an evening. Five shillings admitted one to the gallery, which was subject to far less annoyance than the pit of the theatres: the orchestra was distinguished by its sweet and melodious grandeur from all English orchestras, the composition of which, I confess, is not acceptable to my ear, from the predominance of the clangorous instruments, and the absolute tyranny of the violin. The choruses were divine to hear: and when Grassini appeared in some interlude, as she often did, and poured forth her passionate soul as Andromache, at the tomb of Hector, &c. I question whether any Turk, of all that ever entered the Paradise of opium-eaters, can have had half the pleasure I had. But, indeed, I honour the Barbarians too much by supposing them capable of any pleasures approaching to the intellectual ones of an Englishman. For music is an intellectual or a sensual pleasure, according to the temperament of him who hears it. And, by the bye, with the exception of the fine extravaganza on that subject in Twelfth Night, I do not recollect more than one thing said adequately on the subject of music in all literature: it is a passage in the Religio Medici[4] of Sir T. Brown; and, though chiefly remarkable for its sublimity, has also a philosophic value, inasmuch as it points to the true theory of musical effects. The mistake of most people is to suppose that it is by the ear they communicate with music, and, therefore, that they are purely passive to its effects. But this is not so: it is by the re-action of the mind upon the notices of the ear, (the matter coming by the senses, the form from the mind) that the pleasure is constructed: and therefore it is that people of equally good ear differ so much in this point from one another. Now opium, by greatly increasing the activity of the mind generally, increases, of necessity, that particular mode of its activity by which we are able to construct out of the raw material of organic sound an elaborate intellectual pleasure. But, says a friend, a succession of musical sounds is to me like a collection of Arabic characters: I can attach no ideas to them. Ideas! my good sir? there is no occasion for them: all that class of ideas, which can be available in such a case, has a language of representative feelings. But this is a subject foreign to my present purposes: it is sufficient to say, that a chorus, &c. of elaborate harmony, displayed before me, as in a piece of arras work, the whole of my past life -- not, as if recalled by an act of memory, but as if present and incarnated in the music: no longer painful to dwell upon: but the detail of its incidents removed, or blended in some hazy abstraction; and its passions exalted, spiritualized, and sublimed. All this was to be had for five shillings. And over nd above the music of the stage and the orchestra, I had all around me, in the intervals of the performance, the music of the Italian language talked by Italian women: for the gallery was usually crowded with Italians: and I listened with a pleasure such as that with which Weld the traveller lay and listened, in Canada, to the sweet laughter of Indian women; for the less you understand of a language, the more sensible you are to the melody or harshness of its sounds: for such a purpose, therefore, it was an advantage to me that I was a poor Italian scholar, reading it but little, and not speaking it at all, nor understanding a tenth part of what I heard spoken.

        These were my Opera pleasures: but another pleasure I had which, as it could be had only on a Saturday night, occasionally struggled with my love of the Opera; for, at that time, Tuesday and Saturday were the regular Opera nights. On this subject I am afraid I shall be rather obscure, but, I can assure the reader, not at all more so than Marinus in his life of Proclus, or many other biographers and auto-biographers of fair reputation. This pleasure, I have said, was to be had only on a Saturday night. What then was Saturday night to me more than any other night? I had no labours that I rested from; no wages to receive: what needed I to care for Saturday night, more than as it was a summons to hear Grassini? True, most logical reader: what you say is unanswerable. And yet so it was and is, that, whereas different men throw their feelings into different channels, and most are apt to show their interest in the concerns of the poor, chiefly by sympathy, expressed in some shape or other, with their distresses and sorrows, I, at that time, was disposed to express my interest by

sympathising with their pleasures. The pains of poverty I had lately seen too much of; more than I wished to remember: but the pleasures of the poor, their consolations of spirit, and their reposes from bodily toil, can never become oppressive to contemplate. Now Saturday night is the season for the chief, regular, and periodic return of rest to the poor: in this point the most hostile sects unite, and acknowledge a common link of brotherhood: almost all Christendom rests from its labours. It is a rest introductory to another rest: and divided by a whole day and two nights from the renewal of toil. On this account I feel always, on a Saturday night, as though I also were released from some yoke of labour, had some wages to receive, and some luxury of repose to enjoy. For the sake, therefore, of witnessing, upon as large a scale as possible, a spectacle with which my sympathy was so entire, I used often, on Saturday nights, after I had taken opium, to wander forth, without much regarding the direction or the distance, to all the markets, and other parts of London, to which the poor resort on a Saturday night, for laying out their wages. Many a family party, consisting of a man, his wife, and sometimes one or two of his children, have I listened to, as they stood consulting on their ways and means, or the strength of their exchequer, or the price of household articles. Gradually I became familiar with their wishes, their difficulties, and their opinions. Sometimes there might be heard murmurs of discontent: but far oftener expressions on the countenance, or uttered in words, of patience, hope, and tranquility. And taken generally, I must say, that, in this point at least, the poor are far more philosophic than the rich -- that they show a more ready and cheerful submission to what they consider as irremediably evils, or irreparable losses. Whenever I saw occasion, or could do it without appearing to be intrusive, I joined their parties; and gave my opinion upon the matter in discussion, which, if not always judicious, was always received indulgently. If wages were a little higher, or expected to be so, or the quartern loaf a little lower, or it was reported that onions and butter were expected to fall, I was glad: yet, if the contrary were true, I drew from opium some means of consoling myself. For opium (like the bee, that extracts its materials indiscriminately from roses and from the soot of chimneys) can overrule all feelings into a compliance with the master key. Some of these rambles led me to great distances: for an opium-eater is too happy to observe the motion of time. And sometimes in my attempts to steer homewards, upon nautical principles, by fixing my eye on the pole-star, and seeking ambitiously for a north-west passage, instead of circumnavigating all the capes and head-lands I had doubled in my outward voyage, I came suddenly upon such knotty problems of alleys, such enigmatical entries, and such sphynx's riddles of streets without thoroughfares, as must, I conceive, baffle the audacity of porters, and confound the intellects of hackney- coachmen. I could almost have believed, at times, that I must be the first discoverer of some of these terrae incognitae, and doubted, whether they had yet been aid down in the modern charts of London. For all this, however, I paid a heavy price in distant years, when the human face tyrannized over my dreams, and the perplexities of my steps in London came back and haunted my sleep, with the feeling of perplexities moral or intellectual, that brought confusion to the reason, or anguish and remorse to the conscience.

        Thus I have shown that opium does not, of necessity, produce inactivity or torpor; but that, on the contrary, it often led me into markets and theatres. Yet, in candour, I will admit that markets and theatres are not the appropriate haunts of the opium-eater, when in the divinest state incident to his enjoyment. In that state, crowds become an oppression to him; music even, too sensual and gross. He naturally seeks solitude and silence, as indispensable conditions of those trances, or profoundest reveries, which are the crown and consummation of what opium can do for human nature. I, whose disease it was to meditate too much, and to observe too little, and who, upon my first entrance at college, was nearly falling into a deep melancholy, from brooding too much on the sufferings which I had witnessed in London, was sufficiently aware of the tendencies of my own thoughts to do all I could to counteract them. -- I was, indeed, like a person who, according to the old legend, had entered the cave of Trophonius: and the remedies I sought were to force myself into society, and to keep my understanding in continual activity upon matters of science. But for these remedies, I should certainly have become hypochondriacally melancholy. In after years,

however, when my cheerfulness was more fully re-established, I yielded to my natural inclination for a solitary life. And, at that time, I often fell into these reveries upon taking opium; and more than once it has happened to me, on a summer-night, when I have been at an open window, in a room from which I could overlook the sea at a mile below me, and could command a view of the great town of Liverpool, at about the same distance, that I have sate, from sun-set to sun-rise, motionless, and without wishing to move.

        I shall be charged with mysticism, behmenism, quietism, &c. but that shall not alarm me. Sir H. Vane, the younger, was one of our wisest men: and let my readers see if he, in his philosophical works, be half as unmystical as I am. -- I say, then, that it has often struck me that the scene itself was somewhat typical of what took place in such a reverie. The town of Liverpool represented the earth, with its sorrows and its graves left behind, yet not out of sight, nor wholly forgotten. The ocean, in everlasting but gentle agitation, and brooded over by a dove-like calm, might not unfitly typify the mind and the mood which then swayed it. For it seemed to me as if then first I stood at a distance, and aloof from the uproar of life; as if the tumult, the fever, and the strife, were suspended; a respite granted from the secret burthens of the heart; a sabbath of repose; a resting from human labours. Here were the hopes which blossom in the paths of life, reconciled with the peace which is in the grave; motions of the intellect as unwearied as the heavens, yet for all anxieties a halcyon calm: a tranquility that seemed no product of inertia, but as if resulting from mighty and equal antagonisms; infinite activities, infinite repose.

        Oh! just, subtle, and mighty opium! that to the hearts of poor and rich alike, for the wounds that will never heal, and for "the pangs that tempt the spirit to rebel," bringest and assuaging balm; eloquent opium! that with thy potent rhetoric stealest away the purposes of wrath; and to the guilty man, for one night givest back the hopes of his youth, and hands washed pure from blood; and to the proud man, a brief oblivion for

Wrongs unredress'd, and insults unavenged;that summonest to the chancery of dreams, for the triumphs of suffering innocence, false witnesses; and confoundest perjury; and dost reverse the sentences of unrighteous judges: -- thou buildest upon the bosom of darkness, out of the fantastic imagery of the brain, cities and temples, beyond the art of Phidias and Praxiteles -- beyond the splendour of Babylon and Hekatompylos: and "from the anarchy of dreaming sleep," callest into sunny light the faces of long-buried beauties, and the blessed household countenances, cleansed from the "dishonours of the grave." Thou only givest these gifts to man; and thou hast the keys of Paradise, oh, just, subtle, and mighty opium!

***

[1] Evanesced: -- this way of going off the stage of life appears to have been well known in the 17th century, but at the time to have been considered a peculiar privilege of blood-royal, and by no means to be allowed to druggists. For about the year 1686, a poet of rather ominous name (and who, by the bye, did ample justice to his name), viz. Mr. Flat-man, in speaking of the death of Charles II. expresses his surprise that any prince should commit so absurd an act as dying; because, says he,Kings should disdain to die, and only disappear.They should abscond, that is, into the other world.

[2] Of this, however, the learned appear latterly to have doubted: for in a pirated edition of Buchan's Domestic Medicine, which I once saw in the hands of a farmer's wife who was studying it for the benefit of her health, the Doctor was made to say -- "Be particularly careful never to take above five- and-twenty ounces of laudanum at once;" the true reading being probably five- and-twenty drops, which are held equal to about one grain of crude opium.

[3] Amongst the great herd of travellers, who show sufficiently by their stupidity that they never held any intercourse with opium, I must caution my readers especially against the brilliant author of "Anastasius." This gentleman, whose wit would lead one to presume him an opium-eater, has made it impossible to consider him in that character from the grievous misrepresenta- tion which he gives of its effects, at pp. 215-17, of vol. I. -- Upon consideration it must appear such to the author himself: for, waiving the errors I have insisted on in the text, which (and others) are adopted in the fullest manner, he will himself admit, that an old gentleman "with a snow-white beard," who eats "ample doses of opium," and is yet able to deliver what is meant and received as very weighty counsel on the bad effects of that practice, is

but an indifferent evidence that opium either kills people prematurely, or sends them into a madhouse. But, for my part, I see into this old gentleman and his motives: the fact is, he was enamoured of "the little golden receptacle of the pernicious drug" which Anastasius carried about him; and no way of obtaining it so safe and so feasible occurred, as that of frightening its owner out of his wits (which, by the bye, are none of the strongest). This commentary throws a new light upon the case, and greatly improves it as a story: for the old gentleman's speech, considered as a lecture on pharmacy, is highly absurd: but, considered as a hoax on Anastasius, it reads excellently.

[4] I have not the book at this moment to consult: but I think the passage begins --"And even that tavern music, which makes one man merry, another mad,in me strikes a deep fit of devotion..."

Confessions of an English Opium-Eater by Thomas de Quincey (1785 - 1859)

(first published 1821; revised edition 1856)

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Thomas de Quincey

Opioid Receptors

Alistair Corbett, Sandy McKnight and Graeme Henderson

Dr Alistair Corbett is Lecturer in the School of Biological and Biomedical Sciences, Glasgow Caledonian University, Cowcaddens Road, Glasgow G4 0BA, UK.

Dr Sandy McKnight is Associate Director, Parke-Davis Neuroscience Research Centre, Cambridge University Forvie Site, Robinson Way, Cambridge CB2 2QB, UK.

Professor Graeme Henderson is Professor of Pharmacology and Head of Department, Department of Pharmacology, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK.

Introduction

Preparations of the opium poppy papaver somniferum have been used for many hundreds of years to relieve pain. In 1803, Sertürner isolated a crystalline sample of the main constituent alkaloid, morphine, which was later shown to be almost entirely responsible for the analgesic activity of crude opium. The rigid structural and stereochemical requirements essential for the analgesic actions of morphine and related opioids led to the theory that they produce their effects by interacting with a specific receptor.1 The concept that there is more than one type of opioid receptor arose to explain the dual actions of the synthetic opioid nalorphine, which antagonises the analgesic effect of morphine in man but also acts as an analgesic in its own right. Martin (1967) concluded that the analgesic action of nalorphine is mediated by a receptor, later called the -opioid receptor, that is different from the morphine receptor.2 Evidence for multiple receptors, , and , came from the demonstration of different profiles of pharmacological activity in the chronic spinal dog with the prototype agonists morphine, ketazocine and N-allylnormetazocine (SKF 10047).3 The existence of the -receptor was subsequently proposed to explain the profile of activity in vitro of the enkephalins (the first endogenous opioid peptides), and on the basis of the relative potency of the non-selective opioid antagonist naloxone to reverse endogenous opioid peptide inhibition of the nerve-evoked contractions of the mouse vas deferens.4 Its existence was further confirmed by radioligand binding studies using rat brain homogenates.

It is now clear from work carried out in many laboratories over the last 20 years that there are 3 well-defined or "classical" types of opioid receptor µ, and . Genes encoding for these receptors have been cloned.5, 6, 7, 8 More recently, cDNA encoding an "orphan" receptor was identified which has a high degree of homology to the "classical" opioid receptors; on structural grounds this receptor is an opioid receptor and has been named ORL1 (opioid receptor-like).9 As would be predicted from their known abilities to couple through pertussis toxin-sensitive G-proteins, all of the cloned opioid receptors possess the same general structure of an extracellular N-terminal region, seven transmembrane domains and intracellular C-terminal tail structure. There is pharmacological evidence for subtypes of each receptor and other types of novel, less well-characterised opioid receptors, , , , , have also been postulated. The -receptor, however, is no longer regarded as an opioid receptor.

Receptor Subtypes

-Receptor subtypesThe MOR-1 gene, encoding for one form of the -receptor, shows approximately 50-70% homology to the genes encoding for the -(DOR-1), -(KOR-1) and orphan (ORL1) receptors. Two splice variants of the MOR-1 gene have been cloned, differing only in the presence or absence of 8 amino acids in the C-terminal tail. The splice variants exhibit differences in their rate of onset and recovery from agonist-induced internalization but their pharmacology does not appear to differ in ligand binding assays.10 Furthermore, in the MOR-1 knockout mouse, morphine does not induce antinociception

demonstrating that at least in this species morphine’s analgesia is not mediated through - or -receptors.11 Similarly morphine did not exhibit positive reinforcing properties or an ability to induce physical dependence in the absence of the MOR-1 gene.

1 and 2: The 1/2 subdivision was proposed by Pasternak and colleagues to explain their observations, made in radioligand binding studies, that [3H]-labelled-, - and - ligands displayed biphasic binding characteristics.12 Each radioligand appeared to bind to the same very high affinity site (1) as well as to the appropriate high affinity site (, or ) depending on the radioligand used. Naloxazone and naloxonazine were reported to abolish the binding of each radioligand to the 1-site. Furthermore, in in vivo studies it was observed that naloxazone selectively blocked morphine-induced antinociception but did not block morphine-induced respiratory depression or the induction of morphine dependence.13, 14 Subsequent work in other laboratories has failed to confirm this classification.

Is there another, novel form of the -opioid receptor?Several related observations suggest the existence of a novel form of -receptor at which analogues of morphine with substitutions at the 6 position (e.g. morphine-6-glucuronide, heroin and 6-acetyl morphine) are agonists, but with which morphine itself does not interact.15 In antinociception tests on mice it has been reported that morphine does not exhibit cross tolerance with morphine-6-glucuronide, heroin or 6-acetyl morphine. Furthermore, in mice of the CXBX strain morphine is a poor antinociceptive agent whereas morphine-6-glucuronide, heroin and 6-acetyl morphine are all potently antinociceptive. The 6-substituted morphine analogues do not appear to be acting through - or -receptors because the antinociception they induce is not blocked by selective - or receptor antagonists, whereas 3-methoxynaltrexone has been reported to antagonise morphine-6-glucuronide- and heroin-induced antinociception without affecting that induced by morphine, [D-Pen2, D-Pen5]enkephalin (DPDPE , -selective) or U50488 (-selective).16

Recently it has been reported that heroin and morphine-6-glucuronide, but not morphine, still produce antinociception in MOR-1 knockout mice in which the disruption in the MOR-1 gene was engineered in exon-1.17 The same authors observed that in other MOR-1 knockout mice in which exon-2, not exon-1, had been disrupted, all three agonists were ineffective as antinociceptive agents. They conclude that the antinociceptive actions of heroin and morphine-6-glucuronide in the exon-1 MOR-1 mutant mice are mediated through a receptor produced from an alternative transcript of the MOR-1 gene differing from the MOR-1 gene product, the -opioid receptor, in the exon-1 region. To substantiate this conclusion they report that in RT-PCR experiments using primers spanning exons 2 and 3, a MOR-1 gene product was still detected in MOR-1 knockout mice.

-Receptor subtypesThe DOR-1 gene is the only -receptor gene cloned to date. However, two, overlapping subdivisions of -receptor have been proposed (1/2 and cx/ncx) on the basis of in vivo and in vitro pharmacological experiments.

1 and 2: The subdivision of the -receptor into 1 and 2 subtypes was proposed primarily on the basis of in vivo pharmacological studies (Table 1). In rodents in vivo, the supraspinal antinociceptive activity of DPDPE can be selectively antagonised by 7-benzylidenenaltrexone (BNTX) or [D-Ala2, D-Leu5]enkephalyl-Cys (DALCE)18, 19 whereas the antinociceptive activity of [D-Ala2]-deltorphin II (deltorphin II) and [D-Ser2, Leu5]enkephalyl–Thr (DSLET) can be reversed by naltriben or naltrindole 5-isothiocyanate (5-NTII).18, 19, 20 Furthermore, while mice develop tolerance to the antinociceptive effects of repeated injections of either DPDPE or deltorphin II, this tolerance appears to be homologous in that there is no cross tolerance between these ligands.21 In vivo, 1- and 2-receptor-induced antinociception can be differentially antagonised by blockers of different types of potassium channels.22

Table 1 . Putative ligands for -receptor subtypes

Receptorsubtype

AntagonistsCompetitive Nonequilibrium

1 DPDPE / DADLE BNTX DALCE2 Deltorphin II / DSLET Naltriben 5-NTII

N.B. DPDPE may not in fact be a selective 1 agonist but may also be a partial agonist at 2-sites.23

The best evidence from in vitro experiments to support the 1 and 2 subdivision of -receptors comes from inhibition of adenylyl cyclase activity in membranes from rat brain24, 25 and from the -receptor-mediated elevations of intracellular Ca2+ in the ND8-47 cell line26 where BNTX selectively antagonised DPDPE, and naltriben selectively antagonised deltorphin II. Surprisingly, little selectivity was seen in radioligand displacement studies.24 The converse has been observed in studies on neuronal cell lines. Two distinct -receptor binding sites were observed in radioligand binding experiments on SK-N-BE cells.27 Studies on NG108-15 cells28 or the human neuroblastoma cell line, SH-SY5Y,29, 30 have failed to find any functional evidence for -receptor subtypes.

The pharmacological properties of the cloned DOR-1 receptor are somewhere between those predicted for either the 1 or 2 subtypes. DPDPE and deltorphin II are both potent displacers of [3H]-diprenorphine binding to mouse and human recombinant receptors, which is not consistent with either the 1 or 2 classifications.31 In contrast, [3H]-diprenorphine binding to the mouse recombinant receptor is more potently displaced by naltriben than BNTX, suggesting that the cloned receptor is of the 2 subtype. It will be of importance to determine in the DOR-1 knockout mouse if analgesia can still be induced by either 1- or 2-receptor selective agonists.

cx andncx: The cx and ncx subdivision of -receptors was based on the hypothesis that one type of -receptor (cx) was complexed with -receptors (and perhaps also -receptors) whereas the other type of -receptor (ncx) was not associated with an opioid receptor complex.32 It was originally observed that sub-antinociceptive doses of agonists at the cx receptor (e.g. low doses of DPDPE), potentiated -receptor-mediated analgesia, an effect which could be antagonised by 5-NTII. On the other hand, at higher doses, DPDPE then acted as an agonist at the ncx-receptor and itself induced analgesia which was reversed by DALCE. Data obtained from subsequent radioligand binding studies have been interpreted as demonstrating the existence of further subtypes of the ncx receptor i.e. ncx-1) and (ncx-2). More recently it has been suggested that the (ncx-1) receptor is in fact synonymous with the 1-receptor and the cx-receptor synonymous with the 2-receptor of the previous classification.33

-Receptor subtypesThe situation regarding the proposals for subtypes of the -receptor is rather more complex than for the - and -receptors, perhaps because of the continuing use of non-selective ligands to define the putative sites. The evidence for the need for sub-division of the -receptor comes almost entirely from radioligand binding assays.

The first characterisation of a -receptor binding site in brain came from work using [3H]-ethylketocyclazocine (EKC).34 Crucial to this success was the use of the guinea-pig brain where -sites are present in relative abundance, and of "suppression", or quenching of the binding of this non-selective ligand to - and -sites, by incubation with non-radioactive ligands that bound selectively at these other sites.

Studies of [3H]-EKC binding in guinea-pig spinal cord pointed to the existence of a non-homogeneous population of high-affinity binding sites, and led to the first proposal for 1- and 2-sites distinguished by their sensitivity to DADLE.35 The DADLE-sensitive 2 site bound -endorphin with high affinity, and was later identified with the recognition site of the -receptor in brain.36 Another study using [3H]-EKC

identified a -site in bovine adrenal medulla, with a pharmacology similar to that of the 1-site in guinea-pig cord37 but labelling with [3H]-etorphine revealed two additional sites, one resembling 2 that bound [Met]enkephalyl-Arg-Gly-Leu with high affinity and another termed "3" or "MRF" that bound [Met5]enkephalyl-Arg-Phe with high affinity.

The 1/2 terminology has more recently been applied by other groups to the putative subtypes defined in other tissues in their hands, but it is not always clear how closely the common nomenclature reflects a common pharmacology. The introduction of the first selective -agonist U-50,488 and its congeners (U-69,593, PD 117302, CI 977, ICI 197067) led to a refinement of the definition of the putative subtypes, but pointed to the need for careful considerations of the effect of technical differences in assays and of species as a possible explanation for discrepancies. Thus a direct comparison of the binding of [3H]-EKC in guinea-pig and rat (with suppression of binding to - and -sites) pointed to the existence of a high affinity 1-site that predominated in guinea-pig brain and was selectively sensitive to U-69,593, and a low affinity, U-69,593-insensitive 2-site that predominated in rat brain.38 Others resorted to the binding of [3H]-bremazocine to reveal U-69,593-insensitive 2-binding sites; in contrast to the 2-site originally defined in guinea-pig spinal cord, the 2-site in brain after suppression of 1 was insensitive to DADLE.39

Subdivision of the 1-site in guinea-pig brain into 1a and 1b, was proposed to resolve the complex displacement of either [3H]-EKC or [3H]-U-69,593 with dynorphin B and -neo-endorphin which both preferentially bound to the proposed 1b sub-subtype.40 The same study proposed the existence of a 3

subtype, insensitive to U-50,488, that was identified from the binding of [3H]-naloxone benzoylhydrazone. The pharmacology of this later "3-site" is rather different from the 3/MRF site of bovine adrenal medulla, and has been proposed to be the receptor mediating the antinociceptive effect of nalorphine, Martin’s "N"-receptor.41

Nomenclature differences appear to have arisen in the context of subtyping of the 1-subtype. Using binding surface analyses to allow highly accurate estimation of binding parameters, the binding of [3H]-U-69,593 resolved two binding sites termed 1a and 1b. The ligand demonstrating the highest affinity, and around 30-fold preference, for the "1a binding site" was -neo-endorphin.42 More recently putative 1a- and 1b-sites in mouse brain were identified from complex displacement curves against the binding of [3H]-U-69,593, in an attempt to compare the pharmacology of the mouse 1-sites, with that at the cloned rat KOR stably expressed in a host neuroblastoma cell line.43 Based on the high affinity of bremazocine and -neo-endorphin, it was deemed "consistent to term the cloned KOR a 1b subtype".

Rothman (1990) also reported subdivision of the 2-binding of [3H]-bremazocine into 2a- and 2b-sub-subtypes.42 The 2b-site had high affinity for -endorphin and DADLE, reminiscent of the original 2-binding site of guinea-pig spinal cord. The 2a- and 2b-sites in guinea-pig brain have undergone a further subdivision (sub-sub-subtypes?) on the basis of investigations using a combination of depletion (of - and -sites) and suppression, against the binding of 6-[125I]-3,14-dihydroxy-17-cyclopropylmethyl-4,5-epoxymorphinan ([125I]OXY).44 So were defined the 2a-1 and 2a-2 sites, having relatively high and low affinities respectively for nor-BNI and enadoline (CI-977), and 2b-1 and 2b-2 sites with high and low affinities for DAMGO and -neo-endorphin.

Definitive functional pharmacological evidence supporting the existence of this confusing number of putative subtypes of the -receptor is lacking, because of the absence of subtype-specific antagonists. It has been reported however, that pretreatment with the isothiocyanate analogue of U-50,488 called (-)-UPHIT, was able to produce a long-lasting block of the antinociceptive effect of U-69,593 in the mouse without affecting the action of bremazocine, while treatment with the non-selective antagonist WIN 44,441 (quadazocine) blocked selectively the antinociception with bremazocine.45,46 These findings provide obvious support for the 1-2 subdivision; the pharmacological corollary is that (-)-UPHIT and WIN 44,441 are antagonists with selectivity for the 1-and 2-subtypes respectively, at least

in the mouse.

Correlating genes with -, - and -receptor subtypesAlthough there is as yet little evidence for different genes encoding the different subtypes of -, - and -receptor these subtypes may result from different post-translational modifications of the gene product (glycosylation, palmytoylation, phosphorylation, etc), from receptor dimerization to form homomeric47 and heteromeric complexes,48, 49, 50 or from interaction of the gene product with associated proteins such as RAMPs.51

The Orphan Receptor

Extending the screening of genomic and cDNA libraries, perhaps in an effort to identify putative subtypes of the classical opioid receptors, resulted in the identification of a novel receptor that bore as high a degree of homology towards the classical opioid receptor types, as they shared among each other. The receptor was identified in three species: rat, mouse and man, with the degree of homology among the species variants more than 90%. Although the putative receptor has had as many names as the number of groups who reported its identification,52 there is some consensus for the use of the original designation for the human form, "ORL1". Workers in the field are, however, divided in their preferred terminology for the endogenous peptide agonist for ORL1 with both "nociceptin"53 or "orphanin FQ"54 being used with roughly equal frequency.

Although the ORL1 receptor was accepted as a member of the "family" of opioid receptors on the basis of its structural homology towards the classical types, there is no corresponding pharmacological homology. Even non-selective ligands that exhibit uniformly high affinity towards -, - and -receptors, have very low affinity for the ORL1 receptor, and for this reason as much as for the initial absence of an endogenous ligand, the receptor was called an "orphan opioid receptor". Close comparison of the deduced amino-acid sequences of the four receptors highlights structural differences that may explain the pharmacological anomaly. Thus there are sites near the top of each of the trans-membrane regions, that are conserved in the -, - and -receptors, but are altered in ORL1. Work with site-directed mutants of ORL1 (rat) has shown that it is possible to confer appreciable affinity on the non-selective benzomorphan bremazocine by changing Ala213 in TM5 to the conserved Lys of , and , or by changing the Val-Gln-Val276-278 sequence of TM6 to the conserved Ile-His-Ile motif.55

A splice variant of the ORL1 receptor from rat has been reported ("XOR")56 with a long form (XOR1L) containing an additional 28 amino acids in the third extracellular loop. In the homologous receptor from mouse (also sometimes referred to as "KOR-3") five splice variants have been reported to date.57

ORL1-Receptor subtypesSelective high affinity ligands with which to attempt pharmacological definitions of the ORL1 receptor are few in number (Table 2). Besides the natural heptadecapeptide agonist nociceptin/orphanin FQ and some closely related peptides, the only other ligands offering high affinity and selectivity belong to a class of peptides obtained by a positional scanning approach to combinatorial libraries of hexapeptides.58 Being basic peptides highly susceptible to degradation, all of those agents are chancy tools in the hands of the unwary. So the paucity of safe and sure pharmacological tools may partly explain some of the confusion in the literature regarding the effect of nociceptin in tests of response latency to noxious stimulation; antinociception, pro-nociception/hyperalgesia, allodynia, or no overt effect, have all been reported.

Table 2. Selective opioid ligands

Receptor type µ-Receptor -Receptor -Receptor ORL1

Selective agonists endomorphin-1endomorphin-2DAMGO

[D-Ala2]-deltorphin I[D-Ala2]-deltorphin IIDPDPESNC 80

enadolineU-50488U-69593

nociceptin / OFQAc-RYYRWK-NH2*

Selective antagonists CTAP naltrindoleTIPP-ICI 174864

nor-binaltorphimine None as yet**

Radioligands [3H]-DAMGO [3H]-naltrindole[3H]-pCI-DPDPE[3H]-SNC 121

[3H]-enadoline[3H]-U69593

[3H]-nociceptin

*Related combinatorial library hits are also selective agonists.58 **Ac-RYYRIK-NH2 has been proposed to be an ORL1 antagonist61 whereas the putative antagonist [Phe1(CH2-NH)Gly2]nociceptin(1-13)NH2

59 appears to be a partial agonist.

Although the results of some studies have been interpreted as pointing to the existence of subtypes of ORL1, this conclusion is so far premature in most cases. The most reliable pharmacological definition of receptors is based on differences in antagonist affinity, and in this context the absence of useful antagonists for ORL1 is particularly galling to pharmacologists. Although the synthetic analogue of the N-terminal tridecapeptide of nociceptin, [Phe1(CH2-NH)Gly2]nociceptin(1-13)NH2 was first reported to be a selective antagonist,59 increased use of this peptide points to it having agonist actions. There are no grounds for saying that this peptide is an antagonist at ORL1 receptors in the periphery, but an agonist in the brain (not least because agonist actions in the periphery, and antagonist actions in the brain have been reported) and that these differences in efficacy point to differences in the receptors. Although differences in the affinity for [Phe1(CH2-NH)Gly2]nociceptin(1-13)NH2 may be found between central and peripheral sites,60 and there may indeed be different "subtypes" of ORL1 in the brain and periphery, the safest conclusion for the moment is just that [Phe1(CH2-NH)Gly2]nociceptin(1-13)NH2 is a partial agonist, and that the observed differences in efficacy are consistent with differences in receptor reserve.

Very recently a peptide related to the combinatorial hexapeptide library hit acetyl-Arg-Tyr-Tyr-Arg-Trp-Lys-NH2 (Ac-RYYRWK-NH2; Table 2), but with isoleucine substituting for tryptophan, was reported to block the effects of nociceptin/orphanin FQ in rat cortex (stimulation of GTP35S binding) or heart (positive chronotropic effect in isolated myocytes). Although this peptide, like all of its structural homologues, was originally reported to be a potent agonist, but with somewhat less than full efficacy,58 it will be important to see if the antagonist activity of Ac-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2 (Ac-RYYRIK-NH2 ) at the ORL1 receptor61 is confirmed.

Less Well-Characterised Opioid Receptors

In addition to the µ-, -, - and ORL1-receptors, several other types of opioid receptor have been postulated. Since the contractions of the isolated vas deferens of the rat are much more sensitive to inhibition by -endorphin than by other opioid peptides, it was suggested that this tissue contains a novel type of opioid receptor, the -receptor, that is specific for -endorphin.62 The rabbit ileum has been proposed to possess -receptors, for which the enkephalins have high affinity but which are distinct from -receptors.63 A very labile -binding site with high affinity for 4,5 epoxymorphinans has been found in freshly-prepared rat membrane fragments64 and there is evidence that opioids inhibit growth in S20Y murine blastoma cells by an action at yet another receptor type called the -receptor.65 The -, -, -and -receptors are poorly characterised and wider acceptance of their existence awaits further experimental evidence, in particular isolation of their cDNAs.

Although originally classified as such, the -receptor appears not to be an opioid receptor but rather the target for another class of abused drugs, phencyclidine (PCP) and its analogues.66 Phencyclidine

is an effective blocker of the ion channel associated with the N-methyl-D-aspartate (NMDA) receptor where it binds to the same site as MK 801.67

Endogenous Ligands

In mammals the endogenous opioid peptides are mainly derived from four precursors: pro-opiomelanocortin, pro-enkephalin, pro-dynorphin and pro-nociceptin/orphanin FQ.68, 69, 70, 53 Nociceptin/orphanin FQ is processed from pro-nociceptin/orphanin FQ and is the endogenous ligand for the ORL1-receptor; it has little affinity for the µ-, - and -receptors.53, 54 The amino acid sequence of nociceptin/orphanin FQ has homology with other opioid peptides especially the prodynorphin fragment dynorphin A (Table 3), suggesting a close evolutionary relationship between the precursors. Nociceptin/orphanin FQ, however, has a C-terminal phenylalanine (F) whereas peptides derived from the other precursors all have the pentapeptide sequence TyrGlyGlyPheMet/Leu (YGGFM/L) at their N-termini. These peptides vary in their affinity for µ, - and -receptors, and have negligible affinity for ORL1-receptors, but none binds exclusively to one opioid receptor type.71, 53 -endorphin is equiactive at µ-and -receptors with much lower affinity for -receptors; the post-translational product, N-acetyl--endorphin, has very low affinity for any of the opioid receptors.72, 73 [Met]- and [Leu]enkephalin have high affinities for -receptors, ten-fold lower affinities for µ-receptors and negligible affinity for -receptors.71 Other products of processing of pro-enkephalin, which are N-terminal extensions of [Met]enkephalin, have a decreased preference for the -receptor with some products, e.g. metorphamide displaying highest affinity for the µ-receptor.71 The opioid fragments of pro-dynorphin, particularly dynorphin A and dynorphin B, have high affinity for -receptors but also have significant affinity for µ- and -receptors.71

Endomorphin-1 and endomorphin-2 are putative products of an as yet unidentified precursor, that have been proposed to be the endogenous ligands for the µ-receptor where they are highly selective.74 The endomorphins are amidated tetrapeptides and are structurally unrelated to the other endogenous opioid peptides (Table 3). Although the study of the cellular localisation of these peptides is at an early stage, endomorphin-2 is found in discrete regions of rat brain, some of which are known to contain high concentrations of -receptors.75 Endomorphin–2 is also present in primary sensory neurones and the dorsal horn of the spinal cord where it could function to modulate nociceptive input.76

In comparison to the mainly non-selective mammalian opioid peptides (the exceptions being the endomorphins), amphibian skin contains two families of D-amino acid-containing peptides that are selective for µ- or -receptors. Dermorphin is a µ-selective heptapeptide Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 without significant affinity at - and -receptors.77 In contrast, the deltorphins - deltorphin (dermenkephalin; Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2), [D-Ala2]-deltorphin I and [D-Ala2]-deltorphin II (Tyr-D-Ala-Phe-Xaa-Val-Val-Gly-NH2, where Xaa is Asp or Glu respectively) - are highly selective for -opioid receptors.78

Table 3. Mammalian endogenous opioid ligands

Precursor Endogenous peptide Amino acid sequence

Pro-opiomelanocortin -Endorphin YGGFMTSEKSQTPLVTL-FKNAIIKNAYKKGE

Pro-enkephalin [Met]enkephalin[Leu]enkephalin

Metorphamide

YGGFMYGGFLYGGFMRFYGGFMRGLYGGFMRRV-NH2

Pro-dynorphin Dynorphin A YGGFLRRIRPKLKWDNQ

Dynorphin A(1-8)Dynorphin B-neoendorphin-neoendorphin

YGGFLRRIYGGFLRRQFKVVTYGGFLRKYPKYGGFLRKYP

Pro-nociceptin / OFQ Nociceptin FGGFTGARKSARKLANQ

Pro-endomorphin* Endomorphin-1Endomorphin-2

YPWF-NH2

YPFF-NH2

*Presumed to exist, awaiting discovery

Effector Mechanisms

The opioid receptor family, in common with the somatostatin receptor family, is somewhat unusual in that all of the cloned opioid receptor types belong to the Gi/Go-coupled superfamily of receptors. Opioid receptors do not couple directly with Gs or Gq and none of the cloned receptors forms a ligand-gated ion channel. It was originally thought that - and -receptors coupled through Gi/Go proteins to activate an inwardly rectifying potassium conductance and to inhibit voltage-operated calcium conductances whereas -receptors only inhibit voltage-operated calcium conductances. However it is now known that the -receptor is, in some cell types, also coupled to activation of an inwardly rectifying potassium conductance.79 It seems highly likely, therefore, that all of the opioid receptors will share common effector mechanisms. Indeed, many papers have recently appeared demonstrating that the ORL1-receptor couples to the same effector systems as the other more extensively studied opioid receptors. It should be borne in mind that, given the heterogeneity of i, o, and subunits which may combine to form a trimeric G protein, there may well be some subtle differences in the downstream effector mechanisms to which opioid receptors are coupled if one type of opioid receptor is unable to interact with a certain form of Gi/Go heterotrimer. However, different responses evoked in different cell types in response to activation of different opioid receptors or even in response to activation of the same receptor are likely to reflect changes in the expression of G proteins and effector systems between cell types rather than any inherent differences in the properties of the receptors themselves.

Opioid receptor activation produces a wide array of cellular responses (Table 4). Although the pertussis toxin sensitivity has not been assessed in all instances it is highly likely that in each the first step is activation of Gi or Go . The functional significance of many of these opioid receptor-mediated effects is still unclear, but two recent observations on changes in neurotransmitter release following acute and chronic exposure to opioids are worthy of special mention because they provide potential solutions to long-asked questions.

Table 4. Opioid receptor-evoked cellular responses

Direct G-protein bg or a subunit-mediated effects• activation of an inwardly rectifying potassium channel• inhibition of voltage operated calcium channels (N, P, Q and R type)• inhibition of adenylyl cyclase

Responses of unknown intermediate mechanism• activation of PLA2

• activation of PLC b (possibly direct G protein bg subunit activation)• activation of MAPKinase• activation of large conductance calcium-activated potassium channels• activation of L type voltage operated calcium channels• inhibition of T type voltage operated calcium channels• direct inhibition of transmitter exocytosis

Responses which are a consequence of opioid-evoked changes in other effector pathways

• activation of voltage-sensitive potassium channels (activation of PLA2)• inhibition of M channels (activation of PLA2)• inhibition of the hyperpolarisation-activated cation channel (Ih) (reduction in cAMP levels following inhibition of adenylyl cyclase)• elevation of intracellular free calcium levels (activation of PLCb, activation of L type voltage operated calcium conductance)• potentiation of NMDA currents (activation of protein kinase C)• inhibition of transmitter release (inhibition of adenylyl cyclase, activation of potassium channels and inhibition of voltage operated calcium channels)• decreases in neuronal excitability (activation of potassium channels)• increases in neuronal firing rate (inhibition of inhibitory transmitter release - disinhibition)• changes in gene expression (long-term changes in adenylyl cyclase activity, elevation of intracellular calcium levels, activation of cAMP response element binding protein (CREB))

The periaqueductal grey region (PAG) is a major anatomical locus for opioid activation of descending inhibitory pathways to the spinal cord and is thus an important site for -receptor-induced analgesia. Opioids do not excite descending fibres directly but disinhibit them by inhibiting spontaneous GABA release from local GABAergic interneurones.80 This inhibition of transmitter release results from activation of a dendrotoxin-sensitive, voltage-sensitive potassium conductance. The mechanism by which the voltage-sensitive potassium conductance is activated appears to be through activation of phospholipase A2 (PLA2) with subsequent metabolism of arachidonic acid along the 12-lipoxygenase pathway because the inhibition of GABA release can be inhibited by quinacrine and 4-bromo-phenacylbromide, inhibitors of PLA2, and by baicalein, an inhibitor of 12-lipoxygenase. This proposed mechanism of opioid action also explains the synergy between opioids and non-steroidal analgesic drugs (NSAIDs) in producing analgesia because in the presence of a NSAID, with the cyclo-oxygenase enzymes inhibited, more of the arachidonic acid produced by opioid activation of PLA2 can be diverted down the 12-lipoxygenase pathway.

The cellular locus of opiate withdrawal has long been the Holy Grail of opioid biologists. Over 20 years ago, it was shown that following chronic exposure of NG108-15 neuroblastoma x glioma hybrid cells to opiates, withdrawal resulted in a rebound increase in adenylyl cyclase;81 the functional significance of this observation for opiate withdrawal in brain neurones has remained obscure. Recently, Williams and colleagues82 have observed an increase in the release of the inhibitory neurotransmitter GABA, in the nucleus accumbens during opiate withdrawal. This effect could be mimicked by the adenylyl cyclase activator, forskolin, and inhibited by protein kinase A inhibitors. Therefore, as proposed over 25 years ago by the late Harry Collier, rebound adenylyl cyclase activity in withdrawal may be the fundamental step in eliciting the withdrawal behaviour.83

Development and Clinical Applications of Opioid Ligands

Among the receptors for the many neuropeptides that exist in the nervous system, the opioid receptors are unique in that there existed before the discovery of the natural agonists, an abundance of non-peptide ligands with which the pharmacology of the receptors was already defined. In current terms relating to the drug-discovery process, we would consider the 4,5-epoxy-methylmorphinan opioid alkaloids morphine, codeine and thebaine as "natural-product hits" on which were based chemical programmes to design analogues with improved pharmacology (Figure 1). The effects of morphine to reduce sensitivity to pain or to inhibit intestinal motility and secretion, have continued to be exploited clinically, however the presence of other undesirable effects (e.g. depression of respiration, tolerance/dependence, effects on mood) provided the stimulus to seek analogues that were selective in producing analgesia. Thus a semi-synthetic di-acetylated analogue of morphine was introduced in the 19th century in the mistaken belief that this compound (heroin) had those desired properties. More radical changes to the morphinan nucleus were subsequently explored in various synthetic programmes, in many early cases resulting in the development of low efficacy partial agonists.

With the benefit of hindsight, it is possible to conceive an evolution of those opioid analogues, with a progressive simplification of chemical structure from the epoxymorphinans (nalorphine, nalbuphine) through the morphinans such as levorphanol, and the benzomorphans such as pentazocine, to the phenyl-piperidines including pethidine and the 4-anilino-piperidines as exemplified by fentanyl (Figure 1). The ultimate simplification of the morphine structure was in the methadone class, with methadone itself and d-propoxyphene (Darvon). Although thebaine is virtually inactive, the compound itself was an important chemical precursor in the synthesis of 14-hydroxy derivatives of morphine, most particularly the antagonists naloxone and naltrexone. Also derived from thebaine were the oripavine derivatives, and here the trend of chemical "simplification" was reversed with the introduction of an additional six-membered ring that appeared to enhance biological potency. For example, etorphine is about one thousand times more potent than morphine as an analgesic, but its use is limited to veterinary medicine as a sedative for large animals.

For the most part, such compounds have highest affinity for the -receptor, and to a greater or lesser extent produce the full panoply of effects, good and bad, obtained with morphine. Depending on the level of affinity and efficacy, such compounds have been used acutely or chronically, to provide analgesia in cases of mild, through moderate to severe pain, alone or with adjuncts. The piperidines related to fentanyl include the most potent non-peptide -agonists known, and are generally used peri-operatively, often for the induction and maintenance of anaesthesia. The use of many of the benzomorphans (as had been found with the first of the "duallists" nalorphine) has been associated with dysphoric and psychotomimetic effects in man, a property originally thought to be attributable to affinity at the non-opioid -site.

The attractiveness of the prospect for development of selective -agonists as analgesics was based on the preclinical pharmacology in animals of the 6,7-benzomorphans such as ketazocine and its derivatives (Figure 1). Although those agents are not selective in terms of affinity, their utility as pharmacological tools is based on their functional selectivity for the -receptor, where their efficacy is high. Such agents produced a powerful antinociceptive effect, but did not substitute for morphine in dependent animals. A full biochemical and pharmacological characterisation of the -receptor was not possible until the discovery of highly selective agonists in the aryl-acetamides that appear unrelated structurally to any of the morphine derivatives. The first compound of this class was U-50,488, but its importance was also as a chemical lead for the attempted design of related compounds of greater selectivity and potency. At least two such compounds have entered clinical trials as centrally acting analgesics, Spiradoline (U-62,066) and enadoline (CI-977). Although CNS-mediated, mechanism-related side effects of sedation and dysphoria may limit the potential for development of such compounds, the prospects for analogues with limited brain penetration to produce a peripherally mediated analgesic effect in inflammatory conditions is under exploration, with at least one compound (asimadoline, EMD-61753) in clinical trials for osteoarthritis. The observation of neuroprotective properties of -agonists in pre-clinical models of cerebral ischaemia has lead to consideration of the possible clinical development of selective -agonists for stroke or traumatic head injury. In this context the sedative properties of -agonists, and even perhaps their characteristic diuretic action, may be advantageous.

The discovery of the enkephalins and of the -receptor, led to the idea that the peptides themselves might be taken as "leads" for the synthesis of a new class of opioid agonist that lacked the addictive properties of morphine. Although such synthetic activities produced many useful experimental tools, no direct benefit in the form of a drug appeared, in spite of the attempted development of several enkephalin analogues. It did become clear from the work of a number of laboratories that activation of the -receptor is associated with antinociception in animals, and the development of a selective non-peptide agonist is under consideration by a number of commercial drug houses. In some cases the synthetic strategy is based directly on structural considerations of the first non-peptide with significant selectivity, the 6,7-indole analogue of naltrexone, naltrindole.84 Applying the "message-address" concept that produced the antagonist naltrindole to a novel series of octahydroisoquinoline derivatives has been successful in producing non-peptide -selective agonists TAN-6785 or SB

213698.86 Similar considerations do not serve to explain the existence of another series of novel piperazine derivatives -agonists, BW 373U8687 or SNC 80.88 Preclinical studies suggest that -agonists may have a superior profile as analgesics, but this will only be established when such an agent is successfully introduced into clinical investigation; other possible applications of selective ligands for this receptor may emerge from clinical experience.

The prospects for clinical utilities of agonists or antagonists for the ORL1 receptor can only be the subject of speculation. Elucidation of the role of the nociceptin/ORL-receptor system in pain control (and in other areas, for the peptide and its receptor have a dense and wide investment in the nervous system) must await the initial results of the drug-discovery process. Only with the availability of non-peptide selective agonists, and perhaps more particularly antagonists, will it be possible to undertake the definitive pre-clinical studies that will serve for the identification of possible clinical targets. There is some agreement that activation of the ORL1 receptor in the brain leads to a motor impairment, so it may be that the development of ORL1 agonists would be difficult.

References

1. Beckett and Casey (1954) J.Pharm.Pharmacol. 6 986.2. Martin (1967) Pharmacol.Rev. 19 463.3. Martin et al (1976) J.Pharmacol.Exp.Ther. 197 517.4. Lord et al (1977) Nature 267 495.5. Evans et al (1992) Science 258 1952.6. Kieffer et al (1992) Proc.Natl.Acad.Sci.USA 89 12048.7. Chen et al (1993) Mol.Pharmacol. 44 8.8. Minami et al (1993) FEBS Lett. 329 291.9. Mollereau et al (1994) FEBS Lett. 341 33. 10. Koch et al (1998) N.S. Archives of Pharmacology 357 SS 44.11. Matthes et al (1996) Nature 383 818.12. Wolozin and Pasternak (1981) Proc.Natl.Acad.Sci.USA 78 6181.13. Ling et al (1984) Science 226 462.14. Ling et al (1985) J.Pharmacol.Exp.Ther. 232 149.15. Rossi et al (1996) Neuroscience Letters 216 1.16. Brown et al (1997) J.Pharmacol.Exp.Ther. 282 1291.17. Schuller et al (1999) Nature Neuroscience 2 151.18. Jiang et al (1991) J.Pharmacol.Exp.Ther. 257 1069.19. Sofuoglu et al (1993) Life Sci. 52 769.20. Sofuoglu et al (1991) J.Pharmacol.Exp.Ther. 257 676. 21. Mattia et al (1991) J.Pharmacol.Exp.Ther. 258 583.22. Wild et al (1991) Eur.J.Pharmacol. 193 135.23. Vanderah et al (1994) Eur.J.Pharmacol. 252 133.24. Buzas et al (1994) Life Sci. 54 PL101.25. Noble and Cox (1995) J.Neurochem. 65 125.26. Tang et al (1994) J.Pharmacol.Exp.Ther. 270 40.27. Polastron et al (1994) J.Neurochem. 62 898.28. Ho et al (1997) Eur.J.Pharmacol. 319 109. 29. Connor et al (1997) Neuropharmacology 36 125.30. Toll et al (1994) Regul.Peptides 54 303.31. Law et al (1994) J.Pharmacol.Exp.Ther. 271 1686.32. Rothman et al (1993) In: Handbook Exp.Pharmacol. Ed. A. Herz 104/1 p217.33. Xu et al (1993) Peptides 14 893.34. Kosterlitz et al (1981) Br.J.Pharmacol. 73 939.35. Attali et al (1982) Neuropeptides 3 53.36. Chang et al (1984) Mol.Pharmacol. 26 484.37. Castanas et al (1985) J.Neurochem. 45 688.38. Zukin et al (1988) Proc.Natl.Acad.Sci.USA 85 4061.39. Tiberi and Magnan (1989) Can.J.Physiol.Pharmacol. 67 1336.40. Clark et al (1989) J.Pharmacol.Exp.Ther. 251 461.41. Paul et al (1991) J.Pharmacol.Exp.Ther. 257 1.42. Rothman et al. (1990) Peptides 11 311.43. Lai et al (1994) Neuroreport 5 2161.44. Ni et al (1995) Peptides 16 1083.45. Horan et al (1991) J.Pharmacol.Exp.Ther. 257 115446. Horan et al (1993) J.Pharmacol.Exp.Ther. 266 926.47. Cvejic and Devi (1997) J.Biol.Chem. 272 26959.48. Jones et al (1998) Nature 396 674.49. White et al (1998) Nature 396 679.50. Kaupman et al (1998) 396 683.

51. McLatchie et al (1998) Nature 393 333-339. 52. Henderson and McKnight (1997) TiPS 18 293.53. Meunier et al (1995) Nature 377 532.54. Reinscheid et al (1995) Science 270 792.55. Meng et al (1996) J.Biol.Chem. 271 32016.56. Wang et al (1994) FEBS Lett. 348 75.57. Pan et al (1998) FEBS Lett. 435 65.58. Dooley et al (1997) J.Pharmacol.Exp.Ther. 283 735.59. Guerrini et al (1998) Br.J.Pharmacol. 123 163.60. Mason et al (1998) Soc. for Neurosci. 24 536.20.61. Berger et al (1999) Br.J.Pharmacol. 126 555.62. Wuster et al (1978) Neurosci.Lett. 15 193.63. Oka (1980) Br.J.Pharmacol. 68 198.64. Grevel and Sadee (1983) Science 221 1198.65. Zagon et al (1989) Brain Res. 482 297.66. Vincent et al (1979) Proc.Natl.Acad.Sci.USA 76 4578.67. Hollmann and Heinemann (1994) Ann.Rev.Neurosci. 17 31.68. Nakanishi et al (1979) Nature 278 423.69. Kakidani et al (1982) Nature 298 245.70. Noda et al (1982) Nature 295 202.71. Corbett et al (1993) In: Handbook Exp.Pharmacol. Ed. A. Herz 104/1 p645.72. Kosterlitz and Paterson (1985) Philos.Trans.R.Soc.Lond. 308 291.73. Akil et al (1981) Peptides 2 289.74. Zadina et al (1997) Nature 386 499.75. Schreff et al (1998) Neuroreport 9 1031.76. Martin-Schild et al (1997) Peptides 18 1641.77. Amiche et al (1988) Int.J.Pept.Protein Res. 32 50.78. Erspamer et al (1989) Proc.Natl.Acad.Sci.USA 86 5188.79. Grudt and Williams (1993) Proc.Natl.Acad.Sci.USA 90 11429.80. Vaughan et al (1997) Nature 390 611.81. Sharma et al (1975) ) Proc.Natl.Acad.Sci.USA 72 3092.82. Chieng and Williams (1998) J.Neurosci. 18 7033.83. Collier et al (1974) Nature 249 471.84. Portoghese et al (1990) J.Med.Chem. 43 1714.85. Nagase et al (1994) Jap.J.Pharamacol. 64 (suppl. 1) 35.86. Dondio et al (1995) Analgesia 1 394.87. Chang et al (1993) J.Pharmacol.Exp.Ther. 267 852.88. Calderon et al (1994) J.Med.Chem. 37 2125.

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Opium TimelineMeet The FamilyJust For Chemists

Confessions of an English Opium-Eater

Future Synthetic Drugs of AbuseDonald A. Cooper

Drug Enforcement Administration

McLean, Virginia

Index

Introduction Hallucinogens

o Indoles Ergot Alkaloids Indolealkylamine

o Phenylalkylamines o Phencyclidine

Stimulants Sedatives-Depressants Analgesics Conclusion Definitions References

Introduction

It seems likely that primitive man wished at times to escape his reality and most probably found some natural drug to facilitate this desire. In fact, abuse of the coca leaf and the opium poppy is thought to have been practiced for at least the last 3400 years (Lathrap 1976; Rosengarten 1969) and the use of peyote may have been known as early as 1000 BC (Schultes 1938; 1940). Perhaps due in part to the long history of opiate products, one of the first derivatives of a natural drug to be used pharmaceutically was heroin. The acceptance of heroin as a pharmaceutical was primal in establishing the concept that certain structural modifications of physiologically active compounds can result in new compounds which cause biological responses which are not only similar, but are enhanced as compared to those of the parent compounds. Other works such as the structural elucidation of mescaline and the preparation of N-methyl and N-acetyl derivatives of mescaline has served to strengthen this concept and to broaden the scope of permissible derivatives (Spath 1919). In the ensuing years much knowledge has been gained regarding biologically useful derivatives of the naturally occurring drugs but, most importantly, the structures of the alkaloids and the protoalkaloids have, one by one, been elucidated. This knowledge has then allowed researchers of recent times to deduce many of the structure relationships associated with specific biological responses. The sum of this hardwon knowledge allows one to produce pharmaceutically useful compounds, which have no counterpart in nature, from off the shelf chemicals. Unfortunately there are those people who would take this body of knowledge and, rather than use it for the enhancement of medical science, use it for their own financial gain. Individuals such as these have created the so-called designer drug phenomenon.

Henderson (1986) first described a synthetic drug as one which was designed by a clandestine chemist to produce a certain pharmacological response. However, today designer drugs are universally understood to belong to a group of clandestinely produced drugs which are structurally and pharmacologically very similar to a controlled substance but are not themselves controlled substances (Langston and Rosner 1986). The Drug Enforcement Administration (DEA) has noted that the designer drug terminology tends to cast a somewhat glamorous aura onto the concept, and as a result, the DEA feels that it would be wise to refer to these compounds in some other manner and suggests the use of the term Controlled Substance Analogs (CsA).

In October of 1987 the United States Government amended the Controlled Substance Act in an effort to curtail the illicit introduction of new CsA's. This amendment states that any new drug which is substantially similar to a controlled substance currently listed under the Code of Federal Regulations (CFR), Schedule I or II, and has either pharmacological properties similar to a Schedule I or II substance or is represented as having those properties, shall also be considered a controlled substance and will be placed in Schedule I. The amendment further contains provisions which exempt the legitimate researcher as well as compounds that are already being legally marketed from the provisions of the amendment.

Since the CsA amendment has yet to be tested in a court of law, it is much too early to say how successful it will be in limiting the spread of the CsA phenomena. However, it is safe to assume that there will be those who believe that they can manage to evade the provisions of the CsA amendment, and much of the world has not yet even attempted to find a litigious solution to the problem of CsA's. Therefore, an attempt to identify those CsA's which would be logical candidates for synthesis by a clandestine chemist is still a pertinent exercise.

Hallucinogens

A great many compounds, when taken in sufficient quantity, will alter one's perception of reality. For the purposes of this paper, the term hallucinogen is reserved for those compounds that are characterized by the predominance of their actions on mental and psychic functions (Brown 1972).

Hallucinogens can be classified according to structural similarities into four groups of compounds and into one group containing miscellaneous structures. The classifications are: indoles, phenylalkylamines, piperidyl benzilate esters, cannabinoids and miscellaneous.

The piperidyl benzilate esters have been extensively studied and relationships between psychotomimetic activity and chemical structure have been established (Abood et al. 1959; Abood and Biel 1968). The N-methyl and N-ethyl-3-piperidyl benzilate esters are controlled substances and are listed under the CFR Schedule I as hallucinogens. Benactyzine is a noncontrolled drug which is used medically as an antagonist to cholinergic nerve fibers (Biel et al. 1962). It appears that the pharmacological effects of the piperidyl benzilate esters may not be conducive to a good trip for the user. Brown describes the pharmacological effects by explaining how thought processes are severely disrupted. He reports that speech is disorganized and incoherent, and that confusion, disorientation, and amnesia occur often and may be long lasting (Brown 1972). Perhaps these compounds should not be classified as hallucinogens but rather as incapacitating agents. Additionally, although the pharmacological effects of the piperidyl benzilates have been compared to those elicited by phencyclidine (Shulgin 1969), there is no evidence to suggest any significant abuse of these compounds. Therefore, no further discussion will be given to the piperidylbenzilate esters.

Given the world wide ready availability of marijuana, it is somewhat difficult to produce a viable argument for making CsA's of cannabinoids. However, ten years ago (1978) an attempt to produce CsA's from cannabis extracts was encountered in the Jacksonville, Florida area. In this case a concentrated extract of cannabis had been obtained by a soxhlet extraction. The extract had been acetylated with acetic anhydride, and in the final step, the excess acetic anhydride removed by distillation (reference is unretrievable due to its appearance in an underground periodical). The product contained neither quantities of nonderivatized cannabinoid nor any identifiable plant fragments. Since this single instance, no acetalaced cannabinoid samples have been reported by a DEA laboratory. Therefore, this instance is assumed to represent an isolated occurrence and as such, will serve to terminate our discussion of cannabinoid CsA's.

Under the heading miscellaneous, one must include nearly any ingestible compound known to man, as any substance taken at toxic levels will alter one's perception of reality. Obviously a discussion of all such compounds as models for CsA hallucinogens is not within the scope of this article. However, the compound known as phencyclidine (PCP or N-(1-phenylcyclohexyl)piperidine), although developed by Parke Davis and Company (Rochester, Michigan) as an anesthetic, does produce psychotomimetic effects and is widely abused in the United States. It is listed in the CFR under Schedule II, and two of its homologs and one analog are listed under Schedule I.

Therefore, in the following discussions, the indoles, the phenylalkylamines and PCP will be considered as possible candidates for hallucinogenic CsA's.

Indoles

The literature covering indole chemistry is huge and diverse. Over 500 naturally occurring indole alkaloids were known by 1972 and accounted for nearly one fourth of all alkaloids known at that time (Robinson 1968). By 1980, the number of known indole alkaloids had risen to approximately 1200 (Kisakurek and Hesse 1980). Today there have been many more indoles added to the list of naturally occurring alkaloids. These alkaloids include such pharmacologically and structurally diverse compounds as tryptophan (essential amino acid), reserpine (tranquilizer), strychnine (stimulant-convulsant), harmaline (hallucinogen), serotonin (anticholinesterase-monoamine oxidase inhibitor), ergometrine (oxytocic), vinblastine (antitumor agent), and psilocybin (hallucinogen).

Only nine compounds containing the indole nucleus are controlled substances under the United States Federal Statutes. Three of these compounds are classified as ergot alkaloids, five are simple 3-(2-ethylamino)indoles, and one is the pentacyclic alkaloid, ibogaine. The ergot alkaloids are lysergic acid, lysergic acid amide, and lysergic acid diethylamide (LSD). The five controlled indolealkylamines are N,N-dimethyltryptamine (DMT), N,N-diethyltryptamine (DET), N,N-dimethyl-5-hydroxytryptamine (bufotenine), N,N-dimethyl-4-hydroxytryptamine (psilocin), and the phosphate ester of N,N-dimethyl-4-hydroxytryptamine (psilocybin).

Because the major pharmacological effects of ibogaine are probably not those of a hallucinogen (Schneider and Siggs 1957; Turner et al. 1955; Wooley 1962) and because only a very few illicit samples have been encountered, we will not discuss the subject further.

Ergot Alkaloids

Lysergic acid (compound 1, Figure 1) is a tetracyclic compound, and as noted previously, contains an indole nucleus and belongs to the family of ergot alkaloids. Nearly all of the

known naturally occurring hallucinogens have a 3-(2-ethylamino)indole contained within the molecular structure.

The assessment of a particular LSD derivative as a candidate for a future CsA involves the consideration of several points. The most important are those attempts made by other researchers to modify the structure of LSD while retaining hallucinogenic activity. To date, all attempts to modify the tetracyclic ring system have resulted in a loss of hallucinogenic activity. For instance, of the four possible C-8 stereoisomers only the dextro isomer of LSD is hallucinogenic (Rothlin 1957a). Modification of the amide alkyl substituents also reduces hallucinogenic activity substantially (Usdin and Efron 1972). Additionally, substitution with either a hydroxyl or a methoxy at the C-12 of LSD results in a compound with no hallucinogenic activity (Usdin and Efron 1972), whereas a comparably substituted methoxyindolealkylamine appears to always be hallucinogenic (Gessner and Page 1962). The only structural modification which results in the maintenance of hallucinogenic activity on par with LSD is the substitution of either a methyl or an acetyl to the indole nitrogen (Rothlin 1957b).

The total synthesis of LSD derivatives is not simple and requires the talents of an adept synthetic chemist (Jacobs and Craig 1934; Kornfeld et al. 1954; Garbrecht 1959). Much of the LSD produced today uses ergotamine that is obtained from legitimate commercial sources (Golden, L. personal communication). However, if ergotamine becomes difficult to obtain from commercial sources, the ergot alkaloids can be produced easily and in large quantities by cultivating strains of the fungus Claviceps in submerged cultures (Spalla 1980). Given the fact that structural modifications of the tetracyclic ring system are likely to result in a product with either little or no activity, and the fact that there will never be a shortage of ergot alkaloids for clandestine syntheses, it is quite unlikely that the total synthesis of LSD or derivatives thereof will become commonplace in the near term. One final point to consider is that the CFR lists LSD and all optical, geometrical, and positional isomers of LSD under Schedule I, and Iysergic acid and lysergic acid amide under Schedule III.

Because of previously noted pharmacodynamics and the imposing nature of a total synthesis, the immediate precursor of a LSD derivative synthesis will most certainly be a controlled substance, namely Iysergic acid; therefore, much of the impetus for producing noncontrolled LSD derivatives is lost. However, if the CsA amendment were not a consideration there would be a clear first choice via substitution of the indole nitrogen to create either 1-alkyl or 1-acyl derivatives. Derivatives of this type most probably fall under the purview of the CsA amendment. The N,N-methylpropyl isomer of LSD has been the only derivative of LSD examined by the author. Derivatives of this type might seem to be an unlikely choice for a CsA due to a high probability of significant loss in hallucinogenic activity. However, a reduction in hallucinogenic activity may become acceptable to the U. S. clandestine chemist when he notes that lysergic acid amide is listed as a Schedule III substance in the CFR; therefore, structurally similar substances of this compound are exempted from the CsA amendment. A lucid argument can then be made that lysergic acid N,N-dimethylamide is derived from lysergic acid amide rather than LSD. Carrying this theme to the next logical step one would then assume that the 1-alkyl and 1-acyl derivatives of the N,N-dimethyl isomer would also not be controlled by the CsA amendment. At present, no known CsA of LSD has ever been encountered by the DEA.

Indolealkylamine

All of the hallucinogenic indolealkylamines can be classified as belonging to the family of compounds known as tryptamines and are substituted 3-(2-ethylamino)indoles (compound 2, Figure 2).

The tryptamines are a most interesting and biologically useful class of compounds. In the human body, serotonin (5-hydroxytryptamine) functions as a vasoconstrictor, inhibits gastric secretion, stimulates smooth muscle, and is naturally present in the central nervous system where it is involved in neurotransmission (Goodman and Gilman 1970). The 5-methoxy homolog of serotonin is considered to be hallucinogenic in humans as is the 5-methoxy homolog of gramine (3-(N,N-dimethylaminomethyl)indole) (Gessner et al. 1961). Melatonin (N-acetyl-5-methoxytryptamine), formed by the mammalian pineal gland, appears to depress gonadal function and is known to cause contractions of melanophores. Bufotenine, the N,N-dimethyl homolog of serotonin, is classified as a very weakly active hallucinogen and is noted to have extremely unpleasant cardiovascular depressive side effects (Holmstedt et al. 1967). The O-methyl homolog of bufotenine, N,N-dimethyl-5-methoxytryptamine (5-methoxy-DMT), is reported to be an extremely potent hallucinogen, but it, like all other C-5 substituted indolealkylamines, is not active if taken by mouth (Brown 1972). Both DMT and DET are well known for their hallucinogenic activity, just as both of these compounds are also inactive if taken by mouth. The N,N-dipropyl and diallyl derivatives are also hallucinogenic only if used either parenterally or by inhalation at approximately the same level as DET, whereas higher homologs abruptly become inactive (Szara and Hearst 1962). The compound 6-hydroxy-DET has been determined to be a major metabolite of DET in man (Szara et al. 1966), and it does not possess hallucinogenic activity (Szara 1970). Conversely, the 4-hydroxy-N,N-dimethyltryptamines (psilocin and psilocybin), are very active hallucinogens when taken orally. The activity of psilocybin (O-phosphoryl-4-hydroxy-DMT) when taken by mouth is not related lo the phosphoric acid radical since the pharmacological effects of psilocin (4-hydroxy-DMT) are identical (Horita and Weber 1961). Pharmacological information for baeocystin (4-hydroxy-N-methyltryptamine) was not found; however, one would expect hallucinogenic activity to parallel that of the N-alkyl-tryptamines and thereby would expect the drug to be weakly hallucinogenic.

It is thought that in the past most clandestine syntheses of indolealkylamines used indole as the starting material (Speeter and Anthony 1954). A modest literature search will convince a clandestine chemist that the use of the Fischer indole synthesis affords access to a greater variety of indole derivatives (Huisgen and Lux 1960; Robinson 1983) as it will also reduce the chance that law enforcement will be alerted by his purchases of essential chemicals. Hence, in the production of indolealkylamine derivatives, the covert chemist need not be limited by the commercial availability of appropriate indole precursors.

Relative to those which lack an aryl ring substitution, there is no doubt that the activity of psilocybin/psilocin upon ingestion is due to an enhancement of gastrointestinal absorption which, in turn, must be structurally related to the presence of the C-4 hydroxyl substitution. Therefore, if the CsA amendment were not a consideration, derivatives derived from psilocin would be the obvious first choice. These derivatives are the 4-hydroxy-N,N-alkyl homologs starting with N,N-dimethyl, N,N-methyl-ethyl, and on to N,N-diallyl to give a total of 10 possible derivatives. As is also the case for hallucinogenic phenylalkylamines, alkyl substitution, not to exceed a C-3 moiety, at the position alpha to the side chain nitrogen generally will maintain hallucinogenic activity. This brings the total possible number of hallucinogenic CsA's of psilocin to 40. A somewhat removed second choice would be the same series of derivatives in conjunction with either acetylation or methylation of the indole nitrogen. This would then bring the total number of the possible 4-hydroxy substituted tryptamine CsA's (less one for psilocin) to 119.

The 5-methoxy derivatives of gramine and serotonin are first choices for future CsA's when considering the new U. S. amendment. Substitution at the alpha carbon on the side chain will probably maintain psychotropic activity only for serotonin derivatives. Hence, allowing only a methoxy substituent at the aryl C-5 position, and a substitution at the carbon alpha to the nitrogen (the nitrogen being any combination of hydrogen, methyl, ethyl, n-propyl, and allyl) 75 CsA's can be obtained. Then substitution of the indole nitrogen with either methyl or

acetyl brings the total number of possible CsA's that can be argumentatively related to serotonin to 225.

An additional series of compounds that could serve as future CsA's under U. S. law are those which are substituted with alkyl groups at the carbon alpha to the side chain nitrogen. Recently, a commercially available tryptamine which has an ethyl moiety substituted at the alpha carbon has become the newest U.S. tryptamine CsA. Known as ET in the illicit CsA drug market is 3-(2-amino-butyl)indole (etryptamine, monase by Upjohn (Kalamazoo, MI); compound 3, Figure 3). Because ET does not appear in either Schedule I or II of the CFR and is a legally marketed product, ET and derivatives thereof are exempted from control under the CsA amendment. Pharmacokenitic data on ET indicates that it is a monoamine oxidase inhibitor (Govier et al. 1953; Klein and Davis 1969) and psycho-energizer (Robie 1961; deHaen 1964). Hence, ET could produce some degree of hallucinogenic activity in man. In 1986 ET was reported as the she causative agent in a fatal overdose in Duesseldorf, Germany (Daldrup et al. 1986). This may be one of the few times that a CsA has originated outside of the U. S. The sample of ET which was submitted to our laboratory appears to have been obtained from the Aldrich Chemical Company ($48.05/100 gm; Milwaukee, WI). Unfortunately, it is not yet clear if ET is actually the substance which is producing the biological response being sought by the illicit user. It is the case that the sample of ET we examined and the batch of ET which the Aldrich Chemical Company is presently selling contains a major quantity (about 30%) of the agent shown in Figure 4 which could also be a hallucinogen (Turner 1963; Naranjo 1967).

Nomenclature for this possible hallucinogen can either be 1-methyl-3-ethyl-1,2,3,4-tetrahydro-harmane, or 2,2-dimethyl-4-ethyl-2,3,4,5-tetrahydro-[beta]-carboline. The creation of this substance most probably occurred after synthesis and during the purification of ET. Under anhydrous conditions, the reaction of acetone and ET would give the correponding enamine which could then undergo a Mannich condensation to yield the hallucinogen (Whaley and Govindachari 1951; Shoemaker et al. 1979). The compound 2-methyl-8-methoxy-4,5-dihydro-[beta]-carboline (harmaline) is considered to be a hallucinogen (Hochstein and Paradies 1957) as well as a monoamine oxidase inhibitor (Burger and Nara 1965). On the other hand, the compound 2-methyl-8-methoxy-2,3 4,5-tetrahydro-[beta]-carboline is classified as a tranquilizer (Usdin and Efron 1972). We were not able to attain any literature whatsoever on the hallucinogen shown in compound 4 (Figure 3), much less any pharmacokenetic data. Hence, due to the apparently unpredictable pharmacological behavior of structurally similar [beta]-carboline derivatives, I will not speculate as to the pharmacological properties of said substance.

Phenylalkylamines

As was observed for the simple indole alkaloids, there are several simple phenylalkylamines which play important roles in the normal biological function. Some of these are tyrosine, 3,4-dihydroxyphenylalanine (DOPA), 3,4-dihydroxytryptamine (dopamine), and norepinephrine. The naturally occurring hallucinogenic protoalkaloid, mescaline, is 2-(3,4,5-trimethoxyphenyl)ethylamine. Structural modifications which impart hallucinogenic activity to phenylethylamines have een studied and a considerable quantity of that data is easily retrieved. The following constitutes a brief review of some of the most salient concepts relative to hallucinogenic activity chemical structure relationships within the family of phenylethylamine derivatives.

It has been found that the addition of methoxy moieties to the aromatic ring of a phenylethylamine, in general, produces compounds that are psychotomimetic (Shulgin et al. 1969). Further, it has been noted that the methylenedioxy moiety can be used in the place of two adjacent ring substituted methoxy groups with C-3,4 substitution providing the most

potent psychotogens (Alles 1959; Shulgin 1964; Naranjo et al. 1967; Braun et al. 1980a). Historically 3,4-methylenedioxyamphetamine (MDA) has probably been the most consistently abused psychotomimetic phenylethylamine. Amphetamine and methamphetamine are adrenomimetic at low to moderate dose levels; however, at high dose levels they also become psychotomimetic in man (Liddel and Weil-Malherbe 1953; Connell 1958). Additionally, it has been found that the addition of an [alpha]-alkyl moiety (up to C-3) (Snyder and Richelson 1970) to methoxyphenylethylamines results in an increase in hallucinogenic activity and, alkyl only substitutions to the aromatic ring tend to result in a gradual loss of central activity which can be related to the increasing size or the alkyl group (Marsh and Herring 1950; Harris and Worley 1957). Braun et al. (1980b) has determined that a gradual decrease in psychotomimetic activity also occurs with the increasing size of a N-alkyl substituent. Braun also noted that upon N,N-dialkyl substitution an abrupt and significant loss of hallucinogenic activity occurs, whereas N-hydroxy substitution maintains activity.

The bases of structure-activity relationships as determined by aromatic ring substitutions are not obvious. For instance, mescaline has relatively prominent psychotomimetic properties but 3,4-dimethoxyphenylethylamine (3,4-dimethoxydopamine) is not considered to be psychotogenic, and the hallucinogenic potency of 3,4-dimethoxyamphetamine is less than that of mescaline (Hollister and Friedhoff 1966). On the other hand, the hallucinogenic potency of 3,4-methylenedioxyamphetamine is approximately three times that of mescaline (Braun et al. 1980b). Also, tyramine (4-hydroxyphenylethylamine) is devoid of hallucinogenic activity, but 4-methoxy-tyramine is weakly hallucinogenic (Smythies et al. 1969). However, 2-methoxymethamphetamine has no known hallucinogenic activity (Usdin and Efron 1972), and the 4-methoxyphenyl-[alpha]-methylethylamine (4-methoxyamphetamine) has five limes the psychotropic activity of mescaline (Shulgin 1970). To complicate the situation further, one work reported the synthesis of 4-substituted methamphetamine derivatives using both ring activating and ring deactivating substituents of quite different atomic volumes, and found hallucinogenic activity present for all derivatives. The compounds in question are 4-bromo-, 4-amino-, 4-chloro-, 4-nitro-, 4-iodo-, and 4-hydroxymethamphetamine (Knoll et al. 1966). It is a little surprising that substituents of such radically different atomic volumes and electronegativities would all give 4-substituted- phenylisopropylamine derivatives having psychotropic activity. In contrast, another study of hallucinogenic activity as a function of aromatic ring substitution, found the compound 2,5-dimethoxy-4-methylamphetamine to be some eighty times more potent than mescaline but upon going to the 4-ethyl derivative, quite a trivial change, nearly all hallucinogenic activity was supposedly lost (Shulgin 1969). Despite these seeming inconsistencies, many of the necessary structural requirements for producing hallucinogenic phenylethylamine can be understood by noting the common structural features of these psychotogens. The structure activity relationships noted above can be found in a single source review article by Shulgin (1970).

The following phenylalkylamines are listed under Schedule I of the CFR as hallucinogens:

1. 4-bromo-2,5-dimethoxyamphetamine (DOB) 2. 2,5-dimethoxyamphetamine (DMA) 3. 4-methoxyamphetamine (PMA) 4. 5-methoxy-3,4-methylenedioxyamphetamine (MMDA) 5. 4-methyl-2,5-dimethoxyamphetamine (DOM, STP) 6. (MDA) 7. 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) 8. 3,4,5-trimethoxyamphetamine (TMA) 9. 2-(3,4,5-trimethoxyphenyl)ethylamine (mescaline)

The majority of the hallucinogenic phenylethylamines which are presently controlled under U. S. law were first encountered in a relatively short period of time in the latter part of 1960. Since that time the emergence of new CsA's of psychotogenic phenylethylamines has continued but at a much reduced pace. Starting in 1972, several samples of MDMA were analyzed by DEA laboratories. Apparently MDMA was readily accepted by the user and abuse has continued to increase. Presently in the U. S. and Canada there are at least four other CsA's of psychotogenic phenylethylamines in the illicit market. These are N-hydroxy-3,4-methylenedioxyamphetamine (N-hydroxy MDA), N-ethyl MDA (EVE, MDEA), 4-ethoxy-2,5-dimethoxyamphetamine (MEM) (Avdovich et al. 1987), and 4-bromo-2,5-dimethoxyphenylethylamine (DBMPEA) (Sapienza, E personal communication; Allen, A. personal communication). Upon placing MDMA under legal controls, the N-ethyl homolog of MDA (EVE) was immediately introduced as a replacement for MDMA. However, it seems that EVE has not been well accepted by the user, apparently because EVE has a lower potency than MDMA; therefore requiring a larger dose to produce psychotropic effects and often resulting in making the user ill (Jordan 1986).

Assuming the ready availability of the appropriate chemical precursors, and assuming a lack of concern for the legal provisions enacted by governments for the purpose of controlling CsA's, choices for CsA's of ring substituted phenylethylamine psychotogens are numerous. Previously cited literature provides many such CsA possibilities with at least ten aromatic ring substituted amphetamines (compounds numbered 5-15, Figure 4) having potencies greater than mescaline (compound 5). Other CsA's can be obtained from compounds 6 through 15 by modification of the [alpha]-alkyl side chain to either C-2 or C-3 alkyls, and mono-substitution or the nitrogen with either hydroxy or short chain alkyl. These modifications result in a total Of 160 possible CsA's based only upon the ring substitutions of the aforementioned compounds. Additionally, tile ring substituted phenylisopropylamines which are presently controlled substances, can be modified in the same manner, and after excluding controlled substances and N-hydroxy MDA, there are 118 more possible derivatives, giving a total of 278 possible new CsA's. Each time a new ring substitution is introduced, such as MEM, then this number is increased by 16.

If the U. S. CsA amendment is a consideration, then psychotomimetic phenylethylamines could be created from compounds which are structurally related to dopamine, adrenaline (N-methyl-3,4-di-hydroxyphenyl-[beta]-hydroxyethylamine), and norepinephrine (3,4-di-hydroxyphenyl-[beta]-hydroxyethylamine). A case in point is the compound macromerine, N,N-dimethyl-3,4-dimethoxyphenyl-[beta]-hydroxyethylamine, a known psychotogen (Hodgkins et al. 1967). Some other compounds which could be used as CsA models are synephrine (N-methyl-4,[beta]-dihydroxyphenylethylamine), phentermine ([alpha],-[alpha]-dimethylphenylethylamine), 4-chlorophentermine, mephentermine (N,[alpha],[alpha]-trimethylphenylethylamine), phenelzine (phenylethylhydrazine), and tranylcypromine (2-phenylcyclopropylamine). Structural modifications of these compounds could provide quite a few additional CsA's. Because of the sheer size of the task, no attempt was made to determine the total number of possible CsA's that could be derived by using these compounds as models. How ever, the magnitude of the possibilities become evident when one calculates tile possible CsA's which, could be obtained using just dopamine (compound 16, Figure 5) as the model compound, as is demonstrated in the following paragraph.

The total number of possible CsA's were limited by the following considerations:

1. ring substitution at C-3,4 is dimethoxy 2. ring substitution to sites C-2,5,6 were limited to combinations of CH3-, Br-, Cl-, and

CH3-, 3. substitution on the amine nitrogen and the alpha carbon were limited to the

following:

1. of the three ring sites available for substitution, no more than two were allowed for any given structure

2. single substitution on the ring at C-2 to give 2,3,4-trisubstituted derivatives was disallowed

3. mixed halide structures were excluded 4. ring substitutions which would result in any derivative which is presently a

controlled substance were disallowed.

Given these considerations there are 47 structures which can be drawn. Each one of these can then exist as 16 derivatives obtained by substitution as shown above at the alpha carbon and nitrogen. The multiplication product of these two values provides the total number of possible hallucinogenic CsA's (752) which, one could argue, are structurally related to dopamine.

Research targeted at the determination of structure-psychotropic activity relationships has waned in recent years. Perhaps in future years it will be the clandestine chemist who will fill in the blanks.

Phencyclidine

The synthesis of phencyclidine (PCP) was first reported in 1958 (Chen 1958) and patent rights were granted to Parke, Davis & Co. in 1960 and 1963 for medical use as an anesthetic (Parke, Davis & Co. 1960; 1963). PCP first came to the attention of DEA, then the Bureau of Narcotics and Dangerous Drugs, as a drug of abuse in the latter part of the 1960's. Pharmacologically, PCP has been described as a pseudo hallucinogen which has many of the characteristics of a depressant drug (McGlothlin 1971). Without question, PCP deserves a special niche in any discussion of drugs of abuse if for no other reason than the notoriously bizarre effects it has been known to have upon some of the abusing population (Peterson and Stillman 1978).

The now so very familiar synthesis using 1-(1-piperidyl)cyclo-hexyl carbonitrile and phenyl Grignard reagent was published by Maddox et al. in 1965 and, either fortunately or unfortunately depending upon one's point of view, the accompanying pharmacological data was useless as it could not be correlated to the compounds synthesized (Maddox et al. 1965). However, pertinent literature is not hard to find as both the original U. S. patent (Godefroi et al. 1963) and later studies have provided a pharmacological basis for the production of CsA's of PCP (Kalir and Pelah 1967; Kalir et al. 1969).

It does not appear to be possible for one to generate a CsA model structure that will not fail under the CsA amendment provision which stipulates that the term "controlled substance analogue" means a substance-the chemical structure of which is substantially similar to the chemical structure of, in this case, PCP. This is the result of the fact that a one carbon separation between an aryl system and the amine nitrogen, and the fact that the central carbon between these moieties is in a ring system appear to be principal requirements for PCP-like pharmacological activity. Other activity structure relationships are:

1. substituents which decrease lipophilic character generally decrease potency 2. aryl substitution with 2-thienyl generally increases potency 3. substitutions onto the aryl system decreases potency 4. to maintain potency N,N-dialkyl substitutions should be either piperidino or

pyrrolidino ring systems 5. N-ethyl is the most potent N-alkyl monosubstitution and potency falls off rapidly with

either an increase or decrease in the alkyl chain size

6. substitution on the beta carbon of either the cycloalkyl or the cycloalkylamino rings will most likely be synthetically difficult due to steric considerations.

Because of factors noted above, there appears to be a relatively small probability of a PCP CsA appearing in the illicit marketplace that will not fall under the purview of the U. S. CsA amendment. However, it is also the case that under U. S. law there is a reporting requirement placed upon the purveyors of piperidine. Since the implementation of the piperidine reporting requirement it has become much more difficult for the clandestine chemist to safely acquire this chemical precursor of PCP. Therefore, a market force has been introduced that will almost certainly result in the production of PCP CsA's which will not contain a simple piperidino moiety. This thought, taken with the previously discussed activity-structure relationships, allows one to suggest the 50 structures depicted in Figure 6 as being representative of future CsA's of PCP. Of these 50 compounds, two have already been placedin the CFR Schedule I: N,N-(1-phenylcyclohexyl)-ethylamine and N-(1-phenylcyclohexyl)-pyrrolidine.

Stimulants

Relative to medical usage, a stimulant is defined to be an agent that arouses organic activity, strengthens the action of the heart, increases vitality, and promotes a sense of well being. However, as per the medical definition, the effects produced by a stimulant may not be a very accurate term for the effects sought by those who abuse these compounds. For instance, at dose levels usually equated with heavy abuse, both amphetamine (Hampton 1961; Angrist et al. 1969) and methamphetamine (Liddel and Weil-Malherbe 1953) are thought to be psychotogenic. Therefore, several of the amphetamines could be discussed as hallucinogens; however, it seems most likely that a substantial portion of the abuse of stimulant drugs is performed with the intention of inducing a state of euphoria (Brown 1972). Historically, the abuse of stimulants (euphoriants) has been largely confined to amphetamine, derivatives thereof, and cocaine. Some of the amphetamine derivatives which have been controlled under U. S. law are methamphetamine, N-ethylamphetamine, fenethylline, phenmetrazine (preludin), phendimetrazine, benzphetamine, chlorphentermine, clortermine, diethylpropion, methylphenidate, pemoline, and amphetamine. Other derivatives of amphetamine which have been encountered in samples submitted to DEA laboratories, but have not yet been brought under legal controls, are bis-methamphetamine (compound 18, Figure 7), fencamfamine (compound 19, Figure 7) (Nied and Smith 1982), N,N-dimethylamphetamine (dimephenopan; compound 20, Figure 7) (Allen, A. personal communication), and an analog of pemoline, 4-methylaminorex (U4EUH) (compound 21, Figure 7) (Inaba and Brewer 1987). Since pemoline is listed under Schedule IV of the CFR and 4-methylaminorex is clearly an analog Of pemoline, it falls outside of the guide-lines set forth in the CsA amendment; therefore, 4-methylaminorex is not controlled under U. S. law. It is equally clear that bis-methamphetamine and N,N-dimethylamphetamine do fall under the CsA guidelines and would be considered controlled substances under tile CsA amendment. However, it may be that N,N-dimethylamphetamine may not enjoy a long history in the clandestine market as at least one work states that it is considerably less potent than methamphetamine (Schaeffer et al. 1975).

Most of the adrenomimetic activity-structure relationships were delineated in the previous discussion on psychotomimetic phenylethylamines. The principle difference between the pharmacological action, as related to structure for these two classes of compounds, is determined- by the nature of the substituents on the aryl system. In general it is noted that substituents on the aryl system which are orthopara directors tend to produce psychotogenic compounds with methoxy substituents often producing the most pharmacologically active hallucinogens. However, there are several exceptions to this general statement, not the least of which is exemplified by substitution on the phenyl ring of

the electrophilic hydroxy moiety which in nearly every case either eliminates or greatly reduces hallucinogenic activity. On the other hand, adrenomimetic activity is clearly enhanced by branching of phenylethylamine at the carbon alpha to the amine nitrogen and is maintained at reasonable levels by substitution to the nitrogen as shown in table II. Both N-ethylamphetamine and N,N-dimethylamphetamine have appeared in the illicit market and clearly follow the points made above. However, a market factor has been introduced by the fact that phenyl-2-propanone (P2P) has been listed under the CFR as a Schedule II substance. Hence, it makes little sense for the clandestine chemist to produce CsA's of phenylethylamines which have potencies that are less than methamphetamine if he is going to produce his CsA's in a synthesis that uses P2P. The recent illicit use of 4-methylaminorex may well be the result of the clandestine chemist trying to circumvent the legal problems associated with P2P. On the other hand, the sum total of methamphetamine still being covertly produced suggests that the control of P2P has not appreciably reduced the drug's availability in the illicit marketplace.

As before, if the chemist is not concerned about the CsA amendment, the structural possibilities offered by Table II, less the three controlled substances that are included, provides for thirteen possible future stimulant CsA's. It would seem that the single most logical next stimulant CsA would be N-methyl-[alpha]-ethylphenylethylamine. This compound should be pharmacologically very similar to methamphetamine and synthesis could employ 1-phenyl-2-butanone instead of P2P. Alternatively, the use of 1-(4-fluorophenyl)propan-2-one, in place of P2P, would almost certainly give a product with adrenomimetic properties, and may in fact be considerably more potent than methamphetamine.

The clandestine chemist of limited chemical sophistication may not notice the structural similarity of such compounds as methylphenidate (compound 22, Figure 8), phenmetrazine (compound 23, Figure 8), 4-methylaminorex (compound 21), and amphetamine (compound 24, Figure 8). If he does recognize the constancy of the phenylisopropylamine substructure in these compounds he may well explore the literature in an effort to determine the structural outer limits for the phenylisopropylamine stimulants. At what may be near these structural outer limits he will find a class of compounds which are correctly referred to as conformationally rigid phenylethylamines. Some of the conformationally rigid phenylethylamines are fencamfamine (compound 19), tranylcypromine (2-phenylcyclopropylamine) (compound 5, Figure 9), 2-phenyl-cyclohexylamine (compound 26, Figure 9) (Smissman and Pazdernik 1973), 2-amino-3- phenyl-trans-decalin (compound 27, Figure 9), and 2-aminotetralin (compound 28, Figure 9) (Barfknecht et al. 1973). The potency of most of these compounds is highly dependent upon stereochemistry. Those isomeric forms which most closely approximate the anti periplanar conformation observed for amphetamine in solution are the most potent stimulants. Hence, transtranylcypromine is considerably more potent than is the cis isomer (Grunewald et al. 1976). The most active isomer of these compounds does not approach the potency of the simple phenylisopropylamines. Given this reduction in potency for the most active isomers one would think that, in order to obtain amiable product for the illicit market, a stereo specific synthesis would be required. This feature, along with a lowered potency for even the more active isomers, may very well exclude the conformationally rigid phenylethylamines from the synthetic repertoire of the surreptitious chemist. Hence, it is a reasonable expectation that those conformationally rigid phenylethylamines which will be abused in the future will be obtained by diversion of limit supplies rather than by clandestine syntheses.

Unfortunately, it seems to be an axiom that any compound which has any possibility of altering man's perception of himself or his surroundings will at some time be abused. Propylhexadrine, although not an extreme example, is nevertheless an example of a compound which has been abused although adrenogenic potency is far less than that of methamphetamine (Garriott 1975). Therefore, one must expect some abuse of the

conformationally rigid phenylethylamines to occur. It would be my guess however, that the extent of such abuse will never be large.

The parent structure for 4-methylaminorex has been known since 1889 (Gabriel 1889) and many derivatives thereof have been studied for pharmacological activity. Pemoline (2-amino-5-phenyl-2-oxazolin-4-one) (Traube and Ascher 1913; Howell et al. 192) is presently a controlled substance in the U. S., is classified as a stimulant, and is listed under Schedule IV of the CFR. Poos (personal communication) synthesized and performend pharmacological studies for some twenty seven 2-amino-2-oxazoline isomers of which aminorex and 4-methylaminorex were two. In this work, aminorex and 4-methylaminorex, regardless of the steroisomer employed, were found to have anorectic activity on par with d-amphetamine. However, adrenomimetic activity of 4-methylaminorex was determined to be less than that of amphetamine and similar to phenmetrazine (Patil and Yamauchi 1970). It has been suggested that the effectiveness of stimulant drugs as appetite suppressants are the result of the fact that the user forgets to eat and that this behavior is in direct proportion to the adrenomimetic activity of the drug (Cutting 1969). Contrary to previously cited work this suggests that aminorex may in fact be as potent an adrenomimetic as amphetamine. In any case, Poos (personal communication) highlighted eight compounds which may have adrenomimetic activity similar to those of amphetamine and methamphetamine. Shown in Figure 10 and listed in decreasing order of anoretic activity they are compounds:

29) 2-amino-5-(4-fluorophenyl)-2-oxazoline

30) 2-amino-5-(4-Chlorophenyl)-2-oxazoline

31) 2-amino-5-(3-trifluoromethylphenyl)-2-oxazoline

32) 2-amino-5-(4-bromophenyl)-2-oxazoline

33) 2-amino-5-phenyl)-2-oxazoline [aminorex]

34) 2-amino-5-(4-trifluoromethylphenyl)-2-oxazoline

35) 2-dimethylamino-4-methyl)-5-phenyl-2-oxazoline

36) 2-amino-4-methyl-5-phenyl-2-oxazoline [4-methylaminorex]

Although not mentioned in this work, one would immediately assume that the 4-fluoro- and 4-chloro- phenyl derivatives of compounds 35 and 36 would also have significant anoretic activity.

Given the astoundingly simple synthetic process required to produce these compounds, and the fact that the 4-halogen substituted aryl derivatives would require precursors unlikely to titillate the interest of law enforcement agencies, these compounds will most probably be made in future clandestine syntheses. It is also conceivable that some enterprising clandestine chemist will wonder if appropriately substituted methoxy derivatives will have psychotomimetic properties.

The literature contain many references to stimulant drugs of variant structures which may not spark the interest of the less knowledgeable clandestine chemist. However, nearly all of these compounds can be accessed through literature searches for either derivatives of phenylethlamines or stimulant compounds. Several compounds which serve as examples are fenmetramid (Ippen 1968), prolintane, 1-([alpha]-propylphenylethyl) pyrrolidine

(Heinzelman et al. 1960; Hollister and Gillespie 1970), pyrovalerone (1-(4-methylphenyl)-1-oxo-2-pyrrolidino-n-pentane) (Heinemann and Vetter 1965; Heinemann and Lukacs 1965), N,3,3-trimethyl-1-(m-tolyl)-1-phthalanpropylamine (compound 37, Figure 11)(Gill et al. 1970), zylofuramine ([alpha]-benzyl-n-ethyltetrahydro-D-threo-furfurylamine) (Harris et al. 1963), a series of N-substituted phentermine compounds (Borella et al. 1970), 4-hydroxyamphetamine (Mannich and Jacobsohn 1910; Hoover and Hass 1947a,b), N-methylephedrine (Smith 1927), nylidrin, N-(1-methyl-3-phenylpropyl)-2-hydroxy-2-(4-hydroxyphenyl-l-methyl-ethylamine (Treptow et al. 1963), pheniprazine, [alpha]-methyl-phenylethyl hydrazine (Zbinden et al. 1960), and N,N-diethyl-2-phenylcyclopropylamine (SKF). All of these compounds are derivatives of phenylethylamine with the exception of compound 37 which is a 3-phenyl-3-propylamine substituted onto a phthalane at C-1. A number of closely allied derivatives of this compound have been examined and are classified as weak stimulants.

Fenmetramide is noteworthy in that it is a 2-one derivative of phenmetrazine. Any and all of these compounds are subject to abuse; however, the synthesis of simple phenylethylamine derivatives would not appear to offer the clandestine chemist any advantage over the synthesis of methamphetamine. The reasons for this statement are that pharmacological studies have not identified other phenylethylamine structures with stimulant activity appreciably greater than methamphetamine and that either P2P or the [beta]-hydroxyphenylisopropylamines are the preferred precursors. However, in any case, the U. S. CsA amendment should apply for all compounds containing the phenylethylamine substructure.

The stimulant drugs phenmetrazine (preludin; compound 23) and methylphenidate (ritalin; compound 22) are controlled under Schedule II of the CFR. These compounds rank approximately half-way between caffeine and amphetamine in potency (Meier et al. 1954; Tripod et al. 1954a; Gruber et al. 1956). The published synthesis of phenmetrazine, which would seem to be most amenable to the clandestine laboratory, is given in the work by Otto (Otto 1956). The reaction involves the acid-catalyzed cyclization of N-hydroxyethylnorephedrine (N-hydroxyethylphenylpropanolamine). However, this reaction places severe limits on the production of CsA's because suitable precursors are limited. For instance, phenmetrazine CsA could be prepared from compounds such as N-ethyl-2,2-hydroxyphenyl-1-methylethylamine, 1,1-hydroxyphenyl-2-aminobutane, etc, but limited commercial availability would generally require synthesis of these compounds. Additionally, the product CsA would clearly be perceived, even by the untrained, as being structurally similar to phenmetrazine and thereby would be a controlled substance under the CsA amendment. Further, the corresponding phenylethylamine which could be made from these precursors, although also under the purview of the CsA amendment, would most probably have greater adrenergic activity than the phenmetrazine derivative. Hence, clandestine production of phenmetrazine CsA's would most likely be an uncommon event.

Pipradrol (compound 38, Figure 12) is a controlled substance under CFR Schedule IV and can be considered to be an analog derivative of methylphenidate. Methylphenidate can be synthesized by the method of Hartmann and Panizzon (1950). The product exists as two diastereoisomeric enantiomer pairs, one of which is the active stimulant, threo-dl-methylphenidate (Weisz and Dudas 1960), while the other is inactive as a stimulant. Threo-methylphenidate accounts for only 20% of the final reaction product (Rometsch 1958;1960). The synthesis of pipradrol may be more amenable to the clandestine laboratory as it is a relatively simple synthesis and isolation of the final product is straightforward. An appropriate C-2 substituted, N-protected piperidine is a suitable precursor for what is essentially a two step synthesis (Tilford et al. 1948; Werner and Tilford 1953). Numerous derivatives of methylphenidate and pipradrol have been synthesized with the result that structure activity relationships have been well defined (Scholz and Panizzon 1954; Tilford and Van Campen 1954; Heer et al. 1955; Fabing 1955; McCarty et al. 1957; Sheppard et al.

1960; Belleau 1960; Winthrop and Humber 1961; Portoghese and Malspeis 1961; Wilimowski 1962; Lachman and Malspeis 1962). There is little incentive, beyond the not inconsiderable pressure of an already existing and ready market, for producing clandestine CsA's of methylphenidate. However, there are a number of pipradrol derivatives described in the last cited references which are suitable for clandestine production. A best bet for a future CsA is the most potent adrenomimetic compound in this series, 2-diphenylmethylpiperidine (compound 39, Figure 12) (Tripod et al. 1954b), which is estimated to be as potent as methamphetamine (Sury and Hoffmann 1954). In a very similar article to this paper, "Drugs of Abuse in the Future," Shulgin (1975) suggested that levophacetoperane (compound 40, Figure 12) could well be a future clandestine CsA. However, this compound shares the same limitations for clandestine synthesis as does methylphenidate, in that only one diastereoisomer is active (Jacob and Joseph 1960) and it is less potent than methylphenidate (Dobkin 1960).

Although the phenylisopropylamine substructure is an integral part of most known stimulants, the well known and much abused stimulant, cocaine, does not share this structural feature. The cocaine molecule instead compares more closely to the structure of atropine. The synthesis of cocaine has recently been revisited by Casale and many of the procedural techniques are explained in sufficient detail so that any competent organic chemist can now make the C-3 equatorial cocaines (Casale 1987); however, it is still a tedious and demanding synthesis, and in my opinion will only be encountered on rare occasions in clandestine laboratories. The particular pharmacological behavior of cocaine is unquestionably due in major part to the stereochemistry of the molecule as determined by the fused bicyclic tropane ring system (Clarke et al. 1973). Given the present difficulties associated with the synthesis of the tropanes and the ready availability of the natural product, it is unlikely that a synthetic CsA of this compound will appear in the near future. However, it is the case that certain modifications of natural cocaine can result in products having substantially greater potencies than cocaine. The compounds 2-carbomethoxy-3-(4-fluorophenyl)tropane and 2-carbomethoxy-3-phenylnortropane are both some 60 times more potent than cocaine (Clarke et al. 1973). These compounds could well be of interest to some clandestine chemists as taking one kilogram or cocaine and converting it into a product some sixty times more potent would obviously be quite cost effective.

In "Drugs of Abuse in the Future," Shulgin (1975) directed attention to another stimulant which also does not contain the phenylethylamine substructure and, in fact, is reminiscent of the depressant glutethimide. The compound is known commercially as bemegride, 4-ethyl-4-methylpiperidine-2,6-dione, and was first synthesized by Thole and Thorpe in 1911 (Thole and Thorpe 1911). The principal medical use is as an analeptic in barbiturate poisoning. As a stimulant, bemegride is approximately equal to phendimetrazine and pemoline in potency. Although glutethimide and bemegride are structurally similar, their pharmacokinetics are diametrically opposed. Hence, bemegride cannot be described as a CsA. Bemegride, by virtue of being a stimulant, has an obvious potential for abuse, although under the conditions of abuse, rather large quantities of the drug will be required. Increasing the possibility of bemegride abuse are the facts that the synthesis of the compound is not difficult and, of course, does not use either a controlled or watched substance as a precursor (Benica and Wilson 1950).

Sedatives-Depressants

Depressants include such diverse chemical entities as methaqualone, 5,5-disubstituted barbituric acids, glutethimide and methyprylon, benzodiazepines, chlorhexadol, chloral hydrate, paraldehyde, meprobamate, and ethyl alcohol to name a few. Historically in the U. S., the abuse of depressants, alcohol aside, has been in major part confined to the barbiturates, methaqualone, and the benzodiazepines. Barbiturate abuse peaked in the mid

1970's and has since become near nonexistent, in part no doubt, to the well deserved bad press that the barbiturates garnered. The abuse of methaqualone peaked around 1980 and has also declined steadily since that time. However, much counterfeit "lude" is still being sold, but instead of containing methaqualone, the tablets now often contain diazepam. Diazepam has become the most prevalent depressant drug of abuse and its use is apparently continuing to rise. It is somewhat peculiar that of the many benzodiazepines known and readily available in the legal commercial market, diazepam is by far the most extensively abused. The factors controlling this apparent user preference for diazepam is certainly related, in part, to simple product recognition; however, it is my perception that the dominant factor is the ease with which the drug can be diverted from the legitimate market. In 1985 the legitimate diazepam market consisted of 5 billion tablets (Franzosa 1985) and since that time generic diazepam tablet production has increased along with even greater product availability for diversion into the illicit market (Franzosa, E. personal communication).

A typical benzodiazepine synthesis is not be considered difficult and a methaqualone synthesis is quite straightforward (Grimmel et al. 1946). Further, there is a great abundance of literature from which the clandestine chemist can draw in deciding upon a CsA based upon either the benzodiazepines or methaqualone itself. However, with the very notable exception of methaqualone, the clandestine syntheses of depressant drugs in the U. S. have been extremely rare (Franzosa, E. personal communication). It is not likely that a clandestinely synthesized benzodiazepine CsA will be encountered as long as the huge, easily diverted legitimate supplies are at hand.

The use of methaqualone (compound 41, Figure 13) is in decline, but it will be with us as an abused substance for still some time. Given the very large numbers associated with the clandestine synthesis of methaqualone, it is perhaps surprising that only two CsA's of methaqualone (compounds 42 and 43, Figure 13) have been analyzed at this laboratory. Again, past history would suggest a high probability for the appearance of new CsA of methaqualone in the future. A CsA of methaqualone will by necessity have the 3-aryl-quinazoline structure, and as a result will fall under the CsA amendment. One would shell predict that the driving force behind any future clandestine synthesis of a methaqualone CsA will revolve around attempts to use precursor materials which will not alert law enforcement to the existence of the clandestine laboratory. A literature review for CsA candidates will quickly surface several possibilities (Boissier and Piccard 1960; Camillo and David 1960; Jackman et al. 1960; Petersen et al. 1963; Boehringer Sohn 1968a,b; Sumitomo Chemical Company 1968; Hurmer and Vernin 1968; Joshi and Singh 1973; 1974). One of the most intriguing methaqualone CsA's from the perspective of a clandestine chemist would have to be the halo- and thio- derivatives described by Joshi et al. (1975). Two of the compounds from this work (compound 44 and 45, Figure 13) possess depressant activity greater than methaqualone and compound 44 would be particularly well suited to clandestine synthesis.

Analgesics

Literature covering the analgesics is so voluminous that a review of the published data on the subject is far beyond the scope of this work. Most of the potent analgesics are modeled after features found within the structure of morphine and some literature detailing these structural features has been published by Paul Janssen (Janssen 1960; 1961; 1962a,b; 1968). Despite a significant passage of time, the structure activity relationships established in these works still comprise a very sizable portion of our empirical knowledge on this subject.

Some 13 years ago, Shulgin (1975) provided a short overview of many of the known major classes of analgesics. The following constitutes a similar listing:

1. morphines 2. morphinans and isomorphinans 3. benzomorphans 4. pethidines (meperidines), prodines, and ketobemidones 5. fentanyls 6. 3,3-diphenylpropylamines (methadone, propoxyphene) 7. thiambutenes 8. phenampromideandl-dialkylaminoethyl-2-(4-alkyl-oxy)benzyl-5-nitrobenzimidazols 9. pirinitramide derivatives

Numerous works have dealt with the syntheses and pharmacological testing of derivatives of the structures listed above. Synthetic procedures have been improved and refinements aimed at the tailoring of specific analgesics to fulfill certain medical needs have been addressed. However, it has been since 1975 that no work has been found introducing a new class of analgesics of either unusual potency or particularly well suited to synthesis in clandestine laboratories. There has been discovered one compound which may be of minor interest in that it is an analgesic with potency similar to morphine and can be described as a ring condensation product of N,N',3-trimethyl-5-hydroxytryptamine (compound 46, Figure 14) (Brossi 1985). In any discussion of synthetic anlagesics one must include the so called Bentley compounds. These compounds are not, in the purest sense, synthetic analgesics as they are C-ring etheno Diels Alder adducts of thebaine (Bentley et al. 1967a). Etorphine (compound 47, Figure 14) is perhaps the best known compound in the series and has analgesic activity approximately 1000 times that of morphine (Bentley et al. 1967b; Hutchins et al. 1981). Although reaction conditions appear to be critical, the synthesis of etorphine derivatives involves what is essentially a two step reaction with methylvinylketone and an appropriate organometallic reagent (Haddlesey et al. 1972; Hoogsteen and Hirshfield 1983). Hence, the only expected difficulty in the clandestine synthesis of these compounds would lie in the initial acquisition of the thebaine. Therefore, it is somewhat surprising that either etorphine or derivatives thereof have not become a contributor to illicit analgesic supplies. On the other hand, if etorphine were to be admixed with some less potent analgesic, such as heroin, it is doubtful that it would ever be detected.

In his 1975 article, Shulgin pointed to meperidine, prodine, and ketobemidone as possible models for "Drugs of Abuse in the Future." There are some who think that Shulgin's comments were somewhat of a self fulfilling prophecy as it is felt that his article is well worn within the circles of clandestine laboratory operators (Sapienza, F. personal communication). Supporting this premise, at least to some extent, is the fact that the appearance of the first known fentanyl, China White, did not occur until 1979 (Henderson, G. 1.. personal communication). However, it is also the case that desmethylprodine (MPPP; compound 48, Figure 15) was first encountered in a DEA laboratory sample submission in July of 1973 (Kram, T. personal communication), a full two years before Shulgin published his article.

The probability that CsA's of prodine will constitute any appreciable quantity of the clandestine analgesic market in the future is relatively remote. The well publicized neuro-toxicity of the prodine dehydration product, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Langston et at. 1983; Markey et al. 1985; Fries et al. 1986; Parkes 1986), coupled with a limited scope of derivatives having appreciable analgesic activity (Berger et al. 1947; Ziering and Lee 1947; Beckett et al. 1957; Loew and Jester 1975) would seem to remove prodine from consideration as a model for CsA's. The fact that the 3-allyl analog of MPTP is not thought to be neurotoxic (Brossi 1985) and the corresponding prodine analog has greater analgesic activity than does betaprodine (Ziering et al. 1957) may be of some interest to the clandestine laboratory operator. However, allylprodine (compound 49, Figure 15) is already controlled under Schedule 1. A prodine derivative which may be found in a future clandestine laboratory is [alpha]-promedol, (Fries and Portoghese 1976). Analgesic activity for the unresolved stereoisomers of promedol is approximately ten times that of

morphine, but there is some increased difficulty associated with the synthesis and neurotoxicity for it's MPTP analog is a real possibility. It is also the case that [alpha]-promedol is listed in CFR Schedule I under the name of trimeperidine.

In any event, the syntheses of prodine CsA's are fraught with considerable risk from the inadvertent production of either MPTP or an as yet unexplored congener also having neurotoxic properties. It is worth noting that at one time MPTP was tested for use as an insecticide and that there are reports of workers handling MPTP who have suffered full blown Parkinsonian symptoms (Shafer, J. personal communication).

Meperidine (pethidine, demerol; compound 50, Figure 16) is approximately 50% as potent an analgesic as is morphine and has a safety margin of only 4.8 as compared to 71 for morphine (Janssen 1985) Hence, one would assume that the continued abuse of meperidine is most probably related to the ease with which it can be diverted from commercial channels rather than it's applicability to drug abuse per se. It has been noted that there are some 4000 compounds which may be related chemically to meperidine (Burger 1970). It should be pointed out that of these 4000 compounds, many are not classified as analgesics, and they must also include the closely allied prodine and ketobemidone derivatives. The most potent analgesics of the meperidine class of compounds, as is the case with the prodine class of compounds, all appear to already be controlled under Schedule I and the less potent but clinically useful derivatives controlled under Schedule II. The most interesting compound from the view point of clandestine synthesis would have to be phenoperidine (compound 51, Figure 16) as analgesic activity is approximately 30 times that of morphine and the safety margin is increased, relative to meperidine, quite substantially (Janssen 1985). Fentanyl (compound 52, Figure 17) is an analgesic of high potency, approximately 300 times that of morphine, which was developed by Janssen in 1962 (Janssen 1962b) and is N-[(2-phenylethyl)-4-piperidyl]-N-phenyl-propanamide. The first CsA of fentanyl came to the attention of law enforcement in late 1979 but was not identified until 1981 (Allen et al. 1981). In the next three years a procession of new fentanyl CsA's appeared in the illicit drug market. The abuse of fentanyl CsA's peaked in 1985 and has since decreased dramatically (Henderson 1987), a phenomena which was the result of DEA successfully terminating the operation of the responsible laboratories. However, the ripple effect is still being felt as international and national meetings have been held to discuss the problems presented by CsA's. Also, legislation, such as the U. S. CsA amendment, has been passed in order to allow law enforcement to deal more efficiently with the analog problem.

It is the author's opinion that fentanyl CsA's will be back as the future analgesic drugs of abuse. The thoughts behind this statement are that the published synthesis schemes for the fentanyl compounds allow for the use of wide variety of precursors as discovered by the confiscated notes from an anonymous clandestine laboratory that synthesized a drug, based on information presented in two separate volumes of the Journal of Organic Chemistry (Anon. 1957; Janssen 1962a; Riley et al. 1973; Van Bever et at. 1974; Van Daele et al. 1976). Also, several fentanyl derivatives have such high potencies that the quantities required to be synthesized are trivial. For instance, carfentanil (compound 53, Figure 17) is approximately 400 times as potent as heroin and has an extremely favorable therapeutic index (Janssen 1985). Hence, an easy week's work for two chemists could provide 10 kilograms of carfentanil which would be equivalent to 40 metric tons of pure heroin.

Conclusion

In the course of this article, several points have been made concerning those forces which will control the appearance of future synthetic drugs of abuse. The most important of these factors is user acceptance of the marketed drug. Needless to say, the typical clandestine drug dealer and/or chemist is not overly concerned with the health of the user. However,

they are concerned with having a ready market for their product. A reputation for selling "bad stuff" would not be conducive to good business. A recent example of this can be found in MPPP.

The second most important market controlling factor is law enforcement control of the industry. A recent example would be the effects produced when P2P was placed under legal controls. The response so far has been two fold; first there has been a concerted move to either more fundamental precursors or to synthetic routes utilizing [beta]-hydroxyphenylethylamines, and second, there has been an apparent increase in the abuse of 4-methylaminorex. Hence, the methamphetamine market is in a state of flux as a direct result of law enforcement activity and either a CsA will be found which will provide both the user and the clandestine drug chemist with the same advantages as methamphetamine or a new precursor synthesis scheme will be found which will offer nearly the same advantages as P2P. It is axiomatic that for drugs of moderate potency and high consumer demand, such as methamphetamine, a synthesis scheme must be relatively straightforward as it must be amenable to the limited expertise available in the clandestine laboratories in order to meet consumer demand.

In this work, only an occasional attempt was made to address the difficulties associated with the practical synthesis of the various derivatives discussed. Some of the compounds discussed do not have conveniently configured precursors that are commercially available. Hence, synthesis of some of these compounds require using the precursors earth, fire, and water. Additionally, as the number and complexity of substitution on any given chemical structure increases, there is a corresponding increase in the number of byproducts and a decrease in the ultimate yield of target compound. In total then, some of the compounds mentioned in this work are not practical, especially considering the clandestine laboratory, given the present state of synthetic knowledge. However, as time moves on, more efficient and direct methods of synthesis will be found and made available to the informed reader through the scientific literature. This point is easily exemplified even by the work of our own forensic scientists (Sy and By 1984; Casale 1987). The clandestine chemist of the future will be more sophisticated than those of the present and compounds not yet conceived of will be within their reach.

Consumer preferences and law enforcement activities are the two dominate forces affecting today's illicit drug markets. While staying within the confines of consumer demand, the clandestine chemist of the future will synthesize those drugs having the highest possible potency in an effort to limit his exposure to law enforcement activities and to expand his illicit business as well.

Acknowledgement: The author wishes to express his appreciation for the invaluable assistance of Dr. Robert Klein, Ann Wimmers, and Charles Harper in the preparation of this article.

Definitions

ANALGESIC: 1) causing analgesia or freedom from pain. 2) a pain relieving remedy.

ANALOG: Compound with similar electronic structure but different atoms.

CONTROLLED SUBSTANCES: are those drug substances which are listed as of January 1, 1988 under schedules I through V of the United States Title 21 Code of Federal Regulations (CFR) section 1300 to end.

DERIVATIVE: An organic compound containing a structural radical similar to that from which it is derived, for example, benzene derivatives containing the benzene ring.

HOMOLOG: Member of a series of compounds whose structure differs regularly by some radical, for example, methylene, from that of its adjacent neighbors in the series.

SCHEDULE I: Schedule I is a listing of those substances which are controlled under U. S. federal laws, are deemed to have a high potential for abuse, and for which there is no accepted medical use.

SCHEDULE II: Schedule II is a listing of those substances which are controlled under U. S. federal laws, are deemed to have a high potential for abuse, and for which there is a accepted medical use.

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Opium - Poppy Cultivation, Morphine and Heroin Manufacture

First of all, it seems like the information about opium cultivation and preparation and other chemistry came from a 1993 Department of Justice publication that was sponsored by DEA.

That booklet is, I understand, out-of-print, and will not be reprinted. It is an amazing document because it essentially tells you all you really need to know about opium poppies, opium, and the basic procedures for extraction and conversion of morphine to heroin.

I can also tell you that a USDA scientist named Mary Acock, was involved in the larger project that produced the book. It's my opinion that, had any of those government dudes thought about it for more than a few minutes, they never would have published it in the first place. It is simply too full of "dangerous" information. - Jim Hogshire

Opium is the name for the latex produced within the seed pods of the opium poppy, Papaver somniferum. The plant is believed to have evolved from a wild strain, Papaver setigerum, which grows in coastal areas of the Mediterranean Sea. Through centuries of cultivation and breeding for opium, the species somniferum evolved. Today, P. somniferum is the only species of Papaver used to produce opium. Opium contains morphine, codeine, noscapine, papaverine, and thebaine. All but thebaine are used clinically as analgesics to reduce pain without a loss of consciousness. Thebaine is without analgesic effect but is of great pharmaceutical value due to its use in the production of semisynthetic opioid morphine analogues such as oxycodone (Percodan), dihydromorphenone (Dilaudid), and hydrocodone (Vicodin).

The psychological effects of opium may have been known to the ancient Sumerians (circa 4,000 B.C.) whose symbol for poppy was hul, "joy" and gil, "plant". The plant was known in Europe at least 4,000 years ago as evidenced by fossil remains of poppy seed cake and poppy pods found in the Neolithic Swiss Lake Dwellings. Opium was probably consumed by

the ancient Egyptians and was known to the Greeks as well. Our word opium is derived from the Greek. The poppy is also referred to in Homer's works the Iliad and the Odyssey (850 B.C.). Hippocrates (460-357 B.C.) prescribed drinking the juice of the white poppy mixed with the seed of nettle.

The opium poppy probably reached China about the fourth century A.D. through Arab traders who advocated its use for medicinal purposes. In Chinese literature, there are earlier references to its use. The noted Chinese surgeon Hua To of the Three Kingdoms (220-264 A.D.) used opium preparations and Cannabis indica for his patients to swallow before undergoing major surgery.

The beginning of widespread opium use in China is associated with the introduction of tobacco smoking in pipes by Dutch from Java in the 17th century. The Chinese mixed Indian opium with the tobacco, two products that were being traded by the Dutch. This practice was adopted throughout the region and predictably resulted in increased opium smoking, both with and without tobacco.

By the late-1700s the British East India Company controlled the prime Indian poppy growing regions and dominated the Asian opium trade. By 1800, they had a monopoly on opium; controlling supply and setting prices.

In 1805, the German pharmacist Friedrich W. Serturner isolated and described the principal alkaloid and powerful active ingredient in opium. He named it morphium after Morpheus, the Greek god of dreams. We know it today as morphine. This event was soon followed by the discovery of other alkaloids of opium: codeine in 1832 and papaverine in 1848. By the 1850s these pure alkaloids, rather than the earlier crude opium preparations, were being commonly prescribed for the relief of pain, cough, and diarrhea. This period also saw the invention and introduction of the hypodermic syringe.

By the late eighteenth century opium was being heavily used in China as a recreational drug. The Imperial court had banned its use and importation but large quantities were still being smuggled into China. In 1839 the Qing Emperor ordered his minister Lin Zexu to address the opium problem. Lin petitioned Queen Victoria for help but was ignored. In reaction, the emperor confiscated 20,000 barrels of opium and detained some foreign traders. The British retaliated by attacking the port city of Canton. Thus the First Opium War began. The Chinese were defeated and the Treaty of Nanjing was signed in 1842. The British required that the opium trade be allowed to continue, that the Chinese pay a large settlement, and that the Chinese cede Hongkong to the British Empire. The Second Opium War began and ended in 1856 over western demands that opium markets be expanded. The Chinese were again defeated and opium importation to China was legalized.

In the United States during the 19th century, opium preparations and 'patent medicines' containing opium extract such as paregoric (camphorated tincture of opium) and laudanum (deodorized opium tincture) became widely available and quite popular. In the 1860s morphine was used extensively pre- and post-operatively as a painkiller for wounded soldiers during the Civil War. Civil War physicians frequently dispensed opiates. In 1866 the Secretary of War stated that during the war the Union Army was issued 10 million opium pills, over 2,840,000 ounces of other opiate preparations (such as laudanum or paregoric), and almost 30,000 ounces of morphine sulphate. The inevitable result was opium addiction, called the 'army disease' or the 'soldier's disease.' These opium and morphine addiction problems prompted a scientific search for potent but nonaddictive painkillers. In the 1870s, chemists synthesized a supposedly non-addictive, substitute for morphine by acetylating morphine. In 1898 the Bayer pharmaceutical company of Germany was the first to make available this new drug, 3,6-diacetylmorphine, in large quantities under the trademarked

brand name Heroin. 3,6-diacetylmorphine is two to three times more potent than morphine. Most of the increase is due to its increased lipid solubility, which provides enhanced and rapid central nervous system penetration.

Heroin was initially used with much success as a superior cough suppressant for patients with (then incurable) tuberculosis. Tuberculosis patients continued to die, but without the tortuous coughing and pain. A second use of heroin was to combat morphine addiction - just as morphine was originally used to combat opium addiction. Soon after its introduction, however, Heroin was recognized as having narcotic and addictive properties far exceeding those of morphine.

In December 1914, the United States Congress passed the Harrison Narcotics Act which called for control of each phase of the preparation and distribution of medicinal opium, morphine, heroin, cocaine, and any new derivative that could be shown to have similar properties. It made illegal the possession of these controlled substances. The restrictions in the Harrison Act were most recently redefined by the Federal Controlled Substances Act of 1970. The Act lists as a Schedule II Controlled Substance opium and its derivatives and all parts of the P. somniferum plant except the seed.

The first period of large scale heroin smuggling into the United States since its prohibition occurred during the years 1967 through 1971. Turkish opium was processed into heroin in France and then smuggled into New York.

In the mid-1970s Mexican brown heroin appeared. It was sold at a lower price than European heroin and became readily available in the West and Midwest. By the mid-1980s the U.S. heroin market was being supplied from three regions: Mexico, Southwest Asia (Pakistan, Afghanistan, Turkey, Lebanon), and Southeast Asia (Burma, Laos, Thailand). Soon thereafter, South American heroin from Columbia appeared.

In 1997, Southeast Asia still accounts for well over half of the world's opium production. It is estimated that the region has the capacity to produce over 200 metric tons of heroin annually. Although much of it is consumed in Asia, thousands of kilograms of Southeast Asian heroin enter the United States each year.

The chemical structure of opiates is very similar to that of naturally produced compounds called endorphins and enkephalins. These compounds are derived from an amino acid pituitary hormone called beta-lipotropin which when released is cleaved to form met-enkephalin, gamma-endorphin, and beta-endorphin. Opiate molecules, due to their similar structure, engage many of the endorphins' nerve-receptor sites in the brain's pleasure centers and bring about similar analgesic effects. In the human body, a pain stimulus usually exites an immediate protective reaction followed by the release of endorphins to relieve discomfort and reward the mental learning process. Opiates mimic high levels of endorphins to produce intense euphoria and a heightened state of well-being. Regular use results in increased tolerance and the need for greater quantities of the drug. Profound physical and psychological dependence results from regular use and rapid cessation brings about withdrawal sickness.

In addition to the pleasure/pain centers, there is also a concentration of opiate receptors in the respiratory center of the brain. Opiates have an inhibiting effect on these cells and in the case of an overdose, respiration can come to a complete halt. Opiates also inhibit sensitivity to the impulse to cough.

A third location for these receptors is in the brain's vomiting center. Opiate use causes nausea and vomiting. Tolerance for this effect is built up very quickly. Opiates effect the

digestive system by inhibiting intestinal peristalsis. Long before they were used as painkillers, opiates were used to control diarrhea.

The opium poppy, Papaver somniferum, is an annual plant. From a very small round seed, it grows, flowers, and bears fruit (seed pods) only once. The entire growth cycle for most varieties of this plant takes about 120 days. The seeds of P. somniferum can be distinguished from other species by the appearance of a fine secondary fishnet reticulation within the spaces of the coarse reticulation found all over their surface. When compared with other Papaver species, P. somniferum plants will have their leaves arranged along the stem of the plant, rather than basal leaves, and the leaves and stem will be 'glabrous' (hairless). The tiny seeds germinate quickly, given warmth and sufficient moisture. Sprouts appear in fourteen to twenty-one days. In less than six weeks the young plant has grown four large leaves and resembles a small cabbage in appearance. The lobed, dentate leaves are glaucous green with a dull gray or blue tint.

Within sixty days, the plant will grow from one to two feet in height, with one primary, long, smooth stem. The upper portion of this stem is without leaves and is the 'peduncle'. One or more secondary stems, called 'tillers', may grow from the main stem of the plant. Single poppy plants in Southeast Asia often have one or more tillers.

As the plant grows tall, the main stem and each tiller terminates in a flower bud. During the development of the bud, the peduncle portion of the stem elongates and forms a distinctive 'hook' which causes the bud to be turned upside down. As the flower develops, the peduncle straightens and the buds point upward. A day or two after the buds first point upward, the two outer segments of the bud, called 'sepals,' fall away, exposing the flower petals.

Opium poppies generally flower after about ninety days of growth and continue to flower for two to three weeks. The exposed flower blossom is at first crushed and crinkled, but the petals soon expand and become smooth in the sun. Opium poppy flowers have four petals. The petals may be single or double and may be white, pink, reddish purple, crimson red, or variegated. The petals last for two to four days and then drop to reveal a small, round, green fruit which continues to develop. These fruits or pods (also called 'seedpods', 'capsules,' 'bulbs,' or 'poppy heads') are either oblate, elongated, or globular and mature to about the size of a chicken egg. The oblate-shaped pods are more common in Southeast Asia.

The main stem of a fully-matured P. somniferum plant can range between two to five feet in height. The green leaves are oblong, toothed and lobed and are between four to fifteen inches in diameter at maturity. The mature leaves have no commercial value except for use as animal fodder.

Only the pod portion of the plant can produce opium alkaloids. The skin of the poppy pod encloses the wall of the pod ovary. The ovary wall consists of an outer, middle, and inner layer. The plant's latex (opium) is produced within the ovary wall and drains into the middle layer through a system of vessels and tubes within the pod. The cells of the middle layer secrete more than 95 percent of the opium when the pod is scored and harvested.

Cultivators in Mainland Southeast Asia tap the opium from each pod while it remains on the plant. After the opium is scraped, the pods are cut from the stem and allowed to dry. Once dry, the pods are cut open and the seeds are removed and dried in the sun before storing for the following year's planting. An alternative method of collecting planting seeds is to collect them from intentionally unscored pods, because scoring may diminish the quality of the seeds. Aside from being used as planting seed, the poppy seeds may also be used in cooking and in the manufacture of paints and perfumes. Poppy seed oil is straw-yellow in color, odorless, and has a pleasant, almond-like taste. The opium poppy grows best in

temperate, warm climates with low humidity. It requires only a moderate amount of water before and during the early stages of growth. In addition, it is a 'long day' photo-responsive plant. As such, it requires long days and short nights before it will develop flowers. The opium poppy plant can be grown in a variety of soils; clay, sandy loam, sandy, and sandy clay, but it responds best to sandy loam soil. This type of soil has good moisture-retentive and nutrient-retentive properties, is easily cultivated, and has a favorable structure for root development. Clay soil types are hard and difficult to pulverize into a good soil texture. The roots of a young poppy plant cannot readily penetrate clay soils, and growth is inhibited. Sandy soil, by contrast, does not retain sufficient water or nutrients for proper growth of the plant.

Excessive moisture or extremely arid conditions will adversely affect the poppy plant's growth and reduce the alkaloid content. Poppy plants can become waterlogged and die after a heavy rainfall in poorly drained soil. Heavy rainfall in the second and third months of growth can leach alkaloids from the plant and spoil the opium harvest. Dull, rainy, or cloudy weather during this critical growth period may reduce both the quantity and the quality of the alkaloid content.

Opium poppies were widely grown as an ornamental plant and for seeds in the United States until the possession of this plant was declared illegal in the Opium Poppy Control Act of 1942. New generations of plants from the self-sown seed of these original poppies can still be seen in many old ornamental gardens.

The major legal opium poppy growing areas in the world today are in govemment-regulated opium farms in lndia, Turkey and Tasmania, Australia. The major illegal growing areas are in the highlands of Mainland Southeast Asia, specifically Burma (Myanmar), Laos, and Thailand, as well as the adjacent areas of southern China and northwestern Vietnam. The area is known as the 'Golden Triangle'. In Southwest Asia, opium poppies are grown in Pakistan, Iran, and Afghanistan. Opium poppy is also grown in Lebanon, Guatemala, Colombia and Mexico.

The highlands of Mainland Southeast Asia, at elevations of 800 meters or more above sea level, are prime poppy growing areas. Generally speaking, these poppy-farming areas do not require irrigation, fertilizer, or insecticides for successful opium yields.

Most of the opium poppies of Southeast Asia are grown in Burma (Myamnar), specifically in the Wa and Kokang areas which are in the northeastern quadrant of the Shan State of Burma. Laos is the second-largest illicit opium-producing country in Southeast Asia and third-largest in the world.

In Laos, poppy is cultivated extensively in Houaphan and Xiangkhoang Provinces, as well as the six other northern provinces: Bokeo, Louangnamtha, Louangphabang, Oudomxai, Phongsali and Xaignabouli. Poppy is also grown in many of the remote, mountainous areas of northern Thailand, particularly in Chiang Mai, Chiang Rai, Mae Hong Son, Nan and Tak Provinces.

In China, opium poppies are cultivated by ethnic minority groups in the mountainous frontier regions of Yunnan Province, particularly along the border area with Burma's Kachin and Shan States. Son La Province, situated between China and Laos, is a major opium poppy cultivation area in Vietnam, as are Lai Chau and Nghe An Provinces.

It is noteworthy that the dominant ethnic groups of Mainland Southeast Asia are not poppy cultivators. The Burmans and Shan of Burma, the Lao of Laos, the Thai of Thailand, the Han Chinese of Yunnan, China, and the Vietnamese of Vietnam are lowlanders and do not

traditionally cultivate opium poppies. Rather, it is the ethnic minority highlander groups, such as the Wa, Pa-0, Palaung, Lahu, Lisu, Hmong, and Akha who grow poppies in the highlands of the countries of Southeast Asia.

A typical nuclear family of Mainland Southeast Asian highlanders ranges between five and ten persons, including two to five adults. An average household of poppy farmers can cultivate and harvest about one acre of opium poppy per year. Most of the better fields can support opium poppy cultivation for ten years or more without fertilization, irrigation, or insecticides, before the soil is depleted and new fields must be cleared. In choosing a field to grow opium poppy, soil quality and acidity are critical factors and experienced poppy farmers choose their fields carefully. In Southeast Asia, westerly orientations are typically preferred to optimize sun exposure. Most fields are on mountain slopes at elevations of 1,000 meters (3,000 feet) or more above sea level. Slope gradients of 20 degrees to 40 degrees are considered best for drainage of rain water.

In Mainland Southeast Asia, virgin land is prepared by cutting and piling all brush, vines and small trees in the field during March, at the end of the dry season. After allowing the brush to dry in the hot sun for several days, the field is set afire. This method, called 'slash-and burn' or 'swidden' agriculture, is commonly practiced by dry field farmers - both highland and lowland - throughout Mainland Southeast Asia in order to ready the land for a variety of field crops. The slash-and-burn method is also used to clear fields for poppy cultivation. Before the rainy season in April, fields by the hundreds of thousands all over the region are set ablaze. A fog-like yellow haze hangs over the area for weeks, reducing visibility for hundreds of miles. In the mountains, the dense haze blocks out the sun and stings the eyes.

A typical highlander family will plant an area of two or three rai in opium poppy (2.53 rai is equivalent to one acre). In August or September, toward the end of the rainy season, highland farmers in Southeast Asia prepare fields selected for opium poppy planting. By this time, the ash resulting from the burn-off of the previous dry season has settled into the soil, providing additional nutrients, especially potash. The soil is turned with long-handled hoes after it is softened by the rains. The farmers then break up the large clumps of soil. Weeds and stones are tossed aside and the ground is leveled off.

Traditionally, most highland and upland farmers in Southeast Asia do not use fertilizer for any of their crops, including the opium poppy, but in recent years opium poppy farmers have started using both natural and chemical fertilizers to increase opium poppy yields. Chicken manure, human feces or the regions' abundant bat droppings are often mixed into the planting soil before the opium poppy seed is planted.

The planting must be completed by the end of October in order to take advantage of the region's 'long days' in November and December.

The opium poppy seed can be sown several ways: broadcast (tossed by hand); or fix-dropped by hand into shallow holes dug with a metal-tipped dibble stick. About one pound of opium poppy seed is needed to sow one acre of land. The seeds may be white, yellow, coffee-color, gray, black, or blue. Seed color is not related to the color of the flower petals. Beans, cabbages, cotton, parsley, spinach, squash and tobacco are crops typically planted with the opium poppy. These crops neither help nor hinder the cultivation of the opium poppy, but are planted for personal consumption or as a cash crop.

In the highlands of Southeast Asia, it is a common practice to plant maize and opium poppies in the same fields each year. The maize keeps down excessive weeds and provides feed for the farmer's pigs and ponies. It is grown from April to August. After harvesting the maize, and with the stalks still standing in the fields, the ground is weeded and pulverized.

Just before the end of the rainy season, in successive sowings throughout September and October, the poppy seed is broadcast among the maize stalks. These stalks can protect young opium poppy plants from heavy rains.

The opium poppy plants form leaves in the first growth stage, called the 'cabbage' or 'lettuce' stage. After a month of growth, when the opium poppy is about a foot high, some of the plants are removed (called 'thinning') to allow the other plants more room to grow. The ideal spacing between plants is believed to be 20 to 40 centimeters, or about eight to twelve plants per square meter, although some researchers in northern Thailand have reported as many as 18 plants per square meter.

During the first two months, the opium poppies may be damaged or stunted by nature through the lack of adequate sunshine, excessive rainfall, insects, worms, hail storms, early frost, or trampling by animals. The third month of growth does not require as much care as the first two months. Three to four months after planting, from late December to early February, the opium poppies are in full bloom. Mature plants range between three to five feet in height. Most opium poppy varieties in Southeast Asia produce three to five mature pods per plant. A typical opium poppy field has 60,000 to 120,000 poppy plants per hectare, with a range of 120,000 to 275,000 opium-producing pods. The actual opium yield will depend largely on weather conditions and the precautions taken by individual farmers to safeguard the crop. The farmer and his family generally move into the field for the final two weeks, setting up a small field hut on the edge of the opium poppy field.

The scoring of the pods (also called 'lancing,' 'incising,' or 'tapping') begins about two weeks after the flower petals fall from the pods. The farmer examines the pod and the tiny crown portion on the top of the pod very carefully before scoring.

The grayish-green pod will become a dark green color as it matures and it will swell in size. If the points of the pod's crown are standing straight out or are curved upward, the pod is ready to be scored. If the crown's points turn downward, the pod is not yet fully matured. Not all the plants in a field will be ready for scoring at the same time and each pod can be tapped more than once.

A set of three or four small blades of iron, glass, or glass splinters bound tightly together on a wooden handle is used to score two or three sides of the pod in a vertical direction. If the blades cut too deep into the wall of the pod, the opium will flow too quickly and will drip to the ground. If the incisions are too shallow, the flow will be too slow and the opium will harden in the pods. A depth of about one millimeter is desired for the incision.

Using a blade-tool designed to cut to that depth, scoring ideally starts in late afternoon so the white raw opium latex can ooze out and slowly coagulate on the surface of the pod overnight. If the scoring begins too early in the afternoon, the sun will cause the opium to coagulate over the incision and block the flow. Raw opium oxidizes, darkens and thickens in the cool night air. Early the next morning, the opium gum is scraped from the surface of the pods with a short-handled, flat, iron blade three to four inches wide.

Opium harvesters work their way backwards across the field scoring the lower, mature pods before the taller pods, in order to avoid brushing up against the sticky pods. The pods continue to produce opium for several days. Farmers will return to these plants - sometimes up to five or six times - to gather additional opium until the pod is totally depleted. The opium is collected in a container which hangs from the farmer's neck or waist.

The opium yield from a single pod varies greatly, ranging from 10 to 100 milligrams of opium per pod. The average yield per pod is about 80 milligrams. The dried opium weight yield per hectare of poppies ranges from eight to fifteen kilograms.

As the farmers gather the opium, they will commonly tag the larger or more productive pods with colored string or yarn. These pods will later be cut from their stems, cut open, dried in the sun and their seeds used for the following year's planting.

The wet opium gum collected from the pods contains a relatively high percentage of water and needs to be dried for several days. High-quality raw opium will be brown (rather than black) in color and will retain its sticky texture. Experienced opium traders can quickly determine if the opium has been adulterated with tree sap, sand, or other such materials. Raw opium in Burma, Laos and Thailand is usually sun-dried, weighed in a standard 1.6 kilogram quantity (called a 'viss' in Burma; a 'choi' in Laos and Thailand), wrapped in banana leaf or plastic and then stored until ready to sell, trade, or smoke. While opium smoking is common among most adult opium poppy farmers, heavy addiction is generally limited to the older, male farmers. The average yearly consumption of cooked opium per smoker is estimated to be 1.6 kilograms.

A typical opium poppy farmer household in Southeast Asia will collect 2 to 5 choi or viss (3 to 9 kilograms) of opium from a year's harvest of a one-acre field. That opium will be dried, wrapped and stacked on a shelf by February or March. If the opium has been properly dried, it can be stored indefinitely. Excessive moisture and heat can cause the opium to deteriorate but, once dried, opium is relatively stable. In fact, as opium dries and becomes less pliable, its value increases due to the decrease in water weight per kilogram.

Before opium is smoked, it is usually 'cooked'. Uncooked opium contains moisture, as well as soil, leaves, twigs, and other impurities which diminish the quality of the final product. The raw opium collected from the opium poppy pods is placed in an open cooking pot of boiling water where the sticky globs of opium alkaloids quickly dissolve. Soil, twigs, plant scrapings, etc., remain undissolved. The solution is then strained through cheesecloth to remove these impurities. The clear brown liquid that remains is opium in solution, sometimes called 'liquid opium'. This liquid is then re-heated over a low flame until the water is driven off into the air as steam leaving a thick dark brown paste. This paste is called 'prepared', 'cooked', or 'smoking' opium. It is dried in the sun until it has a putty-like consistency. The net weight of the cooked opium is generally only eighty percent that of the original raw opium. Thus, cooked opium is more pure than its original, raw form, and has a higher monetary value.

Cooked opium is suitable for smoking or eating by opium users. Traditionally there is only one group of opium poppy farmers, the Hmong, who prefer not to cook their opium before smoking. Most other ethnic groups, including Chinese opium addicts, prefer smoking cooked opium. If the opium is to be sold to traders for use in morphine or heroin laboratories, it is not necessary to cook it first. The laboratory operators generally use 55-gallon oil drums or huge cooking vats to dissolve the raw opium before beginning the morphine extraction process.

Raw or cooked opium contains more than thirty-five different alkaloids, including morphine, which accounts for approximately ten percent of the total raw opium weight. Heroin manufacturers must first extract the morphine from the opium before converting the morphine to heroin. The extraction is a simple process, requiring only a few chemicals and a supply of water. Since the morphine base is about one-tenth the weight and volume of raw opium, it is desirable to reduce the opium to morphine before transporting the product any great distance. Morphine is sometimes extracted from opium in small clandestine 'laboratories' which may be set up near the opium poppy fields.

The process of extracting morphine from opium involves dissolving opium in hot water, adding lime to precipitate the non-morphine alkaloids and then adding ammonium chloride to precipitate the morphine from the solution. An empty oil drum and some cooking pots are all that is needed.

The following is a step-by-step description of morphine extraction in a typical Southeast Asian laboratory:

1. An empty 55-gallon oil drum is placed on bricks about a foot above the ground and a fire is built under the drum. Thirty gallons of water are added to the drum and brought to a boil. Ten to fifteen kilograms of raw opium are added to the boiling water.

2. With stirring, the raw opium eventually dissolves in the boiling water, while soil, leaves, twigs, and other non-soluble materials float in the solution. Most of these materials are scooped out of the clear brown 'liquid opium' solution.

3. Slaked lime (calcium hydroxide), or more often a readily available chemical fertilizer with a high content of lime, is added to the solution. The lime converts the water insoluble morphine into the water soluble calcium morphenate. The other opium alkaloids do not react with the lime to form soluble calcium salts. Codeine is slightly water soluble and gets carried over with the calcium morphenate in the liquid. For the most part, the other alkaloids become part of the residual sediment 'sludge' that comes to rest on the bottom of the oil drum.

4. As the solution cools, and after the insolubles precipitate out, the morphine solution is scooped from the drum and poured through a filter of some kind. Burlap rice sacks are often used as filters. They are later squeezed in a press to remove most of the solution from the wet sacks. The solution is then poured into large cooking pots and re-heated, but not boiled.

5. Ammonium chloride is added to the heated calcium morphenate solution to adjust the alkalinity to a pH of 8 to 9, and the solution is then allowed to cool. Within one or two hours, the morphine base and the unextracted codeine base precipitate out of the solution and settle to the bottom of the cooking pot.

6. The solution is then poured off through cloth filters. Any solid morphine base chunks in the solution will remain on the cloth. The morphine base is removed from both the cooking pot and from the filter cloths, wrapped and squeezed in cloth, and then dried in the sun. When dry, the crude morphine base is a coffee-colored powder.

7. This 'crude' morphine base, commonly known by the Chinese term p'i-tzu throughout Southeast Asia, may be further purified by dissolving it in hydrochloric acid, adding activated charcoal, re-heating and re-filtering. The solution is filtered several more times, and the morphine (morphine hydrochloride) is then dried in the sun.

8. Morphine hydrochloride (still tainted with codeine hydrochloride) is usually formed into small brick-sized blocks in a press and wrapped in paper or cloth. The most common block size is 2 inches by 4 inches by 5 inches weighing about 1.3 kilograms (3 lbs). The bricks are then dried for transport to heroin processing laboratories.

Approximately 13 kilograms of opium, from one hectare of opium poppies, are needed to produce each morphine block of this size. The morphine blocks are bundled and packed for transport to heroin laboratories by human couriers or by pack animals. Pack mules are able to carry 100-kilogram payloads over 200 miles of rugged mountain trails in less than three weeks.

The conversion of morphine hydrochloride to heroin base is a relatively simple and inexpensive procedure. The necessary chemicals are readily available industrial chemicals. The equipment is very basic and quite portable. Heroin conversion laboratories are generally located in isolated, rural areas due to the telltale odors of the lab's chemicals. Acetic anhydride, in particular, is a key chemical with the easily identified very pungent odor of pickles.

Heroin synthesis is a two-step process which generally requires twelve to fourteen hours to complete. Heroin base is the intermediate product. Typically, morphine hydrochloride bricks are pulverized and the dried powder is then placed in an enamel or stainless steel rice cooking pot. The liquid acetic anhydride is then added. The pot lid is tied or clamped on, with a damp towel used for a gasket. The pot is carefully heated for about two hours, below boiling, at a constant temperature of 185 degrees Fahrenheit. It is never allowed to boil or to become so hot as to vent fumes. It is agitated by tilting and swirling until all of the morphine has dissolved. Acetic anhydride reacts with the morphine to form diacetylmorphine (heroin). This acetylation process will work either with morphine hydrochloride or p'i-tzu (crude morphine base).

When cooking is completed, the pot is cooled and opened. The morphine and the acetic anhydride have now become chemically bonded, creating an impure form of diacetylmorphine (heroin). Water is added at three times the volume of acetic anhydride and the mixture is stirred. Activated charcoal is added and mixed by stirring and the mixture is then filtered to remove colored impurities. Solids remaining on the filter are discarded. Sodium carbonate, used at 2.5 pounds per pound of morphine, is dissolved in hot water and added slowly to the liquid until effervescence stops. This precipitates the heroin base which is then filtered and dried by heating in a steam bath for an hour. For each pound of morphine, about 11 ounces of crude heroin base is formed. The heroin base may be dried, packed and transported to a heroin refining laboratory or it may be purified further and/or converted to heroin hydrochloride, a water-soluble salt form of heroin, at the same site.

Southeast Asian heroin base is an intermediate product which can be further converted to either a smoking form (Heroin No. 3) or an injectable form (Heroin No. 4).

(Smoking Heroin, heroin hydrochloride)

To make heroin No. 3, the crude base is mixed with hydrochloric acid resulting in heroin hydrochloride. Adulterants including caffeine are added after this conversion. For each kilogram of crude heroin base about one kilogram of caffeine is used. Various 'flavorings'

such as quinine hydrochloride or strychnine hydrochloride may be added in 7 gram or 14 gram increments. Next, the wet paste mix is stirred to dryness over the steam bath. The resulting dry Heroin No. 3 will be in the form of coarse lumps. These are crushed and passed through a #8 to #10 mesh sieve, and the grains (pieces) are then packaged for sale. The entire process takes about eight hours and requires only minimal skill. While extra attention to stirring is required to assure dryness, one man can prepare a one-kilogram block of Heroin No. 3 during this time.

(Injectable Heroin)

To the heroin base mixture in the pot, water is added at three times the volume of acetic anydride and mixed by stirring. A small amount of chloroform is added. The mixture is stirred and then allowed to stand for twenty minutes. Doing so precipitates highly-colored impurities and a red, greasy liquid. The water layer is carefully poured off and saved in a clean pot, leaving the red grease in the pot. In a clean pot, activated charcoal is stirred into the aqueous solution and is filtered to remove solid impurities. The decolorizing effects of the charcoal, combined with the chloroform treatment, will leave a light yellow solution. The use of charcoal is repeated one or more times, until the solution is colorless.

Approximately 1.1 kilograms of sodium carbonate per 0.5 kilogram of morphine is dissolved in hot water and added slowly to the mixture until the effervescence stops. This precipitates the heroin base which is then filtered and dried by heating on a steam bath. The heroin base is heated until dryness is complete, an imperative for the preparation of Heroin No.4. The powder should be very white at this stage. If not white, the base is redissolved in diluted acid, treated repeatedly with activated charcoal, reprecipitated and dried. The ultimate purity and color of the resulting heroin hydrochloride depends largely on the quality of the heroin base.

The following optional steps are sometimes taken by skilled heroin chemists to increase quality.

For each pound of heroin base 1,100 milliliters of ethyl alcohol is heated to boiling. The heroin base is added and stirred until completely dissolved. The heated solution is then quickly filtered through a Büchner funnel that has been preheated and poured into a heated flask. This hot filtration removes the traces of sodium carbonate that remained in the base. The solution is quickly cooled in an ice bath, where it becomes very thick; like ice cream. The substance is put into a pan and set in a large refrigerator. A fan is set to blow across the pan to cause slow evaporation of the alcohol while the paste crystallizes. After several hours, it is vacuum-filtered. The filtrate, pure ethyl alcohol, is re-used. The solid material, 'alcohol morphine base', is actually recrystallized heroin base.

The heroin product, either heroin base or recrystallized heroin base, is weighed. For each pound of solid product, 3,000 milliliters of ethyl alcohol, 3,000 milliliters of ether, and 102 milliliters of concentrated hydrochloric acid are measured out. The solid is dissolved by heating with one-third of the alcohol and one-half of the acid. Another one-third of the acid is added and mixed by stirring. Next, acid is added slowly, drop by drop, until the product is completely converted to the hydrochloride. Two methods of testing this end product may be used. Either a drop of solution evaporates on a clean glass plate, leaving no trace of cloudiness in the residue, or a drop of the solution placed on Congo red paper causes the paper to turn blue.

Once the acid is added, the remaining alcohol is stirred in. Half of the ether is then added with stirring and the mixture is allowed to stand for fifteen minutes. It must be examined with great care since it is extremely volatile and flammable. Once the first small crystals are detected, the remaining ether is added at once. The vessel is stirred, covered and allowed to stand for twenty minutes to one hour. The mixture becomes nearly solid after an hour. At this point, it is filtered and the solids are collected on clean filter paper. The paper is wrapped around the crystals and placed on wooden trays, usually over lime rock, to dry. When the crystals of pure heroin hydrochloride are dry, they are packaged. Batches of 5 to 10 kilograms are commonly made at one time, the largest batch being an estimated 20 kilograms.

Chemicals used to isolate morphine from opium include ammonium chloride, calcium carbonate (limestone), and calcium hydroxide (slaked lime). The precursor chemical normally used in the conversion of morphine to heroin is acetic anhydride. Chemical reagents used in the conversion process include sodium carbonate and activated charcoal. Chemical solvents needed are chloroform, ethyl alcohol (ethanol), ethyl ether and acetone. Other chemicals may be substituted for these preferred chemicals, but most or all of these preferred chemicals are readily available through smugglers and suppliers.

Necessary laboratory equipment includes measuring cups, funnels, filter paper, litmus paper and a stainless steel pot. Only the most sophisticated heroin labs use glass flasks, propane gas ovens, Bunsen burners, vacuum pumps, autoclaves, electric blenders, venting hoods, centrifuges, reflux condensers, electric drying ovens and elaborate exhaust systems. Portable, gasoline-powered generators are often used at clandestine heroin conversion laboratories used to power various electrical devices.

Corrections to the text by Jim Hogshire:

Common Misconception Numero Uno appears in Pakker's history of opium. It is the dreaded "soldier's disease"...

He says:

In the 1860s morphine was used extensively pre- and post-operatively as a painkiller for wounded soldiers during the Civil War...The inevitable result was opium addiction, called the 'army disease' or the 'soldier's disease'.

This is an example of anti-drug propaganda which sounds so damned possible few ever question it. And it has worked well for the Drug Warriors from the beginning, which was just a few years before the Harrison act was passed. In fact, this yarn was invented to portray opium and morphine as so powerful and so addicting that it could take over the soul of anyone, even against their will.

But on Cliff Schaeffer's Site there is an essay about "soldier's disease" that does question the story and, lo and behold, it's not true!

No doubt, opium was used very extensively in during the Civil War, and before and after it, too. But there is just no documentation of any mass addiction and the phrase "soldier's disease" or its variants didn't appear for something like 40 years after the war.

I think the essay is called "The Mythical Roots of US drug policy."

Another slight error I think is worth correcting is what Pakker says about the Harrison Act:

"In December 1914, the United States Congress passed the Harrison Narcotics Act which called for control of each phase of the preparation and distribution of medicinal opium, morphine, heroin, cocaine, and any new derivative that could be shown to have similar properties. It made illegal the possession of these controlled substances."

The Harrison Act wasn't that bad. It did not outlaw heroin, for instance. That didn't happen until 1923. And it didn't make possession of opium, opiates or cocaine illegal but pretended to be a tax measure only. The first time it was challenged, in 1916, the Supreme Court knocked it down in a 7-3 vote. Writing for the majority Justice O.W. Holmes acted outraged that the government would try to make criminals out of the majority of American citizens who all had some form of opium in their homes. If Congess were trying to legislate morals by this law with its "coating of constitutionality" coming from its supposed power to tax, they had another think coming.

What's kind of scarey is that in 1919, the Supreme court heard two other cases in which the law was upheld. Between 1916 and 1919 some of the judges had changed but it still wouldn't account for the 5-4 vote in favor of the government and (very strangely) overturning its own opinion so quickly -- something the Supremes just hate to do.

But, looking at the rosters it becomes apparent that Holmes changed his mind. I have still not completely verified this, but it sure looks like it. I can't figure out why in the hell he would do this, though.

As for the part about "any new derivative" with similar properties, etc. is also not correct. That really didn't happen until 1986 with the Analog Substances Act.

Earlier versions of the "Harrison Act" outlawed caffeine, too. So I guess we can count ourselves lucky.

Btw, the poppy plant itself was outlawed in 1943 by the "Poppy Control Act" and then it was "repealed" in 1972 when the congress jerks realized the new Controlled Substances Act was sufficient to make them illegal.

And Pakker is right about what's illegal. Papaver somniferum is illegal. Every pat of the plant is illegal *except the seeds*. As soon as the seed sprouts, it seems to me, the thing is illegal.

Do not, repeat, do not, believe in Harper's author and human jackal Michael Pollan's carefully constructed "innocent gardene" defense because it will not work in front of a real-life judge. With all drugs, "mens rea" or "bad intent" is supposed.

OK, I gotta go now. Till later,

Jim

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On-line, off-shoreand Mexican pharmacies

This list has been added because of the requests we receive for pharmaceutical advice. In particular, site visitors ask where they can obtain pain-relieving medications that alone make their life worth living, but which their physician denies them owing to our prohibitionist drug laws. Some, but not all, of the pharmacies listed here may be of uncertain reliability. In a more enlightened age - and in a free society - none of them will be necessary.

NOTE ADDED 9 DEC. 2011. Our website opioids.com is now back online after "other agencies" (i.e. the US authorities) pressured registrar Godaddy into suspending nameservice. It's a non-commercial site that has been running since 1998. But apparently the US authorities objected to one of our links pages (see below) that contains the third-party URLs of online pharmacies and pain clinics. Opioids.com is mirrored at opioids.co.uk in case the US authorities get the site censored again. When will other countries wake up to the immense and unaccountable power over the Net that control over the root nameservers gives the US government? And whatever happened to the First Amendment?

Online pharmacy sources

o drugbuyers.com - Free information about buying meds online, free pharmacy watch group, and free info on the best and most reliable sources for prescription drugs such as oxycodone, hydrocodone, and other opioids [currently closed]

o PharmacyReviewer.com - information on cheapest prescription medicines, FAQs, pharmacy reviews, blacklisted pharmacies, forum

o Epharmas.com - no-prescription Opana (oxymorphone), Vicodin (acetaminophen & hydrocodone), 'Roxycontin' / OxyContin; UPS or FEDEX delivery; Support 24/7.

o endlessmeds.com - recommends reliable foreign, Mexican and Canadian Pharmacies offering prescription medications

o Budget Medicines - generic drugs and brand alternatives o Canadian Internet Drugs - buy prescription medications shipped directly from

Canada o RX on USA - no-prescription Vicodin & oxycodone; Moneygram only. o Universal Meds - no-prescription Vicodin (hydrocodone and acetaminophen),

Dilaudid (hydromorphone), Percocet (oxycodone and acetaminophen), oxycodone, roxicodone (immediate-release oxycodone - 'Roicontin').

o Certs RX - no-prescription Vicodin (hydrocodone and acetaminophen), Percocet (oxycodone and acetaminophen), oxycodone, roxicodone (immediate-release oxycodone), morphine, methadone.

o Skymed Pharmacy - no-prescription Vicodin, Percocet & oxycodone. o Savers RX - no-prescription Vicodin, Percocet, roxicodone & oxycodone o FirstCall RX - no-prescription Vicodin (hydrocodone and acetaminophen),

Percocet (oxycodone and acetaminophen), oxycodone (Oxycontin), roxicodone (immediate-release oxycodone - 'Roxicontin').

o Pharmasupplynow - no-prescription Vicodin (hydrocodone and acetaminophen), oxycodone (Oxycontin)

o Abroad Pharma - Temgesic Sublingual, buprenorphine; "no prescription required". Buy via credit card, Western Union or Moneygram

o Meds India Ltd - reliable, cheap, guaranteed delivery, but no strong opioids. o No Prescription Drug Vendors - tramadol (Ultram) and codeine without a

prescription

"Other"

o Terumo safety-sealed hypodermic syringes o ACPA Medications and Chronic Pain Supplement 2010 (pdf) - annual update

from the American Chronic Pain Association o Pain Relief Network - "standing up for patients in pain, and the physicians who

treat them"o Partners Against Pain - "Your around-the-clock resource for pain management"o Pain Clinics - US and international list of over 3,000 pain specialists and

clinics. (See Why Use A Pain Clinic? here)o Minnesota RxConnect

- US medicines at Canadian prices

o Online Pharmacies 2011 o Alt.Support.Chronic-Pain Newsgroup o ePharmacyWatch - "pharmacy watch and chronic pain support group helps

you find pain meds, hydrocodone, vicodin, oxycodone, oxycontin"

* * *

o Poppies.org

- "the continuing adventures of the world's most controversial flower"

o Poppies Shop

- "buy dried poppy pods, papaver somniferum seeds or white opium poppy seed"

o Poppies International - "dedicated to the beauty of the papaver" - sells poppy seeds ("for decorative and baking purposes only")

Updates? Suggested additions?

Thanks?Professor-Qe-mail: updates@opioids.com

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OPIOIDS  GLOSSARY

Abstinence syndrome = withdrawal symptoms Affinity = in crude terms, the "strength" of the interaction between a ligand and a

receptor. When two ligands exist at equimolar concentration, the ligand whose affinity is higher will tend to displace the other from a receptor, assuming the low-affinity ligand is bound reversibly to the receptor.

Agonist = a compound that will bind to a receptor to form a complex which elicits a full pharmacological response, peculiar to the nature of the receptor involved.

Antagonist = a compound that will bind to a receptor to form a complex which does not give rise to any response, as if the receptor were unoccupied.

Delta receptors = a term used collectively to refer to two characterised subtypes of opioid receptors (delta-1, delta-2) that possess numerous features in common which are not present in the mu receptors or kappa receptors.

Dynorphin = an endogenous peptide which functions as a selective agonist for the kappa opioid receptors.

Endorphin(s), beta-endorphin = an endogenous peptide which functions as a selective agonist for the mu-opioid receptors.

Endomorphin = a term which refers to two small (5 amino-acids) endogenous peptides, known as endomorphin-1 and endomorphin-2, which function as mu-agonists with greater selectivity than beta-endorphin.

Enkephalin = one of a number of endogenous peptides which function as selective agonists for the delta-opioid receptors.

Full agonist = see "agonist" Inverse agonist = in the context of receptors which exert some basic signalling

activity even the absence of an agonist (characteristic known as "constitutive activity"), an agent which binds to a receptor, suppressing this activity to some degree.

Intrinsic activity = a measure of the maximum response to an agonist. Kappa receptors = a term used collectively to refer to three characterised subtypes

of opioid receptors (kappa-1, kappa-2, kappa-3) that possess numerous features in common which are not present in the mu receptors or delta receptors.

Ligand = molecule which binds to a receptor to form a complex. MMT (methadone maintenence therapy) = medical treatment of addiction with

the (less euphorigenic) opioid methadone Mixed agonist-antagonist = see "partial agonist" Morphinan = compound with the structural core or pharmacophore possesed by

morphine and other opiates - not restricted to opiates Narcotic = literally "sleep/stupor-inducing agent". Term usually applied

indiscriminately to describe any exogenous compound with a "sedating" profile. Use of the term with reference to the opioids is not recommended, due to its ambiguity, and arguably negative connotation.

Neurotransmitter = any endogenous compound that plays a role in synaptic nervous transmission.

Opiate = compound containing the fundamental morphine or thebaine structure possessing some affinity to any, or all, of the opioid receptor subtypes. Examples are heroin, buprenorphine and naltrexone.

Opioid = any compound, peptide or otherwise, which, while not containing the fundamental morphine or thebaine structure, possesses some affinity for any, or all, of the opioid receptor subtypes. Common opioids are endorphin, fentanyl and methadone.

Partial agonist = a compound which possesses affinity for a receptor, but unlike a full agonist, will elicit only a small degree of the pharmacological response peculiar to the nature of the receptor involved, even if a high proportion of receptors are occupied by the compound.

Pharmacophore = the minimum functionality, or 3-D configuration of specific atoms or groups, that a molecule must have in order to exhibit biological activity.

SAR (structure activity relationship) = the relationship between the chemical structure of a psychoactive compound to its strength and/or effects

Selectivity = the relationship between the affinity of a compound for a particular receptor and its affinity for other types of opioid receptor. For instance, a compound that will bind with high affinity to the mu-receptors, but with very low affinity to kappa and delta receptors, is said to possess high selectivity for mu.

Semi-synthetic opiate/opioid = a compound with some opioid receptor affinity, synthesised by functional modification of a product extracted from opium.

Synthetic opiate/opioid = a compound with some opioid receptor affinity, synthesised using no products extracted from opium.

Opium FAQ v1.0

Opium poppy: Papaver somniferum

DISCLAIMER:

This information is presented purely for educational purposes. In many instances, the practices outlined are illegal. I have put together this FAQ with the intention of educating those with less experience than myself, and am infinitely grateful for the assistance of those who are more knowledgable and better educated. If there are any glaring errors or omissions herein, I can be contacted at the email address at the end of the FAQ.

LEGALITIES:

Being no expert on legalities I can sugggest you try the following:

The legalities of Papaver sp. cultivation depends entirely on the law in the state AND region where you live. If you live in a city, you might want to check with your local council, who will usually have a list of banned and/or noxious weeds on file. You could try requesting a list, saying, for example, that you intend to set up a herb garden and want to grow St John's wort (which is a noxious weed in many places) and would they mind sending you a list?

If you're in a rural area, try one of those Lands/Agriculture department type government agencies for a similar list. Then ring your local council. Laws governing the cultivation of plants operate at many levels - down to local.

Most Papaver species are legal to grow: some are NOT and are listed merely as weeds, which means that you _must_ take steps to eradicate them on your property and must not _cultivate_ them. In some instances their prescence on your property is not a problem

PROVIDING that you are not cultivating them directly (ie they are classes as weeds), but not noxious weeds. P. somniferum is most likely to be problematic, but other Papaver spp may also cause legal problems depending on the paranoia of your government agencies.

And it is a question definitely worth following up.

PROPOGATION:

Several varieties of opium yielding poppies exist - Persian White has the largest bulb and subsequently highest yield. Another more common variety has purple petals with a white centre-don't know the variety name - its much easier variety to find than the white, but with smaller pods and a lower opium yield.

Papaver somniferum is basically a winter crop in the Southern hemisphere, preferring cool nights and warm days and will stand slight frosts. It is possible to germinate seeds in summer using plant tissue culture processes and Murashige & Skoog basic medium- stick the cultures in the fridge until they germinate. I have no successful experiences with planting these on- possibly due to the short lifecycle of the poppy, but this could be a useful starting point for experiments where the object is to cultivate poppies year round. I have tried to stratify the seed in my refrigerator with a view to inducing germination for early plantings- this has not been successful, but has not seemed to compromise the fertility of the stratified seed in any way.

All poppies like sandy soils (or at least well drained ones) with a little bit of shelter and not too much shade. Prepare beds in advance by digging fertilisers and any claybreak leaving about six weeks between each dig. Cover the beds with mulch and let them sit for a month or so. You CAN fully mulch the beds, and sow into rows where the mulch has been completely removed to about 7cm away from both sides of the seed row. DO NOT MULCH OVER SEEDS OR MULCH TO THE STEMS OF ADULT PLANTS - this makes them susceptible to fungal infestations of the browning-off type!

Plant on or around Mayday (in the Southern hemisphere) by raking into prepared beds. Broadcast seeds or sow thickly in rows. Young poppy plants resemble lettuce seedlings. Stronger plants will become apparent at about 7cm high. Wait until about 10cm high and thin as follows:

Poppies DO like a bit of companionship, so thin around a clump of 2-3 strong plants. Two thinnings about four weeks apart will ensure that plants have enough 'companionship ' (i.e. shelter, shade and whatever allopathic conditions favour clumps as opposed to individual plants). I tend to thin seedlings progressively, over a month or so, leaving only enough room for strong plants to grow into, without leaving vast spaces between plants. Poppies do not like to be moved and it is better to sow directly into beds than to transplant, which can result in stunted growth and a later, shorter flowering season.

Interplanting with ranunculus and/or anemone, which flower at the same time and have a similar leaf and flower formation, may reduce flower visibility: this is important in areas where cultivation of opium poppies is illegal. Also handy to remember is the fact that flowering plants of equal heights can distract the eye effectively. I have found that milk thistle, parsley and salad rocket all flower at the same time and height as opium, and provide excellent diversion.

Keep the beds well weeded (poppies hate too much competition though shorter type groundcover weeds such as chickweed can keep the soil moist). Keep the water up to them

in dry areas. Opium poppies (particularly the purple ones) are weeds in many places and can stand a bit of neglect. For some strange reason the tallest and most vigorous poppies are often the ones that got walked on by accident in their youth. Experiment!

The plants may look a bit weedy when the flowers start to happen, don't worry, flowering gives the plant a bit of a boost.

You will get a lot of thinnings: young plantlets which have been removed from the garden bed to make room for stronger plants. If you're keen you CAN make use of them. I have references which list young plants 10-20cm high as having up to 71mg/100g dry weight of alkaloids. This can seem insignificant until you consider that opium is only about 12% alkaloids, and you can end up with a kilo of thinnings or more in your home garden. I estimate a couple of grams of smokeable opium type extract can be extracted using methanol. And given that thinnings usually appear prior to flowering commencing, why would you waste a chance?

On the other hand you CAN drop the thinnings into hot water and allow to steep for 10 minutes, which produces a vile tasting tea. Opium tea, in my humble opinion, is fucked. It tastes horrible, needs fresh flowers to be halfway potent, and does not store well. All alkaloids are apparently present in such a tea in roughly equal proportion to that which occurs in crude opium, but this improves the taste not one whit. Potency varies with opium tea: you can drink a glass and feel nothing, or drink a glass and discover in half an hour that you've had too much. Smoking O is a more immediate route and allows for better dose control. Smokeable O is also easier to store and has a long shelf life.

The alkaloids in Papaver somniferum are present in the plant their pure form, and are combined with so called vegetable acids. Combined with acids, alkaloids tend to be more soluble than the free bases. An early method for the extraction of morphine involved addition of calcium chloride to the filtrate of opium 'soup'. The calcium would precipitate the calcium salt of these vegetable acids as a sort of soap scum leaving a crude morphine hydrochloride.

Opium varies in alkaloidal content from batch to batch, and between regions. The British Pharmacoepia 1954 lists Yugoslavian opium as the most potent at 15-17% alkaloid content, followed by opium from Turkey, Iran, and Indian opium was at the bottom of the list with a 9-10.5% alkaloid content.

HARVEST:

As soon as flower petals open, pull them away from the capsule to expose the green seed pod, slice the surface of the pods with a SHARP blade (I find a Stanley blade best) and either place seepage directly onto fresh marijuana which is then dried, or collect the exudation into a vessel ( eggcups are good ) and store to dry. This operation is best done in the early morning- I've found that yields decrease as the temperature rises.

Another method is to slice the seed heads and wipe the opium onto cigarette papers. You can pull the dried opium latex away from the paper to store in airtight bags at a latter stage.I've found opium is best stored in a dry environment - can't remember whether its hygroscopic or not, but keep it dry for best results

In a large harvest two layers of extract will form from the opium seepage. Separate the two layers if possible - it may be possible to do this at harvest stage especially with the Persian White variety as the two layers have distinctly different weights- one can be used to

enhance the potency of heads or leaf, and the other is a high grade opium product best appreciated on its own.

Discard all sliced poppy heads as trash: they are a legal liability and should they be found a charge of cultivation can more easily be proved. For economy's sake, you can also use the weep at both the edges of the cut stem- best taken by wiping straight onto fresh dope leaves. It's not high quality yield from this cut, but hey, why waste it?

Resist temptation and save the first, last and largest heads to ripen without slicing for next year's seed. You can improve your strain over time, selecting for first, last, largest, most potent, whatever. I have not experienced problems with the strain 'running out' of genetic material as a result of inbreeding, as can happen with pot, or corn, or lotsa other stuff. This does not mean its not a potential concern, and ALWAYS take a chance and outbreed your variety: note results of any improvements and con serve your seed stocks

You can reslice yesterdays pods if you choose to keep them, though I've found the best way to increase yields is to remove spent flowerheads at the base of the main stem or where the flower stem joins to a larger branch - this encourages new flowers to form. Leave only the capsules you intend to save for seed.

Flowers continue until end October/start November in the southern hemisphere. Usually pod sizes decrease with the age of the plant- though this is not always the case with transplanted poppies. Keep the seeds from your best pods (if you think that you have enough seed to select for yield) or just keep the seed from any old pods (this is a strategy for preserving genetic variance and is the better practice in small crops).

Poppy seeds are VERY tiny, shake or crush the seed pods and remove any non-seed trash for best storage. Place in an airtight jar in a cool place, use one of those wretched drierite sachets you find in vitamin pill jars to absorb moisture, in my view seeds will remain viable for no more than three years even under optimum conditions. So take care to take fresh seedstock for everyyear

SMOKING OPIUM:

Opium is the name for the brown waxy exudation from the unripe seed capsules of Papaver somniferum. Opium is a combination of chemicals, not a chemical name in itself, as someone so rightly pointed out in Usenet recently. It's active ingredients are morphine, thebaine, codeine, papaverine and several others besides. Yield and proportions of opiates vary between individual plants, crops, varieties, areas. Other parts of the poppy plant (stems, leaves) produce a latex which dries and resembles opium, but the quality of the latexes from the other parts of the plant are not near as high.

Opium is described as a stimulant narcotic. Historically it has been prescribed as a painkiller, for inflammation unaccompanied by dyspnoea, in typhus, typhoid and smallpox etc.

PLEASE KEEP IN MIND THAT OPIUM IS AN ADDICTIVE SUBSTANCE.

Smoking it regularly can increase your tolerance- faster than you think. The good thing about growing your own opium is that usually by the time you think you've picked up a habit, you run out. The other good thing about growing opium is that it's a fiddly, low yield job, particularly using the easier to get, purple variety. You'd only do it if you were fairly dedicated to having a smoke of O. In the quantities it takes to pull a reasonable crop, it is way too much work for the money or the buzz...not to mention the risk.

The best way to smoke O is in a bong. Assume you've cut and grown your own O: store it in small flakes in an airtight bag, or just dry the heads you wiped it on and smoke them. You can mix O with tobacco or pot, or smoke it on its own.

O burns at a higher temperature than pot or tobacco, so keep your lighter at its hottest. Initially pack small cones as O will keep burning long after your tobacco or pot has gone out: you can waste quite a bit without realising it. The taste is a bit of a shock at first, but the smell of the smoke is a delightful sweetish pungent scent. If you've ever read anything about smoking opium you'll recognise the smell immediately...

My first smoke of O, some years ago now, reminded me of nothing so much as the first time I got stoned on pot. I grinned a lot. I snuggled with a friend as we watched TV. The best thing about an O stone is the lack of paranoia, and it's a stunning sex drug which can prolong orgasm etc. It's also a great painkiller, given its history of legitimate prescription that's hardly surprising.

As to the amounts you'd start with, it's best left to the individual really, start with a matchead size portion of opium per person and take it from there. The effects of O are fairly immediate, making it easier to calculate an appropriate smoking dose as opposed to say, dropping acid. It is, of course, much easier to overdose via oral dose of opium, which is why I've recommended the smoking route.

The effects of O last 2-3 hours, depending on body size, tolerance, how much you've smoked. I've absolutely no idea as to how long traces stay in your bloodstream. Side effects- well, you sleep well, and next day you experience a certain amount of lassitude if you've had a fair bit, but that's all I'm aware of. I've heard it can cause nausea and constipation and have experienced neither.

Pharmaceutical incompatibles: Astringents, alkaline carbonates, salts of copper, iron, mercury, lead and zinc.

Antidotes to opium poisoning are: stomach pumps, coffee enemas, 1/6 grain apomorphine hydrochloride hypodermically, emetic of zinc sulphate, 5 grains or so of potassium permanganate in a half pint of water. All sounds most unpleasant - just don't take too much in the first place.

You can purify opium further into its constituent alkaloids- then take the morphine and turn it into smack if you so desire. Wouldn't bother really, opium is a much more pleasant experience overall than heroin. And the skills you'd require are well out of the range of those described in this FAQ. It IS possible though, if you need more information you may well find it at the Lycaeum.

And yes, I believe its possible to get out of it on opium seeds, which CAN contain (depending on the seed source, age and your luck) absolutely minute traces of alkaloids. Positively microscopic traces...I estimate, however, that it would be cheaper and far less hassle to go out and buy a beer..........you'd need that many seeds .......and loads of determination. The presence of alkaloids in opium seeds has been a hotly debated thread on alt.drugs.chemistry for quite some time...check Dejanews index to find out about practically everyone's views on this subject.

Any responses, additions, offers of money re this FAQ, please post them to alt.drugs.chemistry.

Cheers,

Roo

FAQ-Opioid

From: Mdh@debug.cuc.ab.caNewsgroups: alt.drugsSubject: OPIOID FAQ (1st draft)Message-ID: Date: 30 Jan 94 04:33:35 GMT

Ok this is the first draft of the opioid FAQ I put together. It is by no means complete and any contribution would be appreciated. Please send all info to my mail box at mdh@debug.cuc.ab.ca. Most of the information is there and any missing or incorrect info is in the FAQ just let me know.

Here it is....

OPIOID  FREQUENTLY  ASKED  QUESTIONS  FILE

Editor: Mike Hamilton Last Update: 10 Jan. 94Newsgroup : alt.drugs

Article Separation

** Contents **

Glossary on terms used in FAQ

Opioid Info:Natural (known as opiates): MorphineCodeine

Semi-Synthetic (known as opioids): HeroinHydrocodone (Hycodan) Hydromorphone (Dilaudid) Meperidine (Demerol)Oxycodone (Percodan)

Synthetic (also known as opioids): Fentanyl (Sublimaze)Methadone (Dolophine)Propoxyphene (Darvon)Pentazocine (Talwin)

Opioid Addiction and Withdrawal

The FAQ will use morphine as the standard opioid and base all otheropioids in relation to it. (Kinda like class inheritance in C++).

A little glossary to start the FAQ:

opiate - narcotic analgesic derived from a natural source(opium poppy)opioid - narcotic analgesic that is either semi or fully synthetic- also refers to entire family of both opiates and opioidsIM - intramuscular injectionSC - subcutaneous injection

** Morphine **

SynopsisMorphine is naturally occurring substance in the opium poppy, Papaver somniferum. It is a potent narcotic analgesic, and its primary clinical use is in the management of moderately severe and severe pain. After heroin, morphine has the greatest dependence liability of the narcotic analgesics in common use. Morphine is administered by several routes (injected, smoked, sniffed, or swallowed); but when injected particularly intravenously, morphine can produce intense euphoria and a general state of well-being and relaxation. Regular use can result in the rapid development of tolerance to these effects. Profound physical and psychological dependence can also rapidly develop, and withdrawal sickness upon abrupt cessation of heroin use; many of the symptoms resemble those produced by a case of moderately severe flu.

Morphine is infrequently encountered in the North American street drug culture. However, mainly because of its availability in hospitals, there have been several documented cases of morphine dependence among health professionals.

Drug SourceMorphine is isolated from crude opium, which is a resinous prep of the opium poppy, Papaver somniferum.

Trade NameRoxinal, MS Contin, Morphine Sulfate

Street Names"M", morph, Miss Emma

Drug CombinationsUse of morphine plus cocaine, as well as of morphine plus methamphetamine, has been reported. However, such combinations are not frequently encountered.

Medical Uses* symptomatic relief of moderately severe to severe pain;* relief of certain types of difficult or labored breathing;* suppression of severe cough (rarely);* suppression of severe diarrhea (e.g., that produced by cholera).

Physical AppearanceMorphine is legally available only in the form of its water-soluble salts. Most common are morphine sulfate and morphine hydrochloride. Both are fine white crystalline powders, bitter to the taste. Both are soluble in water and slightly soluble in alcohol.

Dosage

MedicalFor moderate to severe pain the optimal intramuscular dosage is considered to be 10 mg per 70 kg body weight every four hours. The typical dose range is from 5 to 20 mg every four hours, depending on the severity of the pain. The oral dose range is between 8 and 20 mg; but with oral administration morphine has substantially less analgesic potency (approximately one-tenth of the effect produced by subcutaneous injection) because it is rapidly destroyed as it passes through the liver immediately after absorption. The intravenous route is employed primarily for severe post-operative pain or in an emergency; in this case the dose range is between 4 and 10 mg, and the analgesic effect ensues almost immediately.

NonmedicalIrregular or intermittent users (who are not substituting the drug for another narcotic analgesic) may start and continue to use doses within the therapeutic range (i.e, up to 20 mg). However, regular users who employ morphine for its subjectively pleasurable effects frequently increase the dose as tolerance develops. To take several hundred milligrams per day is common, and there are reliable reports of up to four or five grams (4000 - 5000 mg) per day.

Routes Of AdministrationMorphine may be taken orally in tablet form, and can also injected subcutaneously, intramuscularly, or intravenously; the last is the route preferred by those who are dependent on morphine.

Short Term Use

Low Doses (single doses of 5 - 10 mg administered by S.C or IM injection in non-tolerant users)

CNS, behavioral, subjective:suppression the sensation of and emotional response to pain; euphoria; drowsiness, lethargy, relaxation; difficulty in concentrating; decreased physical activity in some users and increased physical activity in others; mild anxiety or fear; pupillary constriction, blurred vision, impaired night vision, suppression of cough reflex.

Respiratory:slightly reduced respiratory rate.

Gastrointestinal:nausea and vomiting; constipation; loss of appetite; decreased gastric motility.

Other:slight drop in body temperature; sweating; reduced libido; prickly or tingling sensation on the skin (particularly after intravenous injection).

Duration4 - 5 hours

Dependency Potentialhigh, continued use results in both psychological and physical dependency

** Codeine **

Drug SourceCodeine is found in opium in concentrations between %0.1 and %2. Because of the small concentration found in nature, most codeine found in medical products is synthesized from morphine via the methylation of the hydroxyl group found on the second non-aromatic ring.

Trade NameThere are no commercial name for products containing only codeine in US. Found under common name of codeine. Canada does have a codeine only syrup available under Paveral. Mainly found in combination products.

Street NameT-three's (Tylenol #3 w/ codeine), schoolboy, cough syrup

Medical Uses* relief of mild to moderate pain* relief of non-productive cough* relief of diarrhea

Drug CombinationsSold under many name brand products, the most popular being the Tylenol with Codeine series, the number on the tablet corresponds to the amount of codeine and caffeine found in the each tablet.

Tylenol #1 w/ codeine - 8 mg codeine, 15 mg caffeineTylenol #2 w/ codeine - 15 mg codeine, 15 mg caffeineTylenol #3 w/ codeine - 30 mg codeine, 30 mg caffeine

Tylenol #4 w/ codeine - 60 mg codeine, no caffeine

note: all tablets contain same amount of acetaminophen (300 mg)

Fiorinal (aspirin, caffeine, barbital, codeine)

Many other brand name product combinations.

Physical AppearanceTylenol w/ codeine series are imprinted with number on one side and other side is Tylenol label(McNeil).

Controlled Substance StatusAs a single product codeine is a schedule II controlled substance in the US.When combined with other non-controlled substance, and depending on amount per dose unit, codeine combined products range from schedule III to V. Canada has OTC codeine products available if product has no more than 8 mg of codeine per unit dose. Some US areas may have codeine preps available OTC, but usually require release form. As an interesting fact, a travelers handbook noted that Greece has banned codeine in that country (no idea on what it's status is now) so be careful when traveling there.

Dosage

MedicalPain relief : 30mg - 220mg oral or equivalent dose SC or IM

Diarrhea relief : 10mg - 20mg orally

Cough suppressant : 5mg - 15mg orally

NonmedicalDoses can range from 30mg up to 400mg. LD50 for codeine is 800mg in a average nontolerant person.At doses of > 250mg adverse effects tend to arise, including intense itching, flushed skin, dizziness, sedation, nausea and vomiting

Routes Of AdministrationUsually taken orally but can be injected IM or SC. The IV route is not recommended as reactions such as facial swelling, pulmonary edema and convulsions can occur.

Short Term Use

CNS, Behavioral, Subjective:Effects begin at 30mg and tend to mimic those of morphine, except sedation and euphoria are less intense.

Respiratory:same as morphine but less intense.

Gastrointestinal:same as morphine but nausea and vomiting are less common and constipation less severe.

Other:alleocodone is a schedule II drug, and when combined with other non-controlled drugs, is found from schedule III-IV.

Dosage

Medicalas a cough suppressant 5mg - 10mgfor pain relief 10mg - 30mg

Nonmedicaldoses are similar to those for pain relief

Routes Of AdministrationUsually taken orally but can be inject via three routes. Unknown if hydrocodone can be sniffed or smoked. Sniffing is likely possible.

Short Term Use

CNS, Behavioral, Subjective:Has similar effects as morphine but less sedation and euphoria

Respiratory:Less depression than morphine.

Gastrointestinal:Less likely to cause nausea and vomiting than morphine.

Other:Hydrocodone is a weaker opioid than morphine but still a effective opioid with similar potency to oxycodone.

Duration3 - 4 hours

Dependency Potentialmoderately low, much less potential than morphine

** Hydromorphone **

Drug SourceSynthetically produced from morphine.

Trade NameDilaudid

Street NameDillies

Medical Uses* relief of moderate to severe pain* relief of severe cough

Drug Combinationsmost commonly used as a single product

Physical Appearanceusually bought as tablets, or injectable solution

Controlled Substance StatusHydromorphone, like most single product opioids, is a schedule II opioid.

Dosage

Medicalfor pain relief 1mg - 2mg

Nonmedicalsame as pain relief doses

Routes Of AdministrationCan be administered orally, by three routes of injection, and by sniffing. Unknown if smoking is an effective route.

Short Term Use

CNS, Behavioral, Subjective:Hydrocodone has effects similar to morphine, except euphoria is similar to codeine, nausea and vomiting is quite rare, and sedation is practically non-existent

Respiratory:Hydrocodone depresses respiration minimally.

Gastrointestinal:Hydromorphone effects GI tract very little.

Other:Although hydromorphone's euphoria pales with other opioids it's abuse potential comes from the fact the rush experienced from IV use is very similar to heroin's.

Hydromorphone is one of the most used opioids in the relief of pain for the terminally ill. The reasons being it's minimal side effects, and high potency.

Duration3 - 4 hours

Dependency Potentialmoderately high

** Meperidine **

Drug SourceMeperidine is completely synthetic and can be produced with dichlorodiethyl methylamine and benzyl cyanide.

Trade NameDemerol

Street NameDemmiesMedical Uses* originally found to be useful for muscle spasms but the discovery of it's analgesic properties has resulted in it's almost exclusive use for relief of moderate to severe pain

Drug Combinationsusually found as a single product, with few combination products. Is found in combination with acetaminophen in Demerol APAP

Physical AppearanceDemerol tablets are small white tablets with the nameWinthrop on one side

Controlled Substance StatusSchedule II substance in US

Dosage

Medicalpain relief is achieved with approx. 50mg - 150mg injected or 200mg - 300mg oral

Nonmedicaldoses similar to those used in medical settings are used in recreational use.

Routes Of Administrationorally, three injection routes, and sniffing are possible, unknown if smoking is possible

Short Term Use

CNS, Behavioral, Subjective:same as morphine but less sedation, less intense euphoria

Respiratory:respiratory depression tends to be less common and less intense than morphine

Gastrointestinal:nausea and vomiting are reportedly common with oral use, but less when administered via injection

Duration3 - 4 hours

Dependency Potentialreported to be less than or equal to that of morphine

** Oxycodone **

Drug Sourcesynthesized from codeine

Trade Nameonly found as a compound product combined with aspirin or acetaminophen. Available in Canada as a single product in the form of a suppository

Street NamePercs

Medical Uses* relief of moderate to severe pain

Drug CombinationsPercodan is aspirin and oxycodonePercocet is acetaminophen and oxycodone

Physical AppearancePercodan tablets are color coded according to quantity of oxycodone in each tablet, the pink have ~2.5mg and the orange and green having twice as much

Controlled Substance StatusSchedule II in US

Dosage

Medical10 - 20mg oral for pain relief5 - 15mg injection

NonmedicalDoses similar to those used in a medical setting are used

Routes Of AdministrationCan be administered orally, three injection routes, sniffed and possibly smoked.

Short Term Use

CNS, Behavioral, Subjective:Same as morphine but milder.

Respiratory:Less respiratory depression than morphine

Gastrointestinal:Less constipating than morphine

Duration3 - 4 hours

Dependency PotentialModerate

** Fentanyl **

Drug SourceSynthetically produced

Trade NameSublimaze

Street NameChina white

Medical UsesMainly relief of moderate to severe pain and as a surgical anesthetic

Drug Combinationsnone

Physical AppearanceFound as a injectable solution, and a transdermal patch

Controlled Substance StatusSchedule II in US

Dosage

Medical50ug - 200ug

Nonmedicalsame range as medical use

Routes Of Administrationcan be administered via three injection routes, sniffed and smoked

Short Term Use

CNS, Behavioral, Subjective:euphoria is less than morphine

Respiratory:same as morphine but has potential to cause respiratory muscles to go into spasm and result in respiratory arrest

Gastrointestinal:less constipating that morphine

Duration1 - 2 hours

Dependency Potentialmoderately high

** Methadone **

Drug Sourcesynthetically produced

Trade NameDolophine

Street NameDollies

Medical Usesoccasionally used for pain relief, but main use is in opioid withdrawal treatment as a substitute drug

Drug Combinationsnone

Physical Appearancefound as a fruity solution for oral use, in wafers, and tablets also found as a injectable solution

Controlled Substance Status Schedule II in US

Dosage

Medical3 - 5mg provides same pain relief as 10mg morphine

Nonmedicalrarely used non-medically, but doses used are approx. same as medical doses

Routes Of Administrationcan be injected via three routes, taken orally, unknown if methadone can be smoked, can be sniffed

Short Term Use

CNS, Behavioral, Subjective:Oral use provides little euphoria and tends to block opioid receptors in brain, so commonly used as a maintenance drug during rehab.

Respiratory:Produces little depression in contrast to morphine

Gastrointestinal:produces constipation of less intensity than morphine

Other:Developed by Nazi Germany during WWII as Germany was unable to acquire adequate supplies of morphine.

Durationfirst dose last approx. 8 hours and subsequent doses last 18 - 24 hours.

Dependency Potentialoral use provides little euphoria so little abuse potential in that form. When injected, methadone give very similar effects to morphine so has similar addiction potential.

** Propoxyphene **

Drug SourceSynthetically produced with similar structure to that of methadone

Trade NameDarvon, Darvon N

Street Namenone

Medical Usesfor relief of mild pain

Drug CombinationsDarvon compound is aspirin and propoxyphene

Physical AppearanceDarvon N as pink oval pills

Controlled Substance StatusSchedule III in US

Dosage

Medicalrange from 50mg - 150mg of hydrochloride

Nonmedicalsimilar to medical dose ranges.

Routes Of Administrationcan be taken orally, three possible injection routes, no infoon possible intranasal or smoked administration

Short Term Use

CNS, Behavioral, Subjective:oral use provides very little euphoria, mild sedation; at larger doses sedation becomes quite prominent and symptoms such as staggering and slurred speech become apparent.

Respiratory:little respiratory depression in medical dose range

Gastrointestinal:little effect on GI tract

Other:IV use is reported to give rush similar to heroin;poor analgesic with standard dose providing less pain relief than standard aspirin dose

Duration3 - 4 hours

Dependency Potentiallow

** Pentazocine **

Drug Sourcesynthetically produced

Trade NameTalwin

Street Nameyellow footballs

Medical Usesfor relief of moderate to moderately severe pain

Drug CombinationsTalwin NX - pentazocine and nalaxone (opioid antagonist)

Physical Appearanceusually found in orange-yellow tablets

Controlled Substance Status Schedule III

Dosage

Medical50mg - 100mg for pain relief

Nonmedicalsimilar to medical dosage

Routes Of Administrationcan be taken orally, three injection routes, and sniffed possibly smoked

Short Term Use

CNS, Behavioral, Subjective:poor opioid, very little euphoria, mainly just sedates and clouds mind, little recreational use

Respiratory:less depression than morphine

Gastrointestinal:very little constipation or nausea, vomiting occurs

Other:as a opioid agonist/antagonist has potential to cause psychotic effects such as hallucinations, severe confusion

Duration3 - 4 hours

Dependency Potentialmoderate potential, similar to hydrocodone

Opioid Dependence And Withdrawal

Opioids have specific withdrawal and dependence characteristics common to all opioids, varying according to the specific drug. All opioids cause both physical and psychological dependence with prolonged use.

Depending on the opioid in question withdrawal can become evident after continued use in as little time as 2 weeks or as long as 2 months.

Withdrawal is commonly overstated by media and tends to be similar to bad case of flu. This is due to the fact that most opioid users don't tend to be able to acquire enough drug to result in severe withdrawal. It must be noted that physical symptoms may be similar to flu, psychological symptoms can be quite painful. Depression, mood swings, hypersensitivity to

pain are some common symptoms. Opioid withdrawal DOES NOT endanger life as does alcohol and other depressant withdrawal.

If anyone has any info that they would like to share with me and possibly have included in this FAQ, please send all mail to my mailbox at mdh@debug.cuc.ab.ca

End of FAQ

Written by: Slake.

OPIUM

Opium History Up To 1858 A.D.By

Alfred W. McCoy

Opium as Folk Pharmacopoeia

Regardless of level of development, most societies have used drugs for religion, recreation, and medicine. Discovered and domesticated during prehistoric times in the Mediterranean basin, opium became a trade item between Cyprus and Egypt sometime in the second millennium B.C.

The drug first appeared in Greek pharmacopoeia during the 5th Century B.C. and in Chinese medical texts during the 8th century A.D. Inferring from such slender evidence, it appears that opium farming first developed in the eastern Mediterranean and spread gradually along Asia's trade routes to India, reaching China by the eighth century A.D. Once introduced into China, opium gained a significant role in formal pharmacopoeia.

It was not until the 15th Century that residents of Persia and India began consuming opium mixtures as a purely recreational euphoric, a practice that made opium a major item in an expanding intra-Asian trade. Indeed, under the reign of Akbar (1556-1605), the Mughal state of north India relied upon opium land as a significant source of revenue. Although cultivation covered the whole Mughal empire, it was concentrated in two main areas--upriver from

Calcutta along the Ganges Valley for Bengal opium and upcountry from Bombay in the west for Malwa opium.

The persistent role of opiates as folk medicine and recreational euphoric for nearly 4,000 years raises very real questions about the enormous difficulties in effecting its eradication. Through interaction with opiate receptors in the brain, opium and heroin may well have an inherent biological logic that makes their mass abuse a likelihood at most times, in most societies, where ample supply of the drug is available. Historically, every society that has been introduced to opium as a commercial euphoric has consumed the entire supply made available to it.

Early European Opium Trade (1640-1773)

The earliest European expeditions to Asia also mark the start of their involvement in the region's opium trade. As Portuguese captains first ventured across the Indian Ocean during the early 16th century, they realized the potential of opium. If your Highness would believe me, Affonso de Albuquerque, the conqueror of Malacca, wrote to his monarch from India in 1513, I would order poppies...to be sown in all the fields of Portugal and command afyam [opium] to be made...and the laborers would gain much also, and people of India are lost without it, if they do not eat it.. From their ports in western India, the Portuguese began exporting Malwa opium to China, competing aggressively with Indian and Arab merchants who controlled this trade.

Eager for a commodity to barter for Chinese silks, the Portuguese imported tobacco from their Brazilian colony half a world away. Although the Chinese frustrated the Portuguese by growing their own tobacco, the pipe itself, which had been introduced by the Spanish, turned out to be the key to China's markets. Indian opium, mixed with tobacco and smoked through a pipe, was somehow pleasing to the Chinese palate. By the early 18th century, opium smoking was spreading across China, prompting the empire's first attempt at suppression in 1729 when the Emperor Yung Cheng issued an edict banning the smoking of opium.

Arriving in Asia a century after the Portuguese, the Dutch soon became active in the region's opium commerce. Instead of trading directly with China like the Portuguese, the Dutch established a permanent port at Jakarta in 1619 and began purchasing opium from Bengal in 1640 to supply Java's limited demand. As Dutch colonials won monopoly rights for Java's populous districts, their Company's opium imports from India rose dramatically from 617 kilograms in 1660 to 72,280 kilograms only 25 years later.

Dutch profits from the opium trade were spectacular. Buying opium cheap in India and selling high in Java allowed the Company a 400 percent profit on shipments in the 1670s. Opium, moreover, proved to be a key trade good that drew Asian merchants to Jakarta. By 1681, opium represented 34 percent of the cargo on Asian ships sailing out of Jakarta. No longer a lightweight luxury or medical item, opium was on its way to becoming a commodity.

Although the last of the Europeans to enter the trade, it was the British who finally completed the transformation of opium from luxury good into bulk commodity. The British East India Company had acquired coastal enclaves at Calcutta in 1656 and Bombay in 1661, but it did not become a major factor in the opium trade for another century. In the interim, a syndicate of Indian merchants up the Ganges River at Patna held a monopoly over the

Bengal opium trade, making cash advances to peasant farmers and selling the processed opium to Dutch, British and French merchants. Marching inland from their port at Calcutta, the British conquered Bengal in 1764 and soon discovered the financial potential of India's richest opium zone.

In this period, the major change involved a shift from a limited trade in opium though intra-Asian networks to an expanding European commerce that stimulated both supply and demand. In the 16th century and earlier, there had been a pre-existing, modest demand for opium in China and Southeast Asia, and low-level production of opium in India.

Working separately, European mercantile companies commercialized both opium cultivation and commerce, making it the basis of a profitable long distance trade in low-weight, high-value goods. At first, the Portuguese transported Indian opium to China. Then the Spanish developed a way to mix tobacco with opium so it could be smoked. Finally, the Dutch took advantage of this rising demand for opium, but their main market was limited to Java and some re-export to China. Through these European efforts, the problem of opium addiction became so serious in China that the Emperor had it banned in 1729.

The extraordinary profitability of this low-weight, high-value commodity was a key incentive for escalating European involvement in the Asian opium trade. In particular, the Dutch V.O.C. made a 400 percent profit on its 1679 shipments.

Increase/decrease in World Opium Production:

--Dutch East India Company (VOC) imports from India rose at a rate of 1.5 per annum during the 1660s--rising from 0.6 metric tons in 1660 to 72.3 tons only 25 years later.

--In 1699, the Dutch imported 87 tons of Indian opium for distribution to Java and the Indies.

--British exports of Indian opium to China increased from 15 tons in 1720 to 75 tons in 1773.

Changes in Opium Cultivation by Region:

Indian production increased by unknown amounts in response to stimulus of European and Indian opium traders.

Changes in Quantity of Opium Consumption by Region:

For the first time in its history, China experienced a significant, but unquantified, level of mass opium addiction.

Summary and Analysis of Trends within Epoch:

In this period, opium entered a proto-modern phase in which its capacity for growth as a major commodity first became evident. Significantly, European and Indian merchants played a catalytic role in commercializing and expanding the India-China opium trade.

It is during this era that opium's extraordinarily profitability becomes manifest. Through its peculiar properties, opium is the ideal trade good during this epoch. As an addictive drug, opium requires a daily dose giving it the inelastic demand of a basic foodstuff. Long distance sea-trade in bulk foods was beyond the capacity of current maritime technology, but opium had the low weight and high mark-up of a luxury good like cloves or pepper. In the early

modern era, opium combines the reliable demand of a basic food with the logistics of a luxury good. Compounding its profitability, the Chinese emperor reacted to the rise of mass addiction by banning opium and thus denying China the opportunity to produce opium locally to undercut the high price of Indian imports.

European Mercantilism (1773-1858)

The modern era in the global opium trade began in 1773 when the British Governor-General of Bengal established a monopoly on the sale of opium. Over the next 130 years, Britain actively promoted the export of Indian opium, defying Chinese drug laws and fighting two wars to open China's drug market for its merchants.

Under the British, Indian opium became a major global commodity, giving this modern commerce a scale and organization that distinguishes it from earlier forms. When the East India Company conquered Bengal, it took control of a well-established opium industry involving peasant producers, merchants, and long-distance traders.

In 1773, the British Governor abolished the Indian opium syndicate at Patna and established a colonial monopoly on principles that operated for the next half-century. Under the new regulations, the Company had the exclusive right to purchase opium from Bengal's farmers and auction it for export. Realizing that opium was illegal in China, the Governor barred the Company's ships that called at Canton to load tea from carrying opium, leaving actual sale of the addictive drug to the private European merchants who bid at the Company's Calcutta auctions.

In 1797 the Company eliminated the local opium buyers in Bengal and established a system of direct collection that lasted for over a century. Under the new procedures, the Company, and the colonial state that succeeded it, controlled opium cultivation, processing, and export. At its peak in the late 19th century, Bengal's opium country stretched for 500 miles across the Ganges River Valley, with over a million registered farmers growing poppy plants exclusively for the company on some 500,000 acres of prime land.

From their factories at Patna and Benares in the heart of opium country, senior British officers directed some 2,000 Indian agents who circulated through the poppy districts, extending credit and collecting opium. Processed under strict supervision at the two Company factories, the opium was packed into wooden chests, each containing forty balls and weighing 140 pounds. Bearing the Patna and Benares trade-marks, the chests were sent down to Calcutta under guard and sold at auction to private British merchants.

Since the Chinese state had damned opium as a destructive and ensnaring vice and banned all imports in 1799, British sea captains bribed Canton's mandarins and smuggled the chests into southern China where the Bengal brands commanded twice the price of the inferior local products. For its first quarter century, this system assured prosperity for British India and a stable opium supply for China. Not only did opium solve the fiscal crisis that accompanied the British conquest of Bengal, it remained a staple of colonial finances, providing from six to fifteen percent of British India's tax revenues during the 19th Century.

More importantly, opium exports were an essential component of a triangular trade that was central to England's position as a world power. Trade figures for the 1820s, for example, show that the triangular trade was large and well balanced: 22 million pounds sterling worth

of Indian opium and cotton to China; next, 20 million pounds worth of Chinese tea to Britain; and, then, 24 million pounds of British textiles and machinery back to India.

In managing this trade, the Company prized stability above profit, and for over twenty years it held India's opium exports at 4,000 chests--or 280 tons, just enough to finance its purchase of China's tea crop.

The system's success was the cause of its downfall. The vast profits of the Britain's opium trade attracted competitors. Moreover, the Company's steadfast refusal to raise Bengal's opium exports beyond the quota of 4,000 chests per annum left a vast unmet demand for drugs among China's swelling population of opium smokers. As demand drove the price per chest upward from 415 rupees in 1799 to 2,428 rupees just 15 years later, the Company's monopoly on Bengal opium faced strong competition from Turkey and west India.

Britain's most daring rivals were the Americans. Barred from bidding at the Calcutta auctions, Yankee traders loaded their first cargoes of Turkish opium at Smyrna in 1805 and sailed them around the tip of Africa to China. Through these efforts, Turkish opium remained an alternative to the Bengal brands until 1834 when the Yankee captains were finally allowed to bid at the Calcutta auctions and abandoned the long haul around Africa.

The major threat to the Company's monopoly, however, came from Malwa opium grown in the princely states of west India. Malwa opium captured 40 percent of the China market by 1811. Determined to defend their trade, the Company's directors decided to promote unlimited production in Bengal. In 1831 the Governor-General of India, Lord William Bentinck, toured the upper Ganges with revenue officers to explore new areas for poppy farming and within the decade cultivation doubled to 176,000 acres.

After the East India Company lost its charter in 1834, its informal regulation of the China opium trade collapsed, allowing profit-hungry American and British captains to take control. Indeed, the Company's demise launched a fleet of new opium clippers to tack to China against the monsoon winds. As the Company loosened its restrictions in the 1820s and then lost its monopoly in 1834, China's opium imports increased nearly ten fold--from 270 tons in 1820 to 2,558 tons twenty years later. Opium addiction spread rapidly, reaching some three million Chinese addicts by the 1830s.

In defense of its commerce, Britain fought two wars along the China coast in 1842 and 1858, forcing the empire to open itself to unrestricted opium imports. In 1838, the Emperor's launched a moralistic anti-opium campaign that threatened Britain's China trade, and London dispatched a fleet of six warships, capturing Canton in May 1839. The First Opium war ended in 1842 with the Treaty of Nanking which required China to cede Hong Kong, and open five new ports to foreign trade. But China still refused to legalize opium.

The fifteen years following the First Opium War brought a new peak in the China trade. Illicit imports of Indian opium nearly doubled, rising to 4,810 tons in 1858. At the Calcutta auctions, frenzied bidding drove opium prices and profits to new heights, making a fast run to the China coast essential and launching 48 new clippers for the opium fleet. Among the 95 clippers in the fleet, the Calcutta's Cowasjee family owned six, the Americans of Russell & Co. had eight, and the British giants, Dent and Jardine, operated a total of 27.

The era of the opium clipper ended when China finally legalized the drug trade after its defeat in the Second Opium War (1856-1858). In negotiations over the tariff provisions of this new treaty that ended the war, the British emissary Lord Elgin forced the Chinese to legalize opium imports.

In the aftermath of legalization, Chinese officials began encouraging local production, and poppy cultivation spread beyond the country's southwest. As addiction spread throughout China, imports of Indian opium rose from 4,800 tons in 1859 to 6,700 tons twenty years later. After peaking in 1880, Indian imports declined slowly for the rest of the century as cheaper, China-grown opium began to supplant the high-grade Bengal brands.

Demand Increasing Ahead of Production:

It appears that opium, once commercialized as recreational euphoric, produces a disproportionate demand that soon exceeds the original supply. In this case, the carefully controlled number of chests from Bengal soon proved insufficient for the demand in China. The result was stimulation of production in other opium regions.

Thus, Malwa and Turkish production increased to help meet China's growing demand. In the end, England capitulated to market pressures, abandoned its self-imposed restraint, and encouraged an expansion of opium production in India.

Once introduced, commercial opium stimulated demand in China beyond supply, encouraging thereby increased cultivation back in India; which, in turn, stimulated more demand in China, sparking, yet again, higher poppy plantings in India. In effect, even in this earliest era of commoditized opium trading, demand and supply increase through a process of reciprocal stimulation that makes it difficult, analytically, to determine which is the dominant cause.

During the 18th and 19th Centuries, China had a limitless capacity for opium consumption that continually outstripped all production, both local and global.

Changes in Shipping Technology:

Since there was now an unlimited amount of opium that could be grown in India, improvements in shipping technology were needed to move greater amounts to China. Hence, a competition and the appearance of the clipper ship. Speed now determined profitability in the opium trade.

Chinese Government Policy:

The Chinese Imperial decrees of 1729 and 1799 banning opium smoking and importation did not restrain the rising addiction problem. However, the legalization of opium consumption in 1858 encouraged a sharp rise in both production and consumption. With legalization, domestic opium superseded imports, making speed less important in the shipping of opium and allowing steamships to replace the clippers.

Thus, we must conclude that China's policy of prohibiting opium consumption and cultivation from 1729 to 1858 assured the East India Company a de facto monopoly over this fast growing market and created the basic underlying conditions for the hyper profitability of the India-China opium trade.

Without this prohibition on cultivation, China could have reacted the Company's aggressive exports of Bengal opium by encouraging local opium harvests and destroying both market and profits for the Indian imports. As it was, China's addicts and their near insatiable demand for the illicit drug created high profits and inspired ferocious competition among merchant captains competing for a share of this lucrative market--English out of Calcutta, Indian and English out of Bombay, and Americans out of Smyrna, Turkey.

Nature of Chinese Demand:

In the midst of the acute demographic and caloric crisis of southeastern China in the late 18th and early 19th Centuries, opium attributes as a appetite suppressant may have increased its appeal to users at a time of scarcity and high food prices. At certain periods, the use of opium may have suppressed appetite sufficiently to make its addiction economical in comparison to the cost of eating a normal diet.

Economics of European Mercantilism:

In colonial Asia of this period (1773-1858), all successful European economic initiatives involved commercialization of drugs in some form--caffeine, nicotine, or opiates. This 18th century trade transformed these drugs from luxury goods into commodities of mass consumption, making them integral to the economies and lifestyles of both Asian and Atlantic nations.

In Java after 1720, the Dutch V.O.C. collected a tax in coffee in the Priangen region of west Java and made vast profits through sales in Europe and America, becoming the globe's greatest coffee broker and gaining thereby a substitute for its substantial share of the China opium trade lost to Britain after 1720.

Consciously imitating the V.O.C., Bourbon Spanish reformers in Manila established the Tobacco Monopoly in the 1782 and, for the next century, financed their colonial administration from their exclusive control over the cultivation and sale of this addictive drug to Filipinos.

In Bengal, the British East India Company imposed a monopoly over opium in 1773 and used its sale to China to finance purchase of caffeine, in the form of tea, for export to Europe and North America. Within the monopolistic logic of mercantilism, the East India Company achieved the highest profits from opium because, from 1773 to 1830, its strong controls over key aspects--production, export, and sales.

Increase/decrease in World Opium Production:

--The area under cultivation in Bengal, India increased from 90,000 acres in 1830, to 176,000 by 1840, and, finally, a peak of 500,000 acres by 1900.

Changes in Opium Cultivation by Region:

--Reflecting directly increases in production, Indian opium exports to China rose from 75 tons in 1773 to 4,810 tons in 1858--a sustained, high-level of growth over the space of 75 years.

--Again reflecting increases in production, Turkish exports to China increased from 7 tons in 1805 to 100 tons in 1830--creating another instance of steady, high-level growth in production over a protracted period.

Changes in Quantity of Opium Consumption by Region:

--Rising from insignificant levels in the early 1700s, by the 1830s China had an estimated 3 million opium smokers.

--US imports of opium rose 8 tons in 1840 to 62.7 tons in 1858.

Summary and Analysis of Trends within Epoch:

From the late 18th century onward, opium became a major trade commodity. Under the British East India Company (BEIC), centralized controls accelerated the export of Indian opium to China--from 13 tons in 1729 to and 2,558 tons in 1839. Using its full military and mercantile power, Britain played a central role in making China a lucrative drug market.

The Company's steadfast refusal to raise Bengal's opium exports beyond its self-imposed quota of 4,000 chests per annum left a vast unmet demand for drugs among China's swelling population of opium smokers. When demand drove the price per chest upward from 415 rupees in 1799 to 2,428 rupees just 15 years later, the East India Company's monopoly on Bengal opium faced competition from Turkey and west India.

As the Company loosened its restrictions in the 1820s and then lost its monopoly in 1834, China's opium imports increased nearly ten fold--from 270 tons in 1820 to 2,558 tons twenty years later. Opium addiction grew rapidly, reaching some three million Chinese addicts by the 1830s. Simultaneously, China's illicit imports of Indian opium nearly doubled, rising to 4,810 tons in 1858.

High Imperial Opium Trade (1858-1907)

During the latter half of the 19th century, opium became a major global commodity. Across the Asian opium zone, from the Balkans to Manchuria, there was a steady increase of local opium cultivation and consumption. Moreover, in the latter half of the 19th century, the modern pharmaceutical industry made opiates a drug of mass abuse in the cities of the West--Europe, the Americas, and Australia.

By the early 20th century, opium and its derivatives, morphine and heroin, had become a major global commodity equivalent in scale to other drugs such as coffee and tea.

In retrospect, the growth of mass narcotics abuse in the West seems part of the transformation of diet and health care in the late 19th century. In an era when Western medicine had still not developed genuine therapeutic remedies, self-medication with opium and the profession's reliance on morphine injection encouraged drug abuse.

Indeed, opium was a genuinely effective against the gastrointestinal diseases that were epidemic in the cities of 19th Century England and America. Introduced to skeptical American doctors in 1856, the hypodermic syringe proved an effective means of relieving pain with morphine injection, and by 1881 many physicians used the drug as a panacea for wide range of illness.

With the approval of the medical profession, Western pharmaceutical manufacturers such as Bayer and Parke-Davis began selling substantial quantities of opiates and coca in the form of popular remedies. Such successful marketing made mass addiction to cocaine and heroin a significant feature of late 19th century life in the West.

Soon after the Bayer Company introduced heroin as a non-addictive substitute for morphine in 1898, the American Medical Association (AMA), continuing the profession's long reliance on opiate medications, initially endorsed the new drug as safe for respiratory ailments.

The spread of mass addiction was part of a new diet in the industrial nations based on a global trade in proteins and stimulants. After a century of constant dietary habits, the average Englishman's consumption of sugar, jumped four-fold from 1850 to 1900. During the same period, England's per capita consumption of tea increased three-fold.

Similarly, in the United States between 1865 and 1902 coffee consumption increased nearly three-fold, while sugar jumped four-fold. The simple 18th century diet of milled grains had given way to one spiced with large quantities of protein (eggs and beef), glucose (sugar), and stimulants (coffee and tea).

If an energized diet of proteins, glucose and caffeine could be used to stimulate the body through a long working day, then narcotic-based medicines could be used to relax it in the short hours of rest.

Paralleling the growth of sugar and coffee use, American consumption of opium rose over four-fold from the 1840s to the 1890s, and the number of addicts peaked at 313,000 in 1896. In the United Kingdom, sales of patent medicines, most of them opium-based, increased almost seven-fold between 1850 and 1905. Significantly, the average consumption of opium per 1,000 population increased from 1.3 pounds in 1827 to over 10 pounds 50 years later.

Reflecting and reinforcing these global changes, the legalization of opium in China quickly transformed the country into the world's leading producer. After the Second Opium War ended in 1858, Chinese officials encouraged local production, and poppy cultivation spread beyond the southwest to nearly every province. As addiction rose throughout China, imports of Indian opium increased from 4,800 tons in 1859 to an historic high of 6,700 tons in 1879. Despite the growth of Indian imports after 1858, most of the higher demand was supplied by Chinese domestic production.

By the 1880s, China was in the midst of a major opium boom, particularly in the rugged southwestern provinces of Szechwan and Yunnan. Observers claimed that China's leading opium producing province, Szechwan, was harvesting 10,000 tons of raw opium annually. In 1881, the British consul at Yichang estimated the total opium production in the southwest at 13,525 tons, a figure that at first seemed exaggerated. Twenty-five years later, however, the first official statistics showed that Szechwan and Yunnan were in fact producing 19,100 tons, equivalent to 54 percent of China's total harvest.

Although estimates varied widely, by 1885 China was probably growing twice as much opium as it was importing. By 1906, China had 13.5 million addicts consuming some 39,000 tons of opium. With bountiful supplies and legal retail sales, China had 27 percent of its adult males addicted to opium--a level of mass addiction never equaled by any nation before or since.

During the 19th century, Southeast Asia experienced a confluence of socio-economic forces--demand, supply, and state policy--that expanded its total opium trade and the degree of European dominance. First, Chinese migration to Southeast Asia accelerated the demand for drugs throughout the 19th century, creating a substantial market of wage laborers with the means and motivation for opium smoking. Pressed for revenues to finance public works, European colonial governments established opium farms and leased these revenue contracts to overseas Chinese merchants.

No mere vice, opium became a major factor in Southeast Asia's economic growth in both public and private sectors, reflecting and reinforcing the region's ongoing modernization. In many parts of 19th century Southeast Asia, the opium franchises were integral to the rise of overseas Chinese capital.

In the late 19th century, these franchises gave way to state-licensed opium dens that became a unique Southeast Asian institution, spreading and sustaining addiction throughout the region. At first, the region's colonial governments had restricted their role to importing the opium from India and auctioned opium farms, or franchises, to the highest bidder, usually a consortium of Chinese.

In 1881, however, the French administration in Saigon established the Opium Regie, a direct state marketing monopoly that showed greater profitability. By century's turn, every Southeast Asian state, from Burma to the Philippines, had either an opium monopoly or an officially licensed franchise.

In 1930, for example, Southeast Asia had 6,441 government opium dens that served 272 tons of opium to 542,100 registered smokers. In no other region of the world did so many governments promote mass drug abuse.

Dutch opium commerce on Java fostered both a vast state enterprise and a large illicit traffic. From 1640 to 1799, the Dutch East India Company (V.O.C.) imported an average of 56 tons of opium annually, large quantities for their day that rose steadily throughout the 19th century to 208 tons by 1904.

By starting their retail monopoly two centuries before the other European powers, the Dutch developed a large clientele of native Javanese opium smokers. Despite efforts to reduce sales, the Dutch monopoly was still operating 1,065 opium dens in 1929 that retailed 59 tons of opium to 101,000 registered smokers.

While opium addiction weakened the local populations, it strengthened the finances of colonial governments. In 1905-1906, for example, opium sales provided 16 percent of taxes for French Indochina, 16 percent for the Netherlands Indies, 20 percent for Siam, and 53 percent for British Malaya. Despite heavy opium consumption, Southeast Asia did not become a significant opium producer until the 1950s, a full century after China.

Afraid that smuggling from their remote tribal highlands would undercut high official prices, the state monopolies did everything possible to discourage local opium production. Although poppy cultivation did spread somewhat in the highlands during the decades before World War II, the region still remained a minor producer.

Finding even this level of cultivation troublesome, Burma, Thailand and Indochina mounted suppression operations that reduced region's production to only 15.5 tons in 1940--far from the Golden Triangle's 3,050 ton harvest a half century later.

Increase/decrease in World Opium Production:

--In 1907, the first systematic survey of opium indicated that world production stood at 41,624 tons--over ten times the 1994 world illicit opium supply.

Changes in Opium Cultivation by Region:

--Rising from low levels in the 1840s, China produced 35,000 tons of raw opium in 1906-07--equivalent to 85 percent of world opium supply.

--Reflecting changes in production levels, Indian opium exports to China rose from 4,810 tons in 1858 to peak at 6,700 tons in 1879. Thereafter, Indian exports dropped by half to 3,368 tons by 1905, and then dwindled to insignificant amounts after 1913.

--Of the 41,624 tons produced worldwide, Southeast Asia produced 2 tons; Southwest Asia (Turkey, Iran, India, Afghanistan) 6,258 tons; and China 35,364 tons.

Changes in Quantity of Opium Consumption by Region:

--The number of opium smokers in China increased from 3 million in the 1830s to 13.5 in 1906.

--US opiate addicts increased from low levels in the 1840s to a historic high of 313,000 by 1896.

--US imports of all opium increased dramatically from 32.8 tons in 1859 to 298.1 tons in 1907.

--Average American consumption of opium increased four-fold from 12 grains per person in the 1840s to 52 grains in the 1890s.

Summary and Analysis of Trends within Epoch:

During this period of high imperialism (1858-1907), Britain loses the near monopoly over the Asian opium trade that it enjoyed under mercantilism and the drug becomes, for the first time in its history, a free-market commodity. Traded in mass volume through unrestricted trade, opium gains new markets in the West and expands its trade in Asia.

To maintain profits and tax revenues, European colonial regimes in establish state opium monopolies throughout Southeast Asia in the 1880s and 1890s, continuing an element of the restrictive mercantilism prevalent in an earlier epoch.

While controls remain over opium sales within the colonies, its international trade is now unrestricted. In Asia, China removes its ban on opium cultivation and thereby undercuts the hyper-profitability of British exports. Now fully commoditized, opium spreads beyond its Asian trade axis to become, through the modern pharmaceutical industry, a major item of mass consumption in the West. Driven by this global commerce, world opium production reaches an historic peak of 41,000 tons in 1907--10 times its level in 1993.

Multilateral Control & Syndicate Crime (1907-1940).

In the late 19th century, a Christian crusade, through skillful propaganda and lobbying, transformed itself from a populist movement into a novel form of drug diplomacy that continues today under the United Nations.

Led by Protestant clergy and laity, a global anti-opium movement created mass support for the imposition of legal controls over individual drug abuse, culminating in a series of treaties that restricted the global narcotics trade.

Starting with the Shanghai Opium Commission of 1909 and the International Opium Conference at The Hague in 1911-1912, these early meetings led to a succession of opium control treaties under the League of Nations in 1925 and the United Nations after 1945.

On balance, the most profound and lasting legacy of this movement remains the underlying concept of applying the force of law and police to regulate what individuals do to and with their own bodies. The intrusion of the state into a realm previously thought personal and private marks a small but still significant watershed in modern political history.

As the anti-opium movement grew at century's turn, narcotics were already a global commodity that sustained heavy opiates abuse in China, Europe, and America. With an addict population representing over a quarter of the country's adult males, opium had become a staple of the China's consumer economy.

Moreover, during the late 19th century the steady rise of mass opiates addiction in England and America added a new dimension to the global drug trade, forming a resilient commercial connection between Asian opium growers and Western consumers.

Launched when the drug was already a major commodity, the anti-opium movement's goal of a total prohibition produced a contradictory legacy. The movement did force governments to cease active promotion of drug use through licensed dens or patent medicine sales. Paralleling these prohibition efforts, however, new criminal syndicates quickly emerged in the major cities of Asia and the West to organize a global traffic in illicit drugs.

Between 1895 and 1910, moreover, medical opinion within the U.S. turned against the mass prescription of opiates. From the 1870s onward, a growing number of doctors in both the United Kingdom and the United States documented the dangers of addiction from repeated opiate use.

Moreover, research into bacteriology discovered the causes of previously incurable diseases, thereby discouraging the use of broad-spectrum palliatives. In a sharp reversal of past practice, in 1920 the AMA passed a resolution recommending the prohibition of heroin.

The early anti-opium movement began as a loose alliance between British Protestants, China missionaries, and Chinese imperial officials. Formed in 1874, the Anglo-Oriental Society for the Suppression of the Opium Trade soon attracted the patronage of the Archbishop of Canterbury.

For 30 years Britain's missionaries and moralists fought a relentless campaign that culminated in 1906 when Parliament passed a motion to end India's opium exports. With strong mandates for suppression, a year later British and Chinese diplomats agreed on a ten-year, step-by-step reduction in both Indian imports and Chinese cultivation.

When Britain finally abandoned its advocacy of the Asian drug trade in 1907, opium had become a global commodity comparable in scale to the commerce in stimulants such as coffee and tea. Representing about 85 percent of world production, China's opium harvest of 35,000 tons sustained 13.5 million addicts, or a quarter of its adult male population.

After the revolution of 1911, China's new Republican government proved corrupt and its opium suppression campaign faltered. China's poppy cultivation revived, morphine and heroin pills appeared as substitutes for smoking opium, and the new Republic's cabinet was found taking a bribe from an opium syndicate. Nonetheless, in January 1919, the Republic burned the last chest of Indian opium at a public ritual before invited guests at Shanghai. After more than 300 years, the India-China opium trade had ended.

While Britain engaged in bilateral negotiations with China, the United States sought a solution through multilateral drug diplomacy. After occupying the Philippine Islands in 1898, the United States discovered Manila had 190 dens retailing a total of 130 tons of opium. Responding to pressures from the anti-opium movement in the US, in 1903 the colonial regime appointed the Episcopal missionary Bishop Charles Brent and two medical doctors to an investigative opium committee that recommended total prohibition.

Between 1906 and 1908, the U.S. regime banned opium smoking in the Philippines, becoming the first American government to outlaw narcotic drugs.

The Philippine ban launched America's attempts at domestic suppression and drug diplomacy. Aware that opium smuggling from China was sabotaging the Philippine prohibition, Bishop Brent convinced President Theodore Roosevelt to organize the first international opium commission.

With Brent in the chair, delegations from thirteen countries met at Shanghai for a month in 1909, passing unanimous, non-binding resolutions that urged the gradual suppression...of opium. Two years later, the United States used its influence to draft The Hague Opium Convention which required each signatory nation to pass its own domestic drug legislation.

As a party to the Convention, the United States fulfilled its diplomatic commitments in 1914 when Congress passed the Harrison Narcotics Act, the country's first federal law restricting drug use.

In 1925, the League of Nations convened the Geneva Conference, launching a new round of drug diplomacy, moving away from voluntary national laws to mandatory international controls over drugs.

Restrained by the colonial lobby, this cautious diplomacy produced international treaties that gradually restricted the right of governments to traffic in narcotics, producing an 82 percent decline in world opium supply--from 42,000 tons in 1906 to 16,000 tons in 1934.

Although none of Southeast Asia's states actually abolished their opium monopolies, all made gestures that reduced the region's opium sales by 65 percent in the fifteen years after World War I. The Netherlands Indies, for example, cut the colony's consumption by 88 percent, from 127 to 15 tons.

Although these reforms reduced Southeast Asia's legal opium sales, they could not eradicate a mass demand for the drug cultivated by three centuries of colonial rule. As soon as governments slashed imports or closed opium dens, smugglers and dealers emerged to service the unmet demand. On the mainland, Thailand and Indochina found it impossible to close their mountain borders to the overland caravan trade from Yunnan and Burma. With 50 percent of the region's smokers and 70 percent of its dens, Bangkok and Saigon were Southeast Asia's premier opium markets, offering high profits which drew the caravans southward from the opium hills.

Republican China's attempts at opium prohibition expanded both production and consumption. After 1906, the reduction in British imports and Chinese suppression led gradually to several negative developments: an increase in China's opium cultivation; a shift in consumption from domestic opium to imported heroin; and a centralization of criminal controls over the illicit opiates trade.

Significantly, China's experience in the decades before World War II demonstrated that the international opium trade had already developed a resilience that would allow it to survive almost any attempt at suppression.

After 1909, China's early attempts at eradication created a demand for illicit morphine and opium. As Szechwan's opium production declined, Shanghai's licensed syndicates, notably the Green Gang, began importing morphine and heroin from Europe. Moreover, this localized suppression in Szechwan stimulated both the spread of cultivation to other provinces and smuggling of illicit opiates into China.

Between 1911 and 1915, Japanese traders smuggled major supplies of morphine and heroin into China. By 1923, Shanghai syndicates were importing 10.25 tons of heroin from Japan and Europe annually to meet consumer demand.

Starting in the late 1920s, the country's rising criminal syndicates shifted from the import of heroin to its manufacture and distribution. On balance, the growth of the heroin trade in northeast China was a market response to both global and local attempts at suppression.

In the decade following the League's first attempt at opiates control in 1925, Shanghai emerged as a major center for illicit heroin. During the 1930s, China began to supply a substantial, but unquantifiable, share of the U.S. domestic drug market. In 1931, the League of Nations imposed restrictions on the manufacture of heroin in Europe, and just three years later the U.S. Treasury attache in Shanghai noted a sudden shift of the traffic in narcotics from Europe to the Orient.

When the Geneva convention banning European heroin exports took effect in 1928, Europe's criminal entrepreneurs moved first to Istanbul, the center of a Turkish drug trade which harvested 845 tons of opium in 1928 and manufactured 13.2 tons of heroin and morphine in 1932.

Pushed by that city's violent criminal milieu and pulled by the scale of the Asian drug trade, leading European drug dealers such as the Eliopolos brothers moved to Shanghai and Tientsin in the early 1930s. In his 1934 report to Washington, the U.S. Treasury attache in Shanghai reported that there had been an influx into China of individuals formerly identified with the traffic in Europe.

In particular, the Jewish syndicates that dominated New York's drug trade under the leadership of Yasha Katzenberg and Louis Lepke Buchalter sent agents to purchase heroin through European dealers based in Shanghai.

Simultaneously, Shanghai's Green Gang leader Tu Yueh-sheng emerged as the city's leading drug dealer and a key intelligence operative for the Nationalist Government--an alliance that protected the narcotics network from the regime's anti-opium campaign of the 1930s.

By 1934, the U.S. Treasury attache in Shanghai reported that the Green Gang leader was the opium King of the nation. Through his close relations with the Nationalist regime, Tu's

cartel was a major force in the Yangtze River opium trade that dominated China's drug traffic.

After the annual harvest in the southwestern highlands, according to the US Treasury agent in Shanghai at least 18,000 tons of Szechwan and 10,000 tons of Yunnan opium passed through the major river ports downriver to Shanghai. At the city of Hankow, half way down Yangtze, the government's Special Tax Bureau collected $20 million in annual opium transit fees.

Indicative of Tu's control, the head of the government's Opium Suppression Bureau, was an active member of the Green Gang who still remains loyal to his benefactor, Tu Yueh-sheng. In effect, the League's attempt at global regulation and the Nationalist regime's local suppression combined to expand China's illicit narcotics traffic.

Moving beyond simple opium growing, China had emerged as the world's main heroin manufacturer. As League regulations barred diversion of heroin from legal laboratories to criminals, Shanghai's Green Gang emerged as Asia's first major heroin producing syndicate in the 1930s.

Causality underlying above changes:

Over the space of two centuries, China had thus progressed from opium importer to heroin exporter through the intersection of three key factors--a global commodity trade in opiates, the failure of successive interdiction campaigns, and an alliance between drug syndicates and military intelligence services.

Increase/decrease in World Opium Production:

--World opium production declined from 41,624 tons in 1907 to an estimated 16,653 tons in 1934.

--Licit world heroin production declined from an estimated 20,000 lbs. in 1926 to only 2,200 lbs. in 1931.

Changes in Opium Cultivation by Region:

--Although world total declines markedly during this period, the percentage of world production in each region within the Asian opium zone remains relatively constant.

Changes in Quantity of Opium Consumption by Region:

--Between 1896 and 1924, the number of opiate addicts in the United States declines from 313,000 to an estimated 200,000. --Although there is no indication of any decline in overall level of addiction in China, opium smoking declines and heroin use increases rapidly.

Summary and Analysis of Trends within Epoch:

Anti-Opium Movement:

Within the Protestant churches of England and America, a moral reaction to the excesses of a market-driven expansion of drug abuse inspired a global anti-opium movement in the late 19th Century. Inspired by the larger temperance movement, the anti-opium crusade gained

its force from the institutional strength of the Churches and its urgency from (1.) the influence of their China missions which felt stigmatized by the European opium trade; and, (2.) a moral revulsion against the excesses of alcohol and narcotics. Through the religious origins of the anti-opium movement, the Western, particularly American, debate over drugs becomes bound up in the metaphor of Christian warfare against evil with the parallel political goal of total extirpation.

Law and Body:

For the first time in the modern era, the anti-opium movement, in alliance with the larger temperance crusade, succeeded with new laws from the state restricting the individual's control over the body.

Under the laissez-faire principles of 19th Century social practice, the state did nothing to restrict the individual's right to indulgence. With the passage of the Harrison Narcotics Act in 1914, the American state, for the first time, imposed the force of law over the right to use or abuse the body as the individual saw fit. This change in law constitutes a significant turning point in American social practice.

Failure of Prohibition:

The prewar attempt at multilateral controls over narcotics had a mixed result. In the West, the stronger state apparatus could actively influence social behavior and reduce drug consumption through a ban on legal sales. In the colonies with strong, authoritarian states, such as British India, opium restrictions were even more effective than in the West. But in Third World areas with weak states, such as China, the attempt at prohibition produced a florescence of organized criminality.

Thus, in the 1920s, the legal opium trade, whether by states or corporations, yields to a transnational criminal trade with powerful Chinese syndicates in Shanghai supplying organized crime groups in the United State. With the end of alcohol prohibition in 1932, American syndicates became even more dependent upon drug trafficking, elaborating their transnational contacts and expanding the illicit trade.

One of the main consequences of multilateral controls was the rise of organized crime that blunts the effectiveness of drug prohibition, forcing consumption to the social margins in the First World and production to the spatial margins in the Third. Although repression does reduce both production and consumption, the high profits inherent in the opiates traffic remain to sustain criminal syndicates which now act as an unintended market response to limit state control over the drug trade.

Despite all these considerable drawbacks, multilateral controls do have their successes. By limiting the power of states and corporation to traffic in drugs without restriction, the League of Nations did effect significant reductions in the gross consumption and production of narcotics.

Through these efforts, the constant, century-long upward trajectory in drug abuse was finally broken, and, for the first time since the 18th century, both use and production began to decline. Through these efforts, world opium production declined from 41,600 tons in 1907 to 16,600 tons in 1934, while licit world heroin production, much of it for recreational use, dropped sharply from an 20,000 lbs. in 1926 to only 2,200 lbs. in 1931.

Although the political parameters of the world drug trade in the prewar era were distinct, the legacy of multilateral controls, today found in the UN Commission on Drug Abuse Control, might well prove a viable alternative to our recent attempts at bilateral eradication.

War & Transition (1940-1947)

During World War II, restrictions on shipping and strict port security produced a marked hiatus in global opium trafficking. In sum, the war cut the long-distance smuggling routes between Asia and the West, confining the drug traffic to regional markets. Denied illicit opiates from Asia, the United States drew limited supplies of low-grade heroin from Mexico that failed to meet even a fraction of consumer demand. By the end of the war, the US addict population had dropped to an historic low of some twenty thousand.

In the Middle East, Turkey and Afghanistan continued to supply the large Iranian market without serious disruption. Similarly, China sustained its large addict population from domestic production, with considerable assistance from the Japanese occupation forces who were active participants in the heroin traffic. In Southeast Asia, however, local opium monopolies were cut off from their major source in India and were forced to expand domestic production to meet existing demand.

Despite extensive opium consumption during the colonial era, Southeast Asia had remained a minor producer. In 1936, for example, the Shan States of Burma produced only 8 tons of raw opium, while Laos and northern Vietnam together produced 7.5 tons in 1940. Since India supplied their monopolies with low-cost opium, governments had no reason to encourage local cultivation. How then do we account for the marked increase in the Golden Triangle's opium production of 15.5 tons in 1940 to 3,050 tons in 1989?

The Golden Triangle's rise as an illicit opium producer began slowly during World War II and then expanded rapidly in postwar decades. Cut off from sources in India and China by the war, the French Opium Monopoly reversed its policy of suppression and encouraged poppy cultivation among the colony's hill tribes, particularly the Hmong of Laos and Tonkin, raising Indochina's opium production from 7.4 tons in 1940 to 60.6 tons in 1944.

This 800 percent increase in the local harvest was sufficient to maintain supplies for the colony's 100,000 plus addicts and allow a rise in drug revenues from 15 to 24 million piasters.

During the war, moreover, Thailand annexed the Shan States of northeastern Burma and used its military occupation to supply Bangkok's monopoly with smoking opium. In May 1942, the Thai Northern Army marched into the Shan market town at Kengtung where Major General Phin Choonhawan, governor of what Bangkok now called the United Thai State, established a military administration.

A few months later, the Thai Opium Monopoly imported 36 tons from the Shan States, raising opium revenues to a record level.

At war's end, when Japanese forces began to suffer reverses on the Indian front, Bangkok ordered Governor Phin home from Kengtung and demobilized his Northern Army. Although this operation was a minor footnote to the war's main battles, some of the political links that would later bind these disparate highlands into the Golden Triangle opium zone were forged during the Thai occupation.

Significantly, after World War II many of the key Thai military who dominated the country's politics and controlled the opium traffic with Burma were veterans of Shan State occupation.

Increase/decrease in World Opium Production:

--There is no accurate data of any description on world opium production for this period.

Changes in Opium Cultivation by Region:

--In Burma, opium production increased from 8 tons in 1936 to an approximate 36 tons in 1942.

--In French Indochina (Laos and North Vietnam), opium production increased from 7.4 tons in 1940 to 60.6 tons in 1944.

--Mexico experienced some increase in opium production in response to demand from the United States.

Changes in Quantity of Opium Consumption by Region:

--In the United States, the number of heroin addicts decreased from an estimated 200,000 in 1924 to just 20,000 in 1944-45.

Summary and Analysis of Trends within Epoch:

Developments in the drug trade during World War II show, as China would after the war, that perfect coercion can have an influence, direct and dramatic, on the international heroin trade. Massive wartime security over ports, impossible in peacetime, meant an end of drug smuggling to the United States. By implication, less than perfect coercion will little impact on the global narcotics traffic and will, under most circumstances, produce minor seizures that will serve as a surcharge that will be passed on to consumers.

Cold War Opium Expansion (1948-1972)

The forty years of the Cold War brought major changes to the world's illicit opium traffic. The Communist victory in China eliminated the world's major opium market within a decade, and simultaneously forced remnants of the old Nationalist regime into margins of Southeast Asia where they played a catalytic role in expanding that region's drug traffic.

Although the Asian opium zone contracted geographically, Cold War geo-politics, combined with illicit market forces, stimulated a steady increase in opium production in the remaining area, which now stretched from Turkey to Thailand.

Supplied by the Asian zone, other markets expanded their consumption of opiates steadily during this period. With morphine base from Turkey, the Corsican syndicate laboratories of Marseilles, the so-called French connection, processed an estimated 80 percent of the high-grade No. 4 heroin consumed in the US from 1948 to 1973, nearly a quarter century.

Similarly, Turkey and Afghanistan produced smoking opium for the near insatiable demand among the million plus opium smokers of Iran, which became, after the Chinese revolution, the world's leading opium consumer.

After 1949, the Chinese Communist regime used a mix of unrestrained repression and social reform to eradicate the world's largest opium market. By the mid 1950s, highland opium areas had converted to new crops, dealers had been executed, and the country's estimated 10 million addicts has been forced into compulsory treatment.

The collapse of the Nationalist Chinese regime in 1949 forced its remnants into the drug markets of Hong Kong and Southeast Asia where they soon played a catalytic role in an expansion of opium production. In 1949, Shanghai's narcotics syndicate fled to Hong Kong where they soon opened heroin refineries. Suffering reverses in a struggle for control of the colony's heroin trade against local syndicates, Green Gang faded by the mid 1950s and was replaced by small syndicates of ethnic Chiu Chau criminals who traced their origins to nearby Swatow on China's south coast.

Using the Green Gang's chemists, these new narcotic networks expanded the colony's heroin consumption during the 1950s and then extended their operations into Southeast Asia in the 1960s. Significantly, Hong Kong syndicate chemists opened the first No. 4 heroin laboratories along the Thai-Burma border in the late 1960s, introducing the technology that made the Golden Triangle the world's largest heroin producer.

Through an accident of history, the southern borders of China and the Soviet Union, a major fault line of Cold War confrontation, happened to parallel the Asian opium zone. Since the 18th Century, opium has been cultivated as a cash crop in a highland zone that extends for 5,000 miles across the southern rim of Asia from Turkey to Thailand. During the forty years of the Cold War, the coincidence super power confrontation and opium cultivation made geo-political pressures a real force in shaping the political economy of this zone.

As various national intelligence agencies mounted special operations along the Asian zone, they found that the region's opium brokers and ethnic warlords were their most effective covert-action assets. Surveying the steady increase in world opium production since the end of World War II, we can thus discern periodic surges in opium supply that coincide with ethnic conflicts or special operations in the drug zones.

The sudden growth of Golden Triangle opium production in the 1950s appears, in retrospect, a response to two stimuli. Reacting to international pressures, governments abolished legal opium sales and thereby created a sudden demand for illicit opiates in the Southeast Asia's cities.

Moreover, an informal alliance among four intelligence services--Thai, American, French and Nationalist Chinese--played a catalytic role in promoting the production of opium in northern Laos and the Shan Plateau of northern Burma. In particular, the Nationalist Chinese (Kuomintang, or KMT) occupation in 1950, combined with the Shan secessionist revolt after 1958, transformed the Shan States into a region of conflict that reduced government control and allowed a marked expansion in local opium production.

During the First Indochina War (1947-54), French intelligence officers integrated their covert warfare with the Golden Triangle opium trade through a motivation that seems, on its face, simple. Denied funds by National Assembly, French intelligence merged the opium supply of Laos with the drug demand of Saigon to fund covert operations against Vietnam's communists.

After the French colonial regime abolished the Opium Monopoly in 1950, military intelligence took control of the drug trade. French paratroopers fighting with Hmong guerrillas in Laos and Tonkin shipped their clients' opium south to Saigon on French military aircraft where it was sold in smoking dens run by the Binh Xuyen bandits, a criminal syndicate that controlled the city. Through this operation, French intelligence, particularly the SDECE, integrated narcotics into Indochina's political economy and its anti-Communist political forces.

Across the Mekong in Burma and Thailand, an alliance of intelligence services--Taiwan, Thailand, and US--fought a purer kind of covert warfare by operating indirectly through their local clients.

Controlling the opium hills of northeastern Burma, Nationalist Chinese irregulars supplied the demand for drugs in Bangkok. To provide logistic support for their forces, the Nationalists forged a tactical alliance with Thailand's dominant military leader, Police General Phao Sriyanonda, that soon evolved into a de facto division of the Burma-to-Bangkok opium trade.

Initially, the Nationalist Chinese forces invaded Yunnan Province in southwest China, seeking to inspire a mass uprising against the new Communist regime. After at least three failed invasions of Yunnan with heavy losses of men and equipment in 1951-1952, the KMT forces fell back into Burma's prime opium lands between the Salween River and the China border--7,300 troops in the Wa States and 4,400 further south in Kengtung State.

As allied aid gradually declined, the Chinese KMT irregulars turned to opium trading to finance their operations. Forcing local hill tribes to produce opium through a mix of coercion and market incentives, the Nationalist troops presided over a massive increase of poppy cultivation on the Shan Plateau and sent opium caravans south into Thailand to supply the region's growing illicit markets.

After a joint Burma-China military operation evicted them from the Shan States in 1961, the KMT forces established new base camps just across the border in Thailand and from there dominated the Shan States opium trade until the early 1980s. During their decade-long occupation of Burma's prime opium lands between the Salween River and the Chinese border, the KMT fostered a generation of local opium warlords such as Olive Yang, Lo Hsing-han, and Khun Sa who remained in Burma after the KMT departure to struggle, as both antagonists and allies, for control of the local traffic.

By the mid 1960s, the high profits of the Shan opium trade financed the formation of new armies, notably Khun Sa's Shan United Army (SUA), that would challenge Nationalist Chinese dominion and expropriate much of the traffic by the late 1970s. Even after the KMT's control faded, opium continued to dominate the region's economy, corrupting all contenders for control of Burma's northeast--Shan rebels, Chinese warlords, the Communist Party of Burma, and Rangoon's military regime.

By the mid-1960s, Southeast Asia had a self-contained narcotics industry producing enough raw opium to sustain addicts in the region's cities. Following a pattern seen elsewhere, local demand raised the region's opium harvest to levels sufficient for an eventual entry into the world market, and then sustained it during periodic downturns in global demand. Although Hong Kong's chemists had been producing heroin from Southeast Asian opium since the mid 1950s, heroin laboratories did not open in the Golden Triangle until the US military presence in South Vietnam created a local demand for No. 4 heroin.

In 1968-1969, Hong Kong syndicate chemists opened a cluster of heroin laboratories at the epicenter of the Golden Triangle. Controlled by the Nationalist Chinese generals in Thailand

and the Commander of the Royal Lao Army, these laboratories produced substantial quantities of 90 percent pure heroin.

Fueled by these nearly limitless supplies, heroin use among US troops in South Vietnam reached epidemic proportions. In September 1970, Army medical officers questioned 3,103 soldiers of the American Division and found that 11.9 percent had used heroin since their arrival in Vietnam.

In November, an Army Engineers battalion in the Mekong Delta reported that 14 percent of its troops were regular heroin users. In 1972, the White House Office for Drug Abuse Prevention interviewed 900 enlisted men who had returned from Vietnam in September 1971, the peak of the epidemic, and found that 44 percent had tried opiates while in Vietnam and 20 percent regarded themselves as having been addicted. The full extent of the problem was not revealed until 1974 when the Office for Drug Abuse Prevention published later surveys showing that 34 percent of US troops in Vietnam had commonly used heroin. Assuming this figure to be correct, then by mid 1971 there were more American heroin users in South Vietnam (81,300) than there were in the entire United States (68,000).

The causes underlying the GI drug epidemic were complex. In retrospect, however, boredom and bad morale provided much of the motivation. Under President Nixon's Vietnamization program launched in 1969, US troops were confined to cantonments as a strategic reserve for ARVN, and most units, without a clear mission, suffered a sharp decline in morale.

With days stretching into months without event or ending, soldiers apparently took heroin to dull the psychological pain and accelerate the 365-day clock that marked the maximum tour of each soldier. Not surprisingly, the accelerated withdrawal of U.S. combat forces in 1971-1972 forced Southeast Asian syndicates to seek new markets for their heroin production.

Increase/decrease in World Opium Production:

--World opium production dropped dramatically from an estimated 16,653 tons in 1934 to only 1,094 tons in 1970.

Changes in Opium Cultivation by Region:

--During the 1950s, all opium production in China was eradicated, eliminating the producer of 85 percent of total world production in 1906-07.

--For the first time, Southeast Asia's Golden Triangle region becomes a significant opium producer--increasing from 15.5 tons in 1940, to 97 tons in 1944, to 713 tons in 1970. By 1970, the Golden Triangle accounts for 67 percent of world illicit opium supply.

--In Burma, opium production rose from 8 tons in 1936 to 500 tons in 1970.

--In Southwest Asia (Iran, Afghanistan, India, Turkey) opium production dropped from 1,126 tons in 1934 to 381 tons in 1970.

--Rising from low, unknown levels, Mexican opium production reached 15 tons in 1970.

Changes in Quantity of Opium Consumption by Region:

--The US addict population rose from 20,000 in 1945, to 68,000 in 1969, to an estimated 559,000 in 1973.

Summary and Analysis of Trends within Epoch:

Production Areas:

External intervention in the remote tribal areas along the Asian opium zone contributed to the rise of drug lords and their armies, allowing them to position themselves for a massive expansion of local opium production. By providing arms, logistics, organization, and political protection, external alliances created the preconditions for a later leap in opium production in Burma and Afghanistan.

Chinese Eradication:

During the Cold War era, the most dramatic change was the sudden and complete eradication of opium in China. Under a powerful communist state, perfect prohibition works and produces a major change in the opium trade, eliminating the source of some 85 percent of prewar world supply. This extraordinary event has, however, no real lesson for capitalist democracies struggling with the problem of drug abuse. To extract some tenuous policy prescription from the Chinese Revolution would serve to trivialize a major historical event.

Origins of US Bilateral Suppression (1973-1979)

As American troops were withdrawing from Vietnam in 1972, President Richard Nixon inadvertently created a new market for Southeast Asian heroin by declaring a war on drugs in the Mediterranean.

As the progenitor of the three drug wars the US has fought over the past 20 years, Nixon's effort commands close attention. Despite a short-term victory, there were two long-term consequences of this drug war: (1.) increased global opium production; and, (2.) rising heroin consumption.

Acting on reports that Turkey's poppy fields and France's laboratories supplied 80 percent of America's heroin, Nixon pressed these two allies to eliminate the drug trade. By 1973, Turkey, supported by $35.7 million in U.S. aid, had eradicated all opium production and the French government had closed most of the heroin laboratories in the Marseilles region.

Within months, the street price of heroin in New York had tripled and purity dropped by half--both indicators of a serious shortage. Indeed, the DEA estimated that the U.S. addict population dropped from some 500,000 in 1974-1975 to only 200,000 by the end of the decade. Clearly, President Nixon had scored a major victory in his war on drugs.

Ironically, President Nixon's victory in Turkey increased global drug demand, unleashing market forces that would ultimately expand both production and consumption of illicit narcotics. The Nixon drug war rested on the premise that Turkey was an isolated opium producer that could be eliminated through a strong enforcement effort.

Turkey, in 1970, had produced just 7 percent of the world's illicit supply. It was, moreover, the western extremity of a near continuous opium zone that stretched for 5,000 miles along the mountain rim of Asia--through Iran, Afghanistan, Pakistan, Burma, Thailand, and Laos.

Although U.S. officials seemed to view this broad zone as a series of self-contained sectors (Middle East, South West Asia, and Southeast Asia), this functional economic region responded to stimuli from the global drug market with a simultaneity that seems to indicate economic coherence.

Any reduction of production in a single sector, such as Turkey, soon became a strong market stimulus for increased production elsewhere along the opium zone. Reacting to the decline in heroin shipments from the Mediterranean, the Chinese syndicates of Southeast Asia began exporting their surplus heroin to America, in effect following the GIs home. Rising from insignificant levels in the late 1960s, Southeast Asian heroin captured 29 percent of New York's street supply by 1972.

In Chicago, Southeast Asia's share jumped from 6 percent of all samples seized in 1972 to 48 percent in 1973. A wave of arrests of Chinese merchant seamen jumping ship on the East Coast in 1972 signaled an upsurge of Asian heroin smuggling. During the early 1970s, Southeast Asia's share of the overall U.S. heroin market reached an estimated 26 to 30 percent of total street supply.

Concerned about rising Southeast Asian heroin seizures, the Nixon administration dispatched a fire-break team of 30 Drug Enforcement Administration (DEA) agents to Bangkok in 1973-1974 to cut the flow. Armed with a financial war chest that included $12 million in narcotics assistance funds, the Bangkok DEA seconded a branch of the Thai police to its service and soon began making substantial seizures of US-bound heroin. By 1976, Southeast Asian heroin dropped from a peak of 30 percent to about 8 percent of the total seized on the streets of American cities.

Moreover, the DEA presence contributed to the elimination of several leading exporters of Southeast Asia opiates. In 1973, the Marcos regime executed a Manila heroin manufacturer, Lim Seng, who was exporting major quantities to the United States. In 1974, Hong Kong Police broke the Ng Sik-ho syndicate, disrupting the colony's export operations. As Southeast Asian exports dropped, Mexico's share of the US market jumped from 40 percent in 1972 to 90 percent in 1975.

Since the DEA did not eradicate opium cultivation on the Shan Plateau or close the heroin refineries in northern Thailand, its seizures simply erected a de-facto Custom's shield that deflected exports from the United States to other markets. If the region's loosely structured opium industry were instead a legal corporation, then the import duties it was required to pay for access to key markets were, in effect, becoming prohibitive. Barred from the prime US drug market, Southeast Asia's syndicates were forced to find new markets or go out of business.

There are, of course, only four First World regions capable of sustaining the high costs of the transnational heroin trade--America, Japan, Europe and Australia.

Denied access to the United States by DEA operations and barred from Japan by an entente between the state and syndicates that discouraged narcotics, Southeast Asian syndicates began exporting heroin to Europe and Australia.

During the 1970s, police statistics from both continents indicated a parallel surge in illicit heroin use. Total European seizures of Southeast Asian No. 3 heroin jumped from 22 pounds in 1972 to 873 in 1978. By 1976, European seizures of 1,177 pounds of heroin, almost all from Southeast Asia, were higher than the U.S. total for all source countries. Indicative of Europe's rising addiction rates, the Netherlands' addict population increased from 100 in 1970 to 10,000 by 1975.

In West Germany, deaths from heroin overdose increased from 9 in 1969 to 623 a decade later. By the end of the decade, Europe was, for the first time in its history, consuming more heroin than the United States. Similarly, in Australia narcotics arrests in the state of New South Wales increased five-fold from 173 in 1972 to 909 in 1977; while over-dose deaths were up three-fold from 14 in 1974 to 49 in 1976.

Although Nixon's drug war thus stimulated the global market, its impact on US domestic supply was more ambiguous. In the late 1970s every indicator--addiction, purity, and price--pointed to a decline in America's heroin supply. Why? Did Nixon's drug war succeed in slowing the flow of drugs into the United States? Mexico had captured nearly 90 percent of the US heroin market, but its granular No. 3 heroin failed to satisfy American demand for the No. 4 powder processed in Europe and Southeast Asia.

In the mid 1970s, as Turkish supplies dwindled and Southeast Asia failed to fill the void, Mexico's production boomed and its Sierra Madre became America's major source of heroin. Although Mexican opium cultivation had been extremely low and supplied a tiny slice of the U.S. heroin market in the 1950s, a quarter century later Mexico's expanded poppy cultivation supplied almost the entire US market.

Mexico's dominance of the U.S. supply with low-grade No. 3 heroin coincided with a marked decline in U.S. heroin demand during the mid-1970s, providing some hope that this bilateral approach might have been effective. As U.S. enforcement efforts took effect and the drug flow from Mexico began to slow in the late 1970s, unmet U.S. demand for drugs stimulated renewed Southeast Asian exports that briefly captured about one-third of the American market. Even so, supplies of heroin from all sources were still limited, and US consumption, by all indicators, remained low.

Looking at these changes, we could conclude that Nixon's drug war had actually worked. Examining other evidence, however, we could attribute this decline to President Carter's foreign policy. His cessation of covert operations from 1976 to 1978 may have removed, albeit inadvertently, the protection that drug lords seem to require. Similarly, Carter's abandonment of the Nixon drug war strategy might have stalled the bilateral operations that had in the past stimulated production. Complicating the situation further, Southeast Asia, the world's major opium producer, suffered a major drought in 1978 to 1980 that slashed its opium production by more than 75 percent.

Given the complexities of the global drug trade, we cannot decide this issue with absolute certainty. Whatever the complex causality underlying the decline in US heroin consumption in the late 1970s might have been, a close review of the global traffic indicates that prohibition and protection were, on balance, the operative factors in a sudden revival of heroin abuse during the 1980s.

Causality underlying above changes:

When President Nixon launched America's first drug war in Asia and brought the blunt baton of law enforcement down on a global commodity, heroin, the results were mixed. Although repression disrupted the global heroin trade for several years, over the longer term Nixon's

drug war stimulated both global opium production and heroin consumption. Ignoring these lessons, the Reagan and Bush administrations later pursued parallel policies in Latin America with dismal results.

In essence, all three drug wars extended a local law enforcement model into the international arena in a way that failed to reduce either drug production or exports. Like heroin before it, cocaine grew during the 1980s into a major commodity that was fully, albeit invisibly, integrated into legitimate inter-American economic relations.

Despite Washington's drug wars, U.S. consumption fueled an increase in coca cultivation-- rising in Bolivia from 4,800 metric tons in 1963 to some 56,400 to 155,452 tons in 1988. Stimulated in part by three US drug wars, Asian opium production enjoyed a parallel increase from 1,094 tons in 1970 to 4,016 tons in 1989.

How can we explain the failure of a major US foreign policy initiative? It appears that the policy of repression is based on a misperception of the nature of the global narcotics traffic. White House policy has ignored the market dynamics of the global drug trade. Since the late 18th century, narcotics have emerged as a major commodity with Third World producers and First World consumers linked in an elaborate exchange. The initial prohibition of narcotics during the 1920s did not eradicate the trade, but simply drove it into an illicit economy controlled by upland drug lords and urban crime syndicates.

When law enforcement is applied to such an elaborate commerce, drug syndicates usually react in ways not foreseen by enforcement agencies. Treating the global narcotics traffic as if it were a localized vice such as pornography or prostitution, U.S. drug agencies often apply repression without any awareness of the intricate dynamics of these worldwide marketing systems.

For both legal and illicit commodities, a crop failure in one production zone--whether from war, drought, or disease--creates a shortage of supply and raises the price for producers elsewhere, stimulating increased production in the next crop cycle.

Increase/decrease in World Opium Production:

--World opium production increased steadily from in 1,094 tons in 1970 to 1,450 tons in 1981.

Changes in Opium Cultivation by Region:

--Turkish illicit opium production declined radically from 58 tons in 1971 to zero by 1974-75.

--In Southwest Asia (Iran, Afghanistan, Pakistan), opium production rose from 504 tons in 1971 to an estimated 1,400 tons in 1978.

--In Southeast Asia's Golden Triangle, drought cut opium production from 700 tons in 1971 to only 160 tons in 1979.

--Mexican opium production remains relatively constant at 16 tons in both 1971 and 1981.

Changes in Quantity of Opium Consumption by Region:

--In the United States, estimated number of heroin addicts declined sharply from an estimated 500,000 in 1971 to 200,000 in 1979.

--Rising from low levels in 1970, Western Europe had an estimated 190,000 to 330,000 heroin addicts in 1979-80.

--In the Netherlands, estimated number of heroin addicts grew from 100 in 1970 to 10,000 in 1975.

--In West Germany, heroin overdose deaths increased from 9 in 1969 to 623 in 1979.

Summary and Analysis of Trends within Epoch:

Bilateral Suppression & Crime:

During the mid 1970s, the US attempt at bilateral suppression of opiates (a.) expanded international criminal networks; (b.) increased global opium production; and (c.) encourages a spread of heroin consumption to new regions of the globe.

Limits of Bilateral Suppression:

Although bilateral operations in Turkey during the mid 1970s represent the greatest success of any US drug war, the policy implications are limited. In retrospect, Turkey's suppression worked because, like Iran or British India before World War II, the government licensed and controlled opium cultivation. Moreover, the opium farmers were ethnic Turks, the majority population, working at the epicenter of the nation-state, not an alienated ethnic minority, armed and insurgent.

This combination of a strong state and weak local resistance made this exercise in bilateral suppression effective. These conditions are not, however, likely to be replicated anywhere else in the world. Similarly, the strong French state could eliminate the Corsican laboratories in Marseilles when US pressure was insistent. Elsewhere--in Burma, Afghanistan, or Pakistan--the state is weak and ethnic resistance to opium eradication is strong, making future bilateral operations in these critical areas problematic.

Production Increase In Asian Zone (1979-1989)

After a decline in US drug use from the mid-1970s to the mid-1980s, a complex of factors encouraged a steady recovery in America's demand for heroin. During the 1980s, global production and consumption of the drug increased steadily, laying the foundation for a sudden surge in supply during next decade that would make heroin a world drug by the early 1990s.

During the 1980s, a complex factors led to an increase in Asian opium production. Unusual weather patterns led to a failure in the monsoon rains, bringing a two-year drought that slashed the Golden Triangle's opium production drastically to some 165 tons in 1979 and 225 tons in 1980.

Responding to the market opportunity, heroin production in South West Asia--Afghanistan and Pakistan--suddenly expanded to fill gaps in the global market. By 1979, South West Asian heroin had captured the European market. As Dutch seizures of Southeast Asian heroin dropped from 193 pounds in 1979 to 6.5 in 1980, so European seizures of South West Asian heroin jumped from 911 pounds to 1,980 in the same period. From insignificant levels of heroin use in 1970, Western Europe had developed an addict population estimated at 190,000 to 330,000 users by the end of the decade--a heroin market larger than America's.

In 1980-1981, heroin from South West Asia also fueled a new surge of use in the United States. After a quarter-century of rising heroin addiction, America had enjoyed a brief respite during the late-1970s. U.S. diplomacy in Turkey and DEA interdiction in Bangkok had slowed Asia's drug exports, allowing America its first prolonged heroin drought since World War II.

By late 1980, however, the flood of heroin from Pakistan and Afghanistan captured 60 percent of the US market and brought a renewed heroin crisis. As heroin-related injuries climbed 25 percent during the year, the US addict population climbed back to 450,000. With an estimated production of 1,600 tons, South West Asia's opium crop was three times larger than the 450 tons that the Golden Triangle had produced in its last good year, 1977-1978.

There were signs that the situation would worsen. Without any restraint on production or processing, heroin exports from Pakistan and Afghanistan continued to grow. Rising from about 100 tons in 1971, Afghanistan's opium production reached 300 tons in 1982 and then doubled to 575 tons in the next harvest.

Recovering from a two-year failure of the monsoon rains, Southeast Asia's Golden Triangle produced a bumper opium crop in 1981 that would, in the words of the U.S. Attorney-General, provide enough heroin to glut the world market. Other illicit drug sales were also rising.

Between 1979 and 1980 alone, street sales of all illicit drugs in the United States increased by 22 percent to $79 billion. While America's heroin imports rose by 7 percent to four tons worth about $8 billion, cocaine supply jumped a remarkable 57 percent to 44 tons worth $29 billion.

Despite some initial success, America's drug war had thus produced a paradoxical strengthening of the global narcotics traffic. By the late 1970s, the simplex of the Turkey-Marseilles-New York heroin pipeline had been replaced by a complex of international smuggling routes that tied the disparate zones of First World consumption to Third World narcotics production. With production and consumption now dispersed about the globe, the international traffic was far more resistant to suppression than ever before.

Changes in Italy's heroin market during the 1970s are one example of the negative impact of the US drug war. In effect, the Nixon initiative propelled the mafia to a new plateau of development.

After US diplomatic pressure forced French police to close Marseilles' heroin laboratories in 1973-74, the Corsican syndicates moved their refining operations across the border into Italy in alliance with the mafia. When the Afghan War started in 1979, moreover, the mafia's role in the Atlantic heroin trade reached an unprecedented peak.

By 1981, Pakistani laboratories, with the Sicilian mafia as their intermediaries, were supplying over 60 percent of the US heroin demand and an even greater proportion of Europe's market. By the mid-1980s, an individual mafia cosce, the Badalmenti, was

distributing bulk heroin directly across America through the facade of local pizza parlors and accumulating extraordinarily profits.

As seen in Operation Green Ice of 1987-88, the Madonia family of Palermo allied with the Medellin cartel to import 596 kilograms of cocaine from Colombia for distribution in Europe. In effect, during the 1980s, the mafia had emerged as the prime narcotics broker between Asia, Europe, and the Americas--exporting Asian heroin to North America and importing Latin American cocaine for distribution across Europe.

The influx of heroin profits into Sicily during the 1970s and 1980s expanded the mafia's political power. The sudden wave of high-rise construction in corridors beyond Palermo's central city were financed largely by mafia factions laundering their drug profits, allowing major families to increase their local power.

While the modern mafia may have grown Mercury's wings to move drugs across Asia to the Americas, the logic of laundering brought its cosce back home to Palermo to seek a safe haven for narco profits. Such an expanded local base may also have contributed to mafia's growing penetration of the Italian state. With a vast capital from its role as heroin broker, the mafia increased its control over the hidden politics that operated at the intersection of the Italian state, parties, corporations and criminality. Specifically, the better capitalized mafia cosce were able to begin dictating the agenda for public works and the allocation of their illegal profits, reaching beyond the South to the whole of Italy.

Heroin trafficking also had negative consequences for the mafia. In the 1980s, Europe emerged as the world's second major drug market, with an explosive growth and unprecedented profits. Between 1982 and 1991, Europe's seizures of heroin increased from 1,355 kilograms to 6,770, while its cocaine seizures jumped from 396 kilograms to 13,773.

As heroin leached from the mafia's international routes into local traffic, the number of Italian addicts grew sharply. Between 1977 and 1982, heroin overdose deaths in Italy rose from 40 to 252--a clear indication of a rapidly expanding drug problem. As heroin became a Italian affliction, the mafia's involvement in trafficking contributed to a de facto delegitimation, redoubling public and official opposition.

Paralleling these changes in Italy, by the early 1980s the global opiates market had survived the reverses of the previous decade, emerging with the capacity for explosive growth. In part through U.S. interdiction efforts in the 1970s, narcotics consumption had spread to new continents and global production had expanded, rendering the illicit drug trade far more resistant to suppression.

The Reagan-Bush drug wars of the 1980s provide further evidence of the counterproductive impact of U.S. efforts at supply-side suppression. During the 1980s, America experienced an unprecedented drug crisis. Between 1982 and 1985, U.S. cocaine consumption more than doubled to 72 tons.

As supplies grew and prices dropped between 1981 and 1986, the number of Americans using cocaine rose by 38 percent to 5.8 million. Responding to public panic over cocaine, the Reagan and Bush administrations deployed an escalating repression that drew the military into their drug wars.

By early 1991, the Bush White House, citing survey results showing a decline in cocaine abuse, claimed a near-victory in its war on drugs. A closer look at long term trends indicated, however, that the illicit drug trade had again reacted to repression by adjusting in

unexpected ways. When Bush's campaign reduced the cachet and quantity of illicit cocaine, the drug market filled the void with a new heroin that appealed to both lower-class crack addicts and middle-class cocaine users.

As the war on cocaine escalated in the 1980s, there were signs that the era of experimentation and casual soft drug use was, after twenty years, coming to a close. While casual use faded, the numbers of regular, or hard core, cocaine and heroin users remained high. As Dr. James Van Wert noted in mid 1991, cocaine-related deaths have increased by 10 percent since 1988, daily cocaine users increased by 15 percent.

Moreover, there were indications of an overlapping demand for either heroin or cocaine in America's illicit drug culture. Although some local markets showed a preference for a particular drug, such as Miami for cocaine or New York for heroin, there was a growing tendency across the country for regular drug users to take both. Between 1981 and 1985, for example, deaths from speedballs, a mixture of cocaine and heroin, rose by 754 percent.

Eclipsed by media focus on cocaine and crack, global heroin production and U.S. consumption rose steadily during the 1980s. World opium production tripled from an estimated 1,500 tons in 1982 to 4,100 in 1989.

The U.S. population of heroin addicts had stabilized at about 500,000 in the early 1980s, but there were subsequent signs of rising use. Between 1983 and 1986, the number of heroin-related deaths doubled. Moreover, a new Mexican black tar heroin appeared in the mid 1980s with a high purity and low price that made it competitive with crack in the western United States.

While supplies from Mexico and South West Asia waxed and waned, the Golden Triangle increased its share of the US heroin market from 18 percent in 1987 to 45 percent in 1990. As the long drought in the Golden Triangle ended in 1980, farm-gate opium prices in Burma soared from $91 in January 1979 to $399 the following June, boosting production from a low of 160 tons in 1979 to 2,528 tons in 1989.

Thus, between 1984 and 1990, Southeast Asia's share of the New York City heroin supply jumped from 5 to 80 percent. Following this significant local trend, in 1993-94, Southeast Asia supplied an estimated 80 percent of the total US market for heroin.

Then, in 1989-1990, a flood of Southeast Asian heroin lowered the wholesale price of China white in New York from $100,000 a kilogram to only $60,000, undercutting the cocaine market and creating a new clientele for the drug. Crack addicts seeking an easier withdrawal were reportedly using heroin in large quantities, as were those mixing the two drugs for a more prolonged euphoria. The heroin situation is growing on a daily basis, reported the DEA's heroin specialist in mid 1990. There's big profits, and the production of opium has doubled...It is the tip of the iceberg.

Although White House drug policy treated cocaine and heroin as discreet drug markets, there was in fact an overlapping demand for both narcotics. Within America's polydrug culture, Asian heroin could and did supply a shortfall in demand for Latin American cocaine.

Increase/decrease in World Opium Production:

--During this single decade, world opium production tripled from 1,450 tons in 1981 to a postwar peak of 4,105 tons in 1989.

Changes in Opium Cultivation by Region:

--South West Asia (Iran, Afghanistan, Pakistan) increased its opium production from 800 tons in 1981, to 1,060 in 1989, remaining the world' leading producer until 1986 when it was passed by Southeast Asia.

--Production in Southeast Asia's Golden Triangle rose sharply from 650 tons in 1981 to 2,956 tons in 1989, becoming the source of 72 percent of world opium supply.

--In Burma, opium production grew from 550 tons in 1981 to 2,528 in 1989, making this single country the source of 62 percent of world opium supply.

--Under its new communist regime, Laos increases its opium production from 50 tons in 1981 to 378 tons in 1989.

--In Mexico opium production shot from 16 tons in 1982 to 76 tons in 1989.

Changes in Quantity of Opium Consumption by Region:

--US addict population increased from 200,000 in the late 1970s to 450,000 in 1982.

Summary and Analysis of Trends within Epoch:

Rise of the Drug Lords:

During this period, highland drug lords, for the first time in the history of the traffic, began to act as independent entrepreneurs, responding creatively to market opportunities and taking significant initiatives to expand production and markets for their product.

In Burma, for example, opium production increased exponentially from 550 tons in 1981 to 2,500 in 1989, in large part through the efforts of leading warlords like Khun Sa who controlled some 75 percent of the country's heroin production by the late 1980s. Although there, of course numerous underlying ecological and economic factors, Khun Sa's centralization of control over the Shan revolt and his determination to expand heroin production had a significant impact on the global traffic and the US drug problem. Similarly, the emergence of Gulbuddin Hekmatyar as the dominant rebel leader in Afghanistan created a parallel figure of power who could control much of the country's opium production, heroin processing, and export.

The capacity of powerful warlords such as these to both produce and export has had a growing influence on Western heroin markets--sending vast new supplies of Burmese heroin to America and giving the Sicilian mafia a major new role as brokers for South West Asian heroin to Europe and the United States.

Failure of Tolerance:

While bilateral attempts at suppression may compound the problem beyond the target nation, extreme tolerance or simple inaction over drugs within a producing nation had led to an explosive growth in opium cultivation.

After 1984-85, the Burmese government capitulated to the drug lords and Khun Sa formed a powerful new opium army--a combination that led to a surge in the country's opium

production from 550 tons in 1981 to 2,500 in 1989. Similarly, Afghanistan, the collapse over government control over the countryside since the early 1980s is another apt case of the same proposition. The lesson: if a government abandons any attempt at suppression in its opium areas, the capacity for increased production is restrained only by land and labor.

Failure of Drug Wars:

If the United States is to purse a strategy of international repression, then focusing on a single drug seems a prescription for long-term failure. By focusing on cocaine in Colombia and, in effect, ignoring heroin in Burma, the United States allowed Burma's opium production to grow without restraint, creating an ample supply of an alternative narcotic for the US market.

Global Proliferation of Opium (1989-1994)

In the early 1990s, heroin recovered its historic preeminence as a leading illicit narcotic and became something of a world drug. After 1989, Southeast Asia began a sustained heroin export drive to the US that captured over 80 percent of our market by 1993. Simultaneously, the end of Afghan war and repatriation of refugees led to expanded local heroin production.

Increasing Central Asia's potential for opium cultivation, the break-up of Soviet Union led to independence for its former Central Asian Republics and, through ethnic links with Afghanistan, an extension of poppy farming into Tajikistan and Uzbekistan. Facilitating the export of Central Asian heroin, the rise of new criminal syndicates in Eastern Europe and Russia, in alliance with Colombian cartels and Sicilian mafia, is creating new smuggling routes that lead from Afghanistan across Russia to the West.

Driven by the unequaled profitability of heroin, the Cali cartel has introduced opium cultivation to the northern slopes of the Andes, harvesting some 20 tons annually since 1991.

Increased opium supply has led to a dramatic proliferation of heroin abuse around the globe--a phenomenon so vast that we can speak, without hyperbole, of a globalization of heroin consumption.

Paralleling the rise of use in established consuming regions like Western Europe and North America, heroin abuse shot upward in new areas--Eastern Europe, southern China, mainland Southeast Asia, India, and Pakistan. Rising from a situation of zero heroin addicts in 1979, Pakistan had, according to official statistics, 5,000 addicts in 1980, 1.2 million in 1985, and 1.7 million in 1993.

As cheaper grades of heroin have encouraged mass addiction, intravenous drug use spread across Asia from Pakistan to Thailand, leading to a sudden surge in HIV infection through injection.

By early 1994, Burma's estimated 400,000 heroin users had the highest HIV rate of any addict population. Between January and June 1988, the seropositive rate for sample addict populations in Thailand had jumped from 1 to 40 percent, the edge of an epidemic that is leading to an HIV rate now approaching a fifth of the country's population.

Increased poppy production in the Golden Triangle is being felt on the streets of American cities. In the 1990s, heroin is back is a drug of choice and Southeast Asia is our main source. Between 1984 and 1990, Southeast Asia's share of the New York City heroin market rose from five to eighty percent. Following these trends, in early 1991 Southeast Asia's contribution to the US heroin supply shot to forty-five percent, up from just eighteen percent in 1987. Today, over eighty percent of all heroin seized in the United States comes from the Golden Triangle.

In the early 1990s, as heroin surged into New York in unprecedented quantities, the City's wholesale price per kilo dropped from $100,000 to $60,000--creating a new clientele for this purer, smokeable drug. Ten years ago the purity of street heroin averaged about four percent, but today it has jumped to sixty-five percent. In the first half of 1993, heroin-related hospital emergencies soared to 30,800 nationwide, up forty-four percent over 1992.

With high purity allowing smoking or snorting, heroin no long carries the risk of AIDS infection through shared needles, shattering a barrier that had long restrained its rediscovery. Stigmatized during the 1960s as a ghetto drug, the mark of the social marginal, heroin has been reborn in the 1990s as the badge of the hip American nihilist.

For those at the cutting edge of a young, creative crowd known as Generation X, heroin is the drug of choice, the symbol of authentic alienation. On the East Coast heroin is back as an old friend, a simple respite from the roller-coaster rip of crack-cocaine and all its craziness. It is on the West Coast that heroin's rebirth as a style statement has been most complete.

In Los Angeles, films such as Drug Store Cowboy and My Private Idaho have mythologized the drug, adding an allure to addiction for the city's edge actors. In San Francisco, bands like Pale Horse and Morphine celebrate the drug, making its trademark dragon iconography a fashionable logo for club-cruising gear, stylish caps and T-shirts.

Seattle's grunge movement is wrapping the drug in an ambiguous embrace, and the heroin-related deaths of local rock icons Andrew Love and Kurt Cobain give it a cultish degeneracy.

Although the surge in global heroin supply in the late 1980s had complex causes, it can be traced, in part, to two key factors--the failure in US interdiction efforts and a larger complex of changes springing from the end of the Cold War. Specifically, the increasing opium harvests in Burma and Afghanistan, America's major suppliers, were, in part, the legacy of Cold War operations past and present.

Just as US support for Nationalist Chinese (KMT) troops in the Shan States increased Burma's opium crop in the 1950s, so Western covert aid to the mujaheddin guerrillas expanded opium output in Afghanistan and linked Pakistan's nearby heroin laboratories to the world market. After serving as the sites of major Cold War operations that intensified indigenous ethnic insurgencies, Burma and Afghanistan ranked, in 1993 estimates, as the world's first and second largest suppliers of illicit heroin.

After Soviet support for the Kabul regime and US arms shipments to the rebels ended in January 1992, Afghanistan's role as a major heroin supplier increased sharply. Indeed, in late 1991 the United Nations anti-drug commission had reported that the Afghan guerrillas, anticipating a cut in US covert support, were already planting a greatly expanded opium crop as an alternative source of finance.

There is, moreover, a strong economic and ecological logic drawing Afghanistan into a sudden and sustained increase in opium cultivation. In 1992-93, the four to six million Afghan refugees who have lived for a decade in camps along Pakistan's Northwest Frontier began returning to war ravaged farms with less than a thousand dollars in UN resettlement funds.

Since much of Afghanistan's agriculture involves perennial crops that take several years to regenerate after damage or neglect, Afghan farmers have an obvious need for a profitable annual crop. Even without the disruption of war, opium has long been the country's most viable crop.

In 1972, a US cabinet committee reported that Afghan farmers made $300-$360 per hectare from opium, twice the average of $175 for fruit: There is no substitute crop--except for hashish--that can...provide anywhere near an equal income. With the recent eruption of civil war in Kabul, Afghanistan does not have government to negotiate either foreign aid or trade agreements for the export of primary products, so its farmers have fallen back on an established illicit commodity with ready markets and an informal laissez-passer at every customs barrier.

Since opium cultivation is already well established, heroin processing is skilled, and syndicate connections with Europe are in place, the poppy is becoming is fast becoming a major economic support for rural Afghanistan in this epoch of economic crisis.

A recent UN report published in Pakistan claimed that Afghanistan's 1991 opium crop was already 2,000 tons, while privately UN anti-drug officials predicted a vast Afghan crop of some 4,000 tons for 1992--a harvest large enough to double the world's entire illicit opium supply.

Although unseasonable rainfall during harvest destroyed much of that crop, the UN's field agents still estimate, often privately, that within the next two to three years Afghanistan has the potential to produce bumper crops of 3,000 to 4,000 tons of raw opium.

If these estimates are correct, the Afghan crop will soon exceed Southeast Asia's, and nearly double the supply of heroin for the world market. Indeed, in the US State Department's conservative estimates, Afghanistan's opium production increased from 415 tons in 1990 to either 685 or 900 tons by 1993.

As in Burma twenty years before, Afghanistan experienced a mix superpower confrontation and local ethnic conflict that facilitated formation of drug networks that can continue to grow long after Cold War intervention had ceased.

Moreover, by attacking heroin trafficking in separate sectors of Asia's extended opium zone in isolation, the DEA inadvertently influenced the market in ways that diverted heroin exports from America to Europe, and also shifted opium production from the South West Asia to Southeast Asia and back again--raising both global consumption and production with each move.

Compounding this problem, White House fixation with Latin America's cocaine traffic diverted resources from the interdiction of Asian heroin. By using a massive interdiction effort to cut supplies of Latin American cocaine without reducing the overall U.S. demand for drugs, the White House created a void in the cocaine/crack market that was soon filled by increased supplies of Southeast Asia heroin. Rising without any threat of disruption by law

enforcement, the Asian heroin trade expanded during the 1980s to provide ample supplies of an alternative narcotic when cocaine sales finally declined.

Similarly, in Latin America itself, Colombia's Cali cartel recognized the new market opportunity and in 1991 introduced opium into the northern slopes of the Andes. Within a year Colombia was harvesting 20 tons of opium, half of Mexico's output of 40 tons. Since the United States only consumes about 6 tons of heroin per annum, or 60 tons of opium, Mexico and Colombia combined could supply the entire US heroin market.

In the mid 1990s, the global narcotics trade, operating with the dynamics of a resilient commerce, seems highly resistant to any renewed war on drugs, no matter how extreme the strategy. Since ongoing US and UN policies seem incapable of restraining the opium trade, there is reason to be pessimistic about trends in the global drug problem over the medium term.

Although any prediction about a complex social phenomenon like drugs is prone to error, there are indications that we are at the threshold of a major change in the world drug market. In its recent spread across Central Asia, the opium poppy may have found a natural home where economy, ecology, and society may encourage an quantum increase in production during the next decade.

Just as Szechwan Province once produced 10,000 tons of opium, so Afghanistan, Tajikistan, and Uzbekistan are capable, individually or severally, of comparable harvests. Assuming that production in Southeast Asia continues, there is no reason that world opium supply cannot double from the present 4,000 tons in five years and double again in another five.

Looking into the future of the opium trade, there seem four apparent trends: (1.) a rapid, even dramatic, growth in world opium supply during the coming decade; (2.) a parallel increase in global consumption of opiates, with increased abuse in established areas and an extension of use to new countries or continents; (3.) spread of communicable diseases, such as AIDS and Hepatitis-B, through intravenous injection of heroin; and, (4.) rise in the negative social side-effects of mass heroin use--in particular, police corruption, political venality, syndicate violence, organized crime penetration of politics, gender-specific petty criminality, ethnic insurgency, and illegal arms trading.

Increase/decrease in World Opium Production:

--During this five-year period, world opium production dropped slightly from 4,105 tons in 1989 to 3,969 tons in 1993.

Changes in Opium Cultivation by Region:

--In Southeast Asia's Golden Triangle opium production dropped slightly from 2,956 tons in 1989 to 2,797 tons in 1993.

--Burma's opium production remained constant, changing from 2,528 tons in 1989 to 2,575 in 1993.

--In Southwest Asia (Iran, Afghanistan, Pakistan, Lebanon) production was constant, changing from 1,060 in 1989 to 1,099 in 1993.

--In Afghanistan opium production rose from 585 tons in 1989 to more than 900 tons in 1993.

--Starting opium cultivation, Colombia's production remained largely unchanging, dropping slightly from 27 tons in 1991 to 20 tons in 1993.

Changes in Quantity of Opium Consumption by Region:

--In the United States, the heroin addict population rose from 450,000 in 1982 to some 750,000 in 1993.

--Rising from low levels in the late 1970s, Burma's estimated addict population reached an estimated 400,000 in early 1994.

--In Thailand, the estimated population of heroin addicts rose from 125,000 in 1986 to 375,000 in 1993.

Summary and Analysis of Trends within Epoch:

Globalization:

In the early 1990s, world opium supply is growing without any apparent restraint. Since all opium produced is always consumed, rising supply is now a powerful force driving a sharp increase in world heroin consumption, creating powerful demands that may, in turn, yield further production increases in Latin America or Central Asia.

In the 1990s, we are perhaps witnessing a recurrence of the pattern first evidenced in late 18th Century China: once mass opiate addiction is introduced to a market, demand becomes nearly insatiable and serves to stimulate further increases in global supply.

Opium Production & Consumption:

In the past decade, both production and consumption of opiates have increased in established zones and spread quickly into new areas.

Prognosis:

If current trends continue, there is no reason that world opium production, and consumption, should not double every five years into the foreseeable future.

Books

Anti-Drug Crusades in Twentieth-Century China: Nationalism, History, and State Building

Written by Yongming Zhou, Zhou Yongming, this book chronicles such things as nationalism, reform, and anti-opium mobilization in Late Qing Dynasty; the six-year opium suppression plan and the new life movement; anti-drug crusade in the People's Republic; anti-drug

discourse in contemporary China; anti-drug campaigns in the 1990s; and anti-drug campaigns and ethnic minorities in southwestern china: 1950s and 1990s

The Voyage of the Frolic: New England Merchants and the Opium Trade

The Frolic, a clipper ship from the mid-1800s was employed in the Asian opium trade from 1845 to 1850. The ship's crew ferried Indian opium to China and sold it for silver, which they then used to purchase Chinese tea. A fascinating look at a little known slice of American history.

The Politics of Heroin: CIA Complicity in the Global Drug Trade

A greatly revised and expanded edition of Politics of Heroin in Southeast Asia. Tells a fascinating story, that opium was often the only viable form of currency. The author produces considerable disturbing evidence that US authorities are guilty at least of complicity in the global drug trade. Exposes basic hypocrisy in American policymaking, and demonstrates that, as long as powerful government bureaucracies work at cross-purposes, America's drug problem will not be easily solved.