Early Uses of Cocaine Stimulant effects well known by some cultures

for thousands of years Andes mountains in Bolivia and Peru Ancient practice of chewing coca leaves for

energy Coca was considered sacred by the Incas, used

primarily by priests and nobility.

Images obtained from http://goodcoca.bravehost.com/coca_leaves.jpg

16th century invasion by Spaniards Coca leaves were used as form of payment to

the natives for mining and transporting gold and silver.

19th century discoveries Europeans were unaware of psychological

effects or medicinal properties of coca until the active ingredient was isolated. Albert Niemann

isolated cocaine (1860) Wilhelm Lossen

identified molecular formula C17H21NO4

http://www.worldofmolecules.com/drugs/cocaine.jpg

19th century uses in Europe and U.S. Local anesthetic effects discovered in 1880s

Carl Koller, W.S. Halsted Sigmund Freud

initially a proponent of psychiatric uses treatment for depression, fatigue, neuroses,

morphine dependence Patent Medicines and Other Products

lozenges, teas, wines Angelo Mariani’s vin coca Mariani, 1863 Pemberton’s Coca-Cola, 1886

From 1887 to 1914, 46 states passed laws to regulate cocaine

Pure Food and Drug Act, 1906 Harrison Act, 1914

Racially biased views of politicians and media e.g., several unsubstantiated claims in popular

press linking southern blacks to cocaine Negative publicity influenced Harrison Act of

1914, which mainly focused on opiates and morphine, but also included cocaine.

Drove cocaine distribution and use underground

Amphetamines introduced during WWII By late 1960s, amphetamines were harder to

obtain and cocaine use was again on the rise. Many endorsements by celebrities and

physicians were publicized: Occasional use was considered not addictive or

problematic. Before 1985, cocaine symbolized wealth and fame.

By 1980s, a less expensive ($5 to $10 a hit) form that could be smoked was more widely available; “crack” cocaine.

1986: Anti-drug Abuse Act passed 1988: tougher penalties for first-

time users of crack compared to powder cocaine

Continued concerns about racial profiling Again, the media and politicians have

targeted minorities.

Orally Chewing of the coca leaf

Inhaled into the nasal passages “Snorting”

Injected intravenously Hypodermic syringe

Smoked Freebasing Crack

Absorption Chewing or sucking: slow absorption and

onset of effects Snorting cocaine powder: absorbed rapidly

and reaches the brain quickly I.V. use: no absorption, delivers a high

concentration to the brain, rapid and brief effects

Smoking (Freebase or Crack): less invasive than I.V. use, onset of effects is just as rapid

Elimination Metabolized by blood and liver enzymes Short half-life (approx. one hour) Metabolites have longer half-life (approx. 8

hours)

Chemical structure is unlike known neurotransmitters

Main mechanism of action in CNS Blocks reuptake of monoamines (DA, NE, 5-HT) Actions on CNS DA neurons are particularly

important for reinforcing properties of cocaine. However, selective DA reuptake blockers don’t

reliably produce cocaine-like subjective or behavioral effects.

Behavioral effects rely on complex interactions among multiple neurotransmitter systems, including GABA and glutamate as well as the monoamines.

Acute Toxicity High doses can cause convulsions, respiratory and cardiac

arrest Lethal dose difficult to estimate Rare and unpredictable effects on heart related to local

anesthetic effects May trigger ventricular fibrillation

Cocaethylene toxicity (metabolic product when cocaine and alcohol combined)

Chronic Toxicity Intranasal use irritates nasal septum Repeated use of high doses can produce paranoid

psychosis Risk of cardiomyopathy (damage to heart muscle)

Dependence Potential Throughout 1970s, dependence potential not recognized. Extensive research in humans and nonhumans document

cocaine as powerful reinforcer. Cocaine accounts for a large proportion of admissions for

drug abuse treatment in most major U.S. cities.

The “crash,” the initial abstinence phase consisting of depression, agitation, suicidal thoughts, and fatigue

Withdrawal, including mood swings, craving, anhedonia, and obsession with drug seeking

Extinction, when normal pleasure returns; environmental cues may trigger craving and mood swings.

History and Origin Synthesized in 1920s from ephedrine, active ingredient

in medicinal herbs known as Ephedra (ma huang) Sympathomimetic effects (including bronchial dilation) Amphetamine patented in 1932 First medical use: treatment of asthma (Benzedrine

inhaler, OTC cold medicine introduced in 1932) Tested for treatment of narcolepsy, 1935 Appetite suppressant effects reported, 1939

Wartime use Used by American soldiers in WWII to fight fatigue

Speed Scene of 1960s ‘Speedballs’: cocaine used in combination with heroin Methamphetamine

Most common and heavily-used amphetamine

Oral Use of Pills, Tablets Intravenous Use

Speed freak Smoking

Ice

Absorption Oral: peak effects approx 1.5 hours Intranasal: peak effects within 15-30 min. I.V. or inhalation: peak effects within 5-10

minutes Elimination

Amphetamine half-life: 10-12 hours Methamphetamine half-life: 4-5 hours

Molecular structure of amphetamines are very similar to the catecholamines (DA and NE)

Amphetamines stimulate release of monoamines (DA, NE, 5-HT) also inhibit reuptake but to a lesser degree than

cocaine

DA is implicated in reinforcing effects of amphetamines However, some DA antagonists shown

not to block amphetamine-induced euphoria in humans.

As with cocaine, behavioral and subjective effects are likely mediated by actions on a combination of neurotransmitter systems.

Hyperkinetic behavior (ADHD) Weight reduction Narcolepsy

Agitation, anxiety, panic Irregular heartbeat, increased blood

pressure, and heart attack or stroke Intense and high-dose abuse can

cause severe psychotic behavior, stereotypy, seizures, and severe cardiovascular side effects (similar to cocaine).

Physiological Effects

Increase heartbeatIncrease blood pressureDecreased appetiteIncreased breathing rateInability to sleepSweatingDry mouthMuscle twitchingConvulsionsFeverChest painIrregular heartbeatDeath due to overdose

Behavioral EffectsDecrease fatigueIncreased confidenceIncreased feeling of alertnessRestlessness, talkativenessIncreased irritabilityFearfulness, apprehensionDistrust of peopleBehavioral stereotypingHallucinationPsychosis

Decline in abuse in the late ‘80s and early ‘90s

In 1993, the declines were replaced by an alarming increase.

Increase in use of methamphetamine led to the “National Methamphetamine Strategy” in 1996

“Speed” Due to the ease of production,

methamphetamine is often made in makeshift labs in homes or garages.

Acute Toxicity Panic, impaired decision making Hypertensive crisis High doses may cause neurotoxicity,

particularly illicit (impure) methamphetamine Chronic Toxicity

Development of paranoid psychosis with sustained high dose use

High doses may induce repetitive compulsive behaviors (stereotypy in nonhuman studies)

Dependence Potential Similar to cocaine

Eliminate effects of fatigue on reaction time Improve motor coordination on complex

motor tasks Improve performance on tasks requiring

vigilance and sustained attention e.g. clock test

Performance enhancing effects may be limited to overlearned or well practiced tasks.

Performance on task requiring flexibility and ability to adopt new strategies may actually be impaired by stimulants.

Unconditioned Behavior Low to intermediate doses increase spontaneous

locomotor and exploratory activity in rodents. High doses tend to increase stereotypic

behaviors. e.g. repetitive head bobbing, sniffing, rearing, biting

Automutilation behavior is common in rodents and monkeys following high doses.

Conditioned Behavior Rate dependency, first reported by Dews (1958)

Drug Discrimination Amphetamine and cocaine can be trained as

discriminative stimuli in a variety of species (rats, pigeons, monkeys, humans)

Animals trained to discriminate cocaine generalize to amphetamine and vice versa, but do not generalize to caffeine, nicotine, barbiturates, opiates, or hallucinogens.

Dopamine antagonists block amphetamine and cocaine discrimination.

Drug Self-Administration Pickens and Thompson (1968), first published

study on cocaine self-administration in rats. Cocaine is a more robust positive reinforcer

than most other drugs in this assay. Patterns of cocaine self-administration in

laboratory animals depends on availability When drug is freely available 24 hours a day,

pattern is erratic, similar to the binge-abstinence cycle characteristic of human stimulant use

When daily access is limited, patterns of self-administration are steady and regular, with a fairly constant daily intake.

Drug Self-Administration Reinstatement Procedures

Self-administration can be primed by other stimulants as well as other drugs (morphine, caffeine)

Stress Cocaine self-administration is enhanced by

stress. Alternative Reinforcers

Concurrent availability of alternative reinforcers reduces self-administration.