Psychomotor Stimulants Cocaine & Amphetamines

1. Psychomotor StimulantsCocaine & Amphetamines

2. History of Cocaine • 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

3. History of Cocaine • 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

4. History of Cocaine • 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

5. Early Legal Controls • 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

6. Contemporary Legal Controls on Cocaine • 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.

7. Contemporary Legal Controls on 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.

8. Forms of Cocaine Use • Orally • Chewing of the coca leaf • Inhaled into the nasal passages • “Snorting” • Injected intravenously • Hypodermic syringe • Smoked • Freebasing • Crack

9. Cocaine’s Pharmacokinetics • 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)

10. Cocaine’s Pharmacodynamics • 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.

11. Health Risks • 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.

12. Stages of Cocaine Withdrawal • 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.

13. Amphetamines • History and Origin • Synthesized in 1920s from ephedrine, active ingredient in medicinal herbs known as Ephedra (ma huang) • Sympathomimeticeffects (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

14. Forms of Amphetamine Use • Oral Use of Pills, Tablets • Intravenous Use • Speed freak • Smoking • Ice

15. Amphetamines

16. Amphetamine Pharmacokinetics • 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

17. Amphetamine Pharmacodynamics • 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

18. Amphetamine Pharmacodynamics • 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.

19. Approved Medical Uses of Amphetamines • Hyperkinetic behavior (ADHD) • Weight reduction • Narcolepsy

20. Side Effects of Therapeutic Doses • 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).

21. Summary of the Effects of Amphetamines Physiological Effects Increase heartbeat Increase blood pressure Decreased appetite Increased breathing rate Inability to sleep Sweating Dry mouth Muscle twitching Convulsions Fever Chest pain Irregular heartbeat Death due to overdose Behavioral Effects Decrease fatigue Increased confidence Increased feeling of alertness Restlessness, talkativeness Increased irritability Fearfulness, apprehension Distrust of people Behavioral stereotyping Hallucination Psychosis

22. Current Misuse • 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.

23. Health Risks • 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

24. Effects of Stimulants on Performance • 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.

25. Psychomotor Stimulants in Nonhuman Behavioral Studies • 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)

26. Psychomotor Stimulants in Nonhuman Behavioral Studies • 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.

27. Psychomotor Stimulants in Nonhuman Behavioral Studies • 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.

28. Psychomotor Stimulants in Nonhuman Behavioral Studies • 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.