the federal drug policy under which the manufacture, importation, possession, use and distribution of certain substances is regulated

Categorized certain drugs into 5 classes

high addictive potential – not considered of medicinal value

There is a lack of accepted safety for use of the drug or other substance under medical supervision

No prescriptions may be written for Schedule I substances, and such substances are subject to production quotas by the DEA.◦  mescaline, lysergic acid diethylamide, heroin,

and marijuana, gamma hydroxy butyrate (GHB), ibogaine

Drugs with a high abuse risk, but also have safe and accepted medicinal uses

Abuse of the drug or other substances may lead to severe psychological or physical dependence stimulants, opiates, methadone, codeine,

methylphenidate (Ritalin), mixed salt amphetamine (Adderall),

less abuse potential than Schedule I or II

has a currently accepted medical use in treatment in the United States.

abuse of the drug may lead to moderate or low physical dependence or high psychological dependence.“ ◦ – includes barbiturates, anabolic steroids,

ketamine (?), buprenorphine, marinol (synthetic THC)

medical use, less abuse liablity, less risk of physical dependence◦ benzodiazepenes (?) – although n of prescriptions

is controlled◦ some barbiturates

Schedule V◦ cough suppressants with small amounts of

codeine

History◦ Cocaine◦ Source: leaves of E. coca (indigenous to western

South America◦ word spread through explorers, naturalists,

botanists

History◦ Cocaine◦ Source: leaves of E. coca (indigenous to western

South America◦ word spread through explorers, naturalists,

botanists 1860’s – a variety of medicinal uses

History◦ Cocaine◦ Source: leaves of E. coca (indigenous to western

South America◦ word spread through explorers, naturalists,

botanists 1860’s – wine tonics

Launched in 1863- Europeansuccess; the world's most popular prescription

Some of its advocates; Henrik Ibsen, Jules Verne, Alexander Dumas, Robert Louis Stephenson, Sir Arthur Conan Doyle, Queen Victoria; King George 1 of Greece; King Alphonse XIII of Spain; the Shah of Persia; William McKinley, President of the United States.

double the amount of work could be undergone when Peruvian Wine of Coca was used, and positively no fatigue experienced....."

Sears and Roebuck, 1900

"...sustains and refreshes both the body and brain....It may be taken at any time with perfect safety...

it has been effectually proven that in the same space of time more than

History◦ Cocaine◦ Source: leaves of E. coca (indigenous to western

South America◦ word spread through explorers, naturalists,

botanists 1860’s – wine tonics 1884 - Freud

as a mental stimulant as a possible treatment for digestive

disorders as an appetite stimulant in case of

wasting diseases as a treatment for morphine and

alcohol addiction as a treatment for asthma as an aphrodisiac as a local anaesthetic

mid 1880’s –◦ Atlanta druggist John

Pemberton – devised a patent medicine that contained two naturally occurring stimulants; cocaine and caffeine Coca-cola – advertised as an

intellectual beverage a temperance drink; a brain tonic

Pemberton sold 2/3 of his interest in 1887 for $283.29

late 1800’s until 1903◦ Coca Cola had ~ 60 mg/ 8 ounces◦ 1903 Coca Cola stopped having cocaine

1914 – Harrison Narcotic Act –◦ listed cocaine as a narcotic

synthesized in the lab (in early 1900’s) first marketed in 1927 drug has been abused since its

introduction benzedrine inhalers used by a wide

segment of population during 1930’s amphetamines and war amphetamines and weight reduction

◦ 1967 – estimates of 23,000,000 prescriptions in US for weight reduction

Cocaine use still rose during the 1920’s but then decreased in 1930’s because amphetamines became available (and at the time cost less, were more easily available AND the euphoria lasted longer)

Amphetamine took over in popularity during the 1940’s – 1960’s. In 1970’s restrictions on amphetamine tightened ◦ made amphetamine a schedule II drug so….

some estimate 1.8 million Americans users of cocaine in 1998; majority between 18 and 34◦ males more likely than females◦ males more likely to use higher amount◦ males more likely to use for longer duration◦ significant proportion met criteria for ADHD

coca leaves◦ leaves can be soaked and mashed to form coca

paste oral – 70 – 80% broken down by liver

biotransformation

cocaine hydrochloridecoca paste treated to form saltwater soluble and can be taken intranasally or injected

IV

snorting – not very efficient because cocaine hydrochloride is ionized; also cocaine has vasoconstrictive properties (so it limits its own passage into blood vessels)

IV – onset is rush ~ 30 – 45 secs◦ duration lasts 10 – 20 min; ◦ 100% reaches circulatory system

freebase- extracted from crystalline from with either ether or sodium hydroxide◦ vaporized at lower temps than cocaine hydrochloride

and so can be inhaled

crack – freebase but extracted with alkaline water and premade (or prepackaged)

smoking not really efficient for delivering cocaine to body because significant portion is lost to pyrolysis – but remaining dose produces intense effect

originally regional specificity

spreading across nation (ease of production although dangerous- explosions, toxic substances, etc)

illicit amphetamine production estimated to be in the billions/year

methamphetamine◦ made in growing numbers of clandestine labs◦ produces greater cortical stimulation than

some other amphetamines◦ huge profit margin

ice – free base form of amphetamine

Estimated that for each pound of methamphetamine produced, between five and six pounds of highly toxic waste is generated.

amphetamine◦ causes release of newly synthesized monoamines◦ also blocks reuptake of monoamines

cocaine◦ blocks reuptake of monoamines

stereotypic behavior◦ high doses result in stereotyped behaviors

representative for respective species in rat, can be sniffing, licking, biting or gnawing

Appetite suppression◦ weight loss

Aggression◦ several descriptions of murder and other

violent offenses attributed to amphetamine intoxication

cardiovascular◦ heart disease increased risk for CVA◦ cardiac arrhythmia◦ increased blood pressure

respiratory◦ chest pain respiratory complications◦ difficulty breathing

neurotoxic◦ seizures intracranial hemorrhages◦ cocaine or amphetamine induced psychosis◦ formication

methylphenidate (Ritalin)◦ causes release of newly synthesized DA◦ also blocks reuptake of DA

“Adderall”

Strattera –atomexetine HCl◦ first non stimulant pharmacotherapy for ADHD◦ blocks reuptake of NE instead of DA

methylated amphetamine – text covers this in chapter with

hallucinogens (affects 5HT as well)

UNTIL RECENTLY - sold in health food stores and on internet

Now – no longer on US market!

◦ ephedra – also known as ma huang; herb ◦ FDA received many reports from doctors, government

health authorities and others about adverse-based ephedrine based products

Currently – OTC subject to FDA regulations HOWEVER herbal supplements currently are

essentially unregulated – may soon change!

◦ either decreased effectiveness or potency of a drug

How does tolerance occur?

Data is mixed

acute tolerance

acute tolerance

animal models – ◦ sensitization

Psychological dependence – very strong!

Physical dependence – WD? ◦ Cocaine crash

operant performance

animals will self administer in absence of tolerance, physical dependence, withdrawal or prior drug taking history

two bar test

variation in extent and rate of self administration depends on drug being administered

ex. opiates – uniform and constant administration (moderate and measured with voluntary abstinence)

cocaine – frenzied intake followed by abstinence

enhances basal neuronal firing or basal NT release in “reward circuit”

1. dose-response rates at fixed ratios

2. progressive ratio schedule

◦ how hard is the animal willing to work for drug

drug discrimination –

◦ 2 bar discrimination

◦ what does this tell us?

initially trained to self administer drugs

followed by extinction

priming or nondrug stimuli

good predictive validity - reinstate heroin and cocaine seeking in laboratory animals including as drug reexposure, drug cues, and stress (Self and Nestler, 1998; Shaham et al., 2000a; Stewart, 2000)

1. non specific drug effects

2. only test the rewarding component of drug during “intoxicated” state

rewarding stimulus is repeatedly paired with neutral environmental stimulus

food, water, brain stimulation, sexual partner

drugs

1. can study reinforcing effects of a drug in drug free state

2. can sometimes see CPP in one trial(IV particularly)

Animals find amphetamine and cocaine highly rewarding