• Hallucinogenic Drugs• Drugs that create unusual perceptual and

cognitive distortions• Many different names

– Psychotomimetic (psychosis mimicking)• not used these days

– Drugs no longer considered a model for psychosis

– Psychedelic (mind opening)• Sometimes the term used by those that use the drug class

– Hallucinogenic (hallucination producing)• Modern pharmacological literature uses this term

• Mescaline– Obtained from the peyote

cactus plant– Dried crown of the plant is

know as a mescal button, or peyote button.

– Buttons can be chewed raw or cooked and then eaten

– It is also possible to extract the mescaline from the plant and create a relatively pure powder

• Archeological evidence suggests that natives of Southwestern United States and Northern Mexico Have used for thousands of years

• Native Americans used peyote for religious and healing rituals

• Aldous Huxley (Brave New World)– Used mescaline and advocated use of hallucinogens– Some consider his writings about the experiences of

hallucinogens to have spawned the rise of their popularity in the 1960s

• “The Doors of Perception”• “Heaven and Hell”

• Mescaline is not as readily available in present times as other hallucinogens

Psilocybin, DMT, and 5-MeO-DMT

• “Shrooms” or “Magic Mushrooms”– Numerous species of

mushrooms have hallucinogenic properties

– Psilocybe mushrooms • Depending on the species,

users take about 1-5 g of dried mushrooms to obtain desired effects

• Can be consumed raw, boiled in water to make tea, or cooked with other foods– Tends to be bitter alone

• The major ingredient of mushrooms are psilocybin and the related compound psilocin– Psilocin is the actual

psychoactive agent• Psilocybin is converted by

enzymatic action to psilocin after ingestion

• Use of hallucinogenic mushrooms probably goes as far back as peyote use– Algerian painting dated to at

least 3500 B.C.• Shaman?• Notice mushrooms sprouting

from entire body and held in hands

• The Spaniards tried to suppress the use of mushrooms when they conquered the Aztecs in the early 1500s– They were not completely successful

• The existence of hallucinogenic mushrooms was largely ignored until the 1950s and 60s

• Timothy Leary lecturer at Harvard ate magic mushrooms while visiting Mexico in 1959– Formed the Harvard Psychedelic Drug Research Program– Purpose was “to teach individuals how to self-administer psychoactive

drugs in order to free their psyches without reliance upon doctors or institutions”

– Gave psilocybin to students and faculty– Also experimented with LSD– Dismissed from Harvard in 1963– Became leader in psychedelic movement

DMT and 5-MeO-DMT

• DMT and 5-MeO-DMT are substances found in several plants indigenous to South America

• Native tribes make hallucinogenic snuffs from these plants

• DMT in this country is usually sold in powdered form and taken by smoking

• Synthetic analogs have been gaining popularity– Α-methyltryptramine (AMT)– 5-methoxy-

diisopropyltryptamine• Foxy Methoxy or Foxy

LSD

• LSD is a synthetic compound

• Its structure is based on a family of fungal alkaloids – Alkaloids are chemical compounds containing

nitrogen that have psychopharmacological effects

• often found in plants and fungi

LSD first synthesized in 1938

• Albert Hofmann• Worked for a pharmaceutical

company in Switzerland (Sandoz)• Studying ergot

– a substance produced by a parasitic fungus that can infest rye and wheat

• Ergot is extremely toxic to humans– A core structure of the alkaloids

contained in ergot is lysergic acid• Hofmann combined lysergic acid

with other compounds in an attempt to generate drugs to stimulate the circulatory system

LSD-25 (LSD)

• The 25th compound synthesized was d-lysergic acid diethylamide– LSD-25

• Hoffman accidentally ingested some and had strange sensations

• Later he took a small amount on purpose– Had powerful effects

• Sandoz marketed the drug in 1947– Delysid

• To help neurotic patients uncover repressed thoughts and feelings

• In the 50s and 60s there were a lot of studies published on the effects of LSD– The fact that LSD altered serotonergic activity led many

researchers to consider this a powerful tool to understand human mental activity and behavior

– Some considered the drug psychotomimetic• Perhaps could be a model for a schizophrenia

– Replaced now by PCP and Ketamine– Some considered LSD to be an aid to psychotherapy

• Psycholytic therapy (Europe)– Psychic loosening or opening– Release repressed memories and enhance communication with the

therapist• Psychedelic therapy (US, Canada, Britain)

– Give LSD to patient to help them gain insight through a drug-induced spiritual experience

• US government explored the possibilities of LSD as a psychological weapon

• MK-ULTRA (CIA program)– Designed to investigate LSD as a mind control agent– At one point they gave LSD to unsuspecting members

of the public to observe behavioral reactions.• http://soundmedicine.iu.edu/segment.php4?seg=1644

– Check out the above link for a segment from NPRs Sound Medicine that discusses MK-ULTRA

• As you know LSD was extremely popular in the hippie culture of the 1960s

• There was a backlash against its use– Federal laws in 1965 restricted new research on LSD– Sandoz stopped distributing LSD for research

purposes– Recreational use of LSD was banned in 1967– There has been a resurgence in the interest in LSD

research recently

• LSD is usually taken orally

• A single dose of LSD in crystalline form is barely visible to the naked eye– Larger amounts of LSD are

dissolved in water and then droplets are applied to a sheet of paper and dried (a “blotter”)

– Individual squares of the blotter are sold as a single dose “tabs”

Potency and time course of action of Hallucinogenic Drugs

• The potency of hallucinogenic drugs vary

• Most are taken orally, but as mentioned earlier DMT is usually smoked

• For the drugs taken orally onset of effects usually takes 30-90 minutes– The trip can take 6-12 hours– Psilocybin maybe less

• The effects of smoked DMT are felt within seconds. Peak effects occur within 5-20 minutes– Effects are over in an hour or

less• “businessman’s trip

Psychological and physiological response to hallucinogenics

• Similar across different forms• Text focuses on LSD• Four phases of the “trip”

– Onset - 30 minutes to an hour after ingestion• Visual effects

– Intensification of colors

– Appearance of geometric patterns and strange objects can be seen with eyes closed

– Plateau phase – next 2 hours or so• Sense of time begins to slow• Visual effects become more intense

• Peak phase – about 3 hours into trip; lasts another 2 or 3 hours– May feel like in another world in which time has been

suspended– Continuous stream of bizarre distorted images

• Can be beautiful, or menacing– May experience synesthesia

• Crossing over of senses – colors heard

• Come down phase – 2 more hours or so– Most effects are gone by the end– User may not feel completely normal until the next

day

• hallucinogens can produce other psychological effects in addition to the phases of sensory-perceptual effects above– Emotional shifts

• Euphoria• Anxiety• Fear

– Feelings of depersonalization• Being outside oneself

– Disruption of logical thought

• Sometimes the LSD experience is viewed as mystical or spiritually enlightening– Good trip

• Sometimes it can be disturbing and frightening– Bad trip

• Good trip or bad trip may depend in part on– The dose– Individuals personality– Expectations– Previous experience– Social setting

• Can’t really predict the outcome of an LSD trip in advance

Physiological response to hallucinogens

• LSD effects reflect activation of the sympathetic response– Pupil dilation– Increased

• Heart rate• Blood pressure• Body temperature

• Can cause– Dizziness– Nausea– Vomiting

• These effects are more likely with peyote and psilocybin

Indoleamine hallucinogens

• Most hallucinogens have either a serotonin-like or a catecholamine-like structure– Serotonin-like or

indolamine hallucinogens

• LSD, Psilocybin, psilocyn, DMT, 5-MeO-DMT, synthetic tryptamines

Phenethylamine hallucinogens

• Catecholamine-like hallucinogens– Notice their similarity to

Norepinephrine– of course they are also structurally

similar to DA• Remember Amphetamine chapter

• Mescaline is the catecholamine-like hallucinogen that we have discussed

– but there are also forms of amphetamines that have hallucinogenic properties

• DOM • TMA

• Together these drugs are known as phenethylamine hallucinogens

Hallucinogens are 5-HT2 receptor agonists

• How hallucinogens cause dramatic cognitive and perceptual effects is not well understood

• Evidence for serotonergic effects

• LSD binds with high affinity to multiple serotonergic receptor subtypes– 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT6, 5-

HT7

• If we compare the indolamine and phenethylamine hallucinogen families we find that both bind to only a couple of serotonin receptor subtypes– 5-HT2A and 5-HT2C

• This suggests those receptor subtypes may play a key role

• There is not a lot of human experimental work on the hallucinogens

• Here is 1 nice study– Vollenweider et al. (1998) studied psilocybin.

• Found that visual illusions and hallucinations produced by these drugs were blocked by antagonists of the 5-HT2A receptor.– Ketanserin– Risperidone

• Also blocks D2 receptors • Note in next graph that haloperidol (another D2 antagonist) did not

block these effects– Ruling out D2 effects

14.7 Blockade of psilocybin-induced visual illusions and hallucinations

• Since there is not a lot of human work, animal studies are very important.

• Drug discrimination studies are quite useful here– Train to discriminate LSD

from saline injection• LSD lever

• Saline lever

• Then the animals were tested with various doses of particular 5-HT2A receptor antagonists

• Notice all 3 antagonists decreased responding to The LSD lever.– Switched to saline lever– Implies these antagonists

blocked the subjective effects of LSD

• Drugs that have higher affinity for 5-HT2A do a better job of blocking these effects

Tolerance

• Most hallucinogenic drugs cause rapid tolerance with repeated use

• Humans taking LSD for 4 days showed nearly complete tolerance by day 4– Likely the result of down regulation of 5-HT2A

receptors– A 2005 study with mice showed down regulation of 5-

HT2A receptors after repeated LSD exposure

• Takes 3 or 4 days for tolerance to go away

Neural Mechanisms of hallucinations

• One theory is that the locus coeruleus plays an important role– Remember- dense cluster of NE neurons in

the pons– Receives information from all the major

sensory systems and sends that information to all areas of the cortex.

Neural Mechanisms of hallucinations

• Aghajanian et al found that LSD and mescaline decreased spontaneous firing of neurons in the rat LC

• However, they also found that the LC cells were more easily excited by sensory information

• Put together, these effects make the LC far more sensitive to sensory input.– Baseline is lowered– Responsivity increased

Neural Mechanisms of hallucinations

• Perhaps the increased sensitivity of the LC is the mechanism of perceptual distortion and hallucination following ingestion of LSD– Studies using fMRI with shizophrenic patients

experiencing hallucinations show increased activity in cortical regions that normally code that sense

• Visual – occipital• Auditory – temporal

• Other researchers posit that areas such as the prefrontal cortex, striatum, and thalamus (fronto sub-cortical circuits) might serve as a gating mechanism for sensory information.– The idea is that the hallucinogens may open the gate,

thus, flooding the cortex with information– These researchers believe that this might also explain

the cognitive disturbances common with hallucinogenic drugs as well

Addiction?

• Hallucinogens are not considered addictive• People usually do not binge• Do not cause cravings• Do not cause physical dependence or withdrawal• Do not support self-administration in animals• Doesn’t seem possible to overdose

– No documented human deaths– Eight individuals have been documented as taking massive doses

• Snorted crystaline form (mistaken for cocaine)– Remember a barely visual grain is psychoactive

• Comatose state• Vomiting• Hyperthermia• Light gastric bleeding• Respiratory problems• They all survived without residual effects

• Despite lack of addictive potential and lack of overdose issues, the use of LSD can have consequences– Bad trips– Flashbacks

• Hallucinogen persisting perception disorder (HPPD)– Long lasting flashbacks causing major impairment or

disturbance– Few documented cases

– Psychotic breakdown?• Prolonged psychotic episodes following LSD use invariably

involve individuals – Already diagnosed with a psychiatric disorder – That exhibited prepsychotic symptoms prior to taking the drug

PCP and Ketamine

• PCP and ketamine were both initially developed as anesthetics.– PCP

• 1-(1-phenylcyclohexyl) piperdine– AKA phencylclidine

• Developed in the 1950s as an anesthetic• Produced unusual anesthesia

– No responsiveness to nociceptive stimuli– But, not typical relaxed unconsciousness (like seen with barbiturates).– Trance-like or catatonic-like state– Vacant expression– Fixed staring eyes– Maintenance of muscle tone

» Not uncommon to have rigidity or waxy flexibility like seen in catatonic schizophrenics

• PCP was initially considered a promosing anesthetic– Did not produce respiratory depression like seen with

barbiturates• High therapeutic index

• But some patients had problematic reactions– Agitation – rather than quieting– Postoperative effects ranging from blurred vision,

dizziness, and mild disorientation…to hallucinations, severe agitation, and violence.

• Clinical use of PCP was terminated in 1965

• PCP became a more popular illicit drug in 1967. – AKA – “Angel dust”; “hog”– Never was as popular as marijuana or even

cocaine or heroin

• Ketamine was developed as a safer alternative to PCP

• First synthesized in 1962– CI-581 ---- later renamed ketamine

• Less potent and shorter acting than PCP• Valuable anesthetic particularly for children

– Also animals• Currently available with prescription

– Ketaset– Ketalar– Vetalar

Route of administration

• PCP is generally obtained in powder form

• Can be ingested by any common route– Orally– Intranasally– IV– IM– Smoked

• Applied as a liquid to a cigarette

Route of administration

• Ketamine is marketed as an injectable liquid

• Street sellers commonly evaporate the liquid to yield a powder.– Can be snorted– Compressed into a pill

• AKA: “K,” “special K,” and “cat valium.”

• Studies form the 50s and 60s found that subanesthetic doses of PCP produce– Feeling of being detached from body

• Dissociation– Sensations of vertigo or floating, numbness.– Dream like state– Affective changes

• Drowsiness, apathy, negativism• Sometimes hostility toward experimenters• Sometimes euphoria

– Cognitive disorganization• Difficulty maintaining concentration• Deficiency in abstract thinking• Halting speech

Subjective effects of ketamine

• Low doses of ketamine produce reactions similar to what occurs with PCP

• High doses can produce dissociative anesthesia– Lose mental contact with environment for 10 minutes

or so– Eyes open– Maintain muscle tone

• Some have described the dissocative state as a “near-death” experience– Sometimes called “K-hole”

• Sometimes spiritually uplifting• Sometimes terrifying

Reinforcement

• PCP and ketamine support self-administration in several species

• Rhesus monkeys self-administered PCP at levels to maintain continuous intoxication– Could not stand up.– Lying or sitting on floor near lever

• PCP and ketamine activate midbrain DA cell firing.– Stimulate DA release particularly in prefrontal cortex

• Rats will self-administer PCP directly in the NA– This affect may be driven by inhibition of glutamatergic input to

the NA rather affecting the DA system

PCP and Ketamine’s action at the NA

• Cocaine and amphetamine are indirect DA agonists– DA normally inhibits NA– Slowing NA activity = reinforcement

• PCP and ketamine are antagonists of Glutamate (at NMDA receptor)– Glutamate normally excites NA– Slowing NA activity = reinforcement

14.12 Self-administration of PCP into the nucleus accumbens shell by rats (Part 1)

PCP and ketamine are noncompetitive antagonists of the NMDA receptor

• NMDA is an ionotropic receptor that responds to glutamate

• NMDA and ketamine block at the receptor by binding to a site different from where glutamate binds– Making them noncompetitive antagonists– Remember the binding site is inside the channel

• NMDA receptors found throughout the brain including the cerebral cortex and hippocampus– This probably leads to the cognitive deficits

• The use of ketamine seems to be increasing

• Studies of ketamine use indicate that it can cause strong addiction

• People also take increasing doses indicating tolerance

Model of schizophrenia

• Acute PCP or ketamine exposure causes perceptual, cognitive, and affective responses closely resembling symptoms of schizophrenia– Can cause positive and negative symptoms

• Positive– Hallucinations– Bizarre thought content

• Negative– Blunted affect– Emotional withdrawal– Slowed motor response

– Some of the symptoms can persist for days• Perceptual distortion• Magical ideation

• Animal models– Evidence that chronic PCP administration can

cause lasting deficits that mimic some symptoms of schizophrenia

– Show deficits on tasks that require prefrontal cortex function

14.13 Ketamine administration produces a dose-dependent increase in psychotic-like symptoms