6.1. Cocaine & amphetamines: History and basic pharmacology

Psychostimulant drugs

Cocaine and amphetamines are part of a larger class of drugs known as stimulants, psychomotor stimulants, psychostimulants, or "uppers."

Major behavioral properties of psychomotor stimulants

- Stimulate alertness and arousal

- Stimulate motor activity

Stimulants include

- Cocaine

- Amphetamines

- Nicotine

- Caffeine

Cocaine

- Cocaine is a psychoactive alkaloid found in coca leaves (natural)

- weak base

- 1800s and early 1900s: Widely used; doctors and scientists lauded its properties

Forms of cocaine: Raw leaves

Route of administration: Raw coca leaves are chewed with lime powder or ash to increase saliva pH, which enhances absorption by decreasing the ionization of cocaine (weak base). Absorption in mouth.

Cocaine concentration: < 2% cocaine

Forms of cocaine: Coca paste

- Coca paste is a crude extraction from leaves

- Cocaine concentration: ~80% cocaine sulfate

- Route of administration: Can only be smoked

- “Paco” or “basuco” is very cheap, low-grade cocaine

Forms of cocaine: Cocaine HCl

Cocaine HCl (hydrochloride) is a crystalline powder extracted and purified from coca paste.

Cocaine concentration: Very high,

Route of administration: Water soluble, orally, intranasally, injected IV. Cannot be smoked.

Forms of cocaine: Cocaine free base

- Cocaine free base made from cocaine HCl + water + base extraction with ether (flammable solvent)

- Route of administration: Vaporized and smoked (“freebasing”). But, residual ether can be dangerous and explode with flame.

Forms of cocaine: Crack cocaine

- “Crack” or “rock” cocaine is a cruder preparation made from cocaine HCl. Safer to make because baking soda used instead of solvent.

- Cocaine concentration: 75-90%

- Route of administration: Smoked

- Crack led to a new epidemic of cocaine use in 1980s-90s

History of cocaine use: Cocaine products

Coca/cocaine was widely used in many products by late 1800s.

Current medical use for cocaine

Cocaine has local anesthetic effects (therefore, DEA schedule II)

• Primary mechanism of cocaine: blocks monoamine transporters (like DAT).

• High doses: also inhibits voltage-gated Na+ channels (involved in action potentials).

Cocaine absorption and distribution

Extremely rapid absorption of cocaine with smoking or IV;

- Peak subjective effect for crack cocaine is ~1-2 min

Cocaine metabolism and elimination

- half-life of cocaine is 0.5-1.5 hrs

- Inactive major metabolite benzoylecgonine is detectablein urine for several days

- Active metabolite cocaethylene is formed when cocaineand ethanol are ingested simultaneously; longer half-lifethan cocaine.

Amphetamines and related compounds

Chemical family of synthetic and natural psychostimulants

Forms of amphetamines (natural): Ephedrine

ephedrine and pseudoephedrine:

Decongestants

Forms of amphetamines (natural): Cathinone

- Cathinone comes from “khat” or “qat” shrub leaves (natural).

- Commonly chewed

Forms of amphetamines (synthetic): Bath salts

- Methcathinone (“cat”) and mephedrone (“meow meow”) are synthetic variants of cathinone.

- Designer drugs disguised as household products like bath salts.

- DEA Schedule I.

Forms of amphetamines (synthetic):Amphetamine and methamphetamine

Amphetamine

Methamphetamine

History of use

1920-30s: Medical use developed

• Benzedrine inhaler (for congestion) - 1932

• First use for narcolepsy - 1935

1940s: Widespread adoption during WWII

Early 1970s: Peak use of “speed,”

Forms of amphetamines (synthetic): Amphetamine

- D-Amphetamine

- L-amphetamine

- Amphetamine: Adderall

Route of administration: Taken orally or by injection (IV, SC)

Forms of amphetamines (synthetic): Methamphetamine

Methamphetamine

- most potent of amphetamines

Route of administration: Oral, snorted, injected IV, or smoked.

Amphetamine-related synthetics

“Amphetamine-like” stimulants differ in chemical structure:

- Methylphenidate

- Modafinil

History of amphetamine use: Mood and weight control

- Amphetamines used for narcolepsy wake promoting effects.

- Was used for mild depression and as a diet pill (NOT a current medical use though).

History of amphetamine use: Military

Amphetamines used widely by military during WWII and subsequent conflicts.

History of amphetamine use: General use for fatigue

1970: >10% of population were regular users

Current methamphetamine use: Meth epidemic

- Can be smoked

- faster route of administration = more abuse potential.

- Easily prepared from common household ingredients.

Current medical uses for amphetamines

(DEA schedule II):

1) Narcolepsy

2) Attention deficit disorder (ADD, ADHD)

Amphetamines metabolism and excretion

Amphetamines have a slower metabolism and elimination as compared to cocaine; half-life is 7-30 hrs.

Stimulants: Major effects

Behavioral and subjective effects of cocaine and amphetamines in humans

Autonomic effects also: increased blood pressure, hyperthermia, bronchodilation.

Cocaine vs. amphetamines

Effects of cocaine (as compared to amphetamines)

- Shorter duration of action

- Worse cardiovascular effects (can be lethal)

- Higher convulsive/seizure properties of cocaine

Stimulants: Major effects in animals

Animals: hyperlocomotion

Locomotor activity can appear to go down with high AMPH doses because rats perform stereotypy behavior instead.

Reinforcing/rewarding effects

Effects of repeated stimulant use: Withdrawal

Chronic, high-dose users of stimulants withdrawal symptoms are mostly psychological (as opposed to physical) and not fatal

Effects of repeated stimulant use: Tolerance and sensitization

Tolerance to some effects of psychostimulants:

• Autonomic effects

• Anorexic effects

Sensitization to other effects of psychostimulants:

• Rewarding effects

• Psychotomimetic effects (psychosis)

• Locomotor stimulant effects

Negative effects of chronic amphetamine use

- Psychosis

- Anorexia

- Physical damage

MDMA and related drugs

- MDMA

- MDA

- MDE or MDEA

History of MDMA

- Never used clinically

- Recent evidence that MDMA can enhance communication and openness (similar to psychedelics)

MDMA Use

- Club drug during 1980s-90s

- Schedule I

- Mostly taken orally; long half-life (8 hrs).

MDMA: Major effects. MDMA effects at low doses

Behavioral: Increased energy and sociability/empathy; mild euphoria

Autonomic: Increased heart rate and temperature

MDMA: Major effects. MDMA effects at high doses

Behavioral: Mild hallucinogenic

Autonomic: Hyperthermia & dehydration; increased H.R. and B.P. → stroke