Drug study guide

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 ("psycho-")

- Stimulate motor activity ("-motor")

Stimulants include

Cocaine, amphetamines, nicotine, caffeine

Amphetamines and related compounds

Amphetamines: chemical family of synthetic and natural psychostimulants

MDMA and related drugs

MDMA, MDA, MDE or MDEA

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 and can be taken orally (e.g. Coca-Cola), 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-1990s

Forms of amphetamines (natural): Ephedrine

Ephedrine comes from Ephedra or "Mormon tea" plant (natural);

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. These designer drugs bath salts

DEA Schedule I.

Forms of amphetamines (synthetic): Amphetamine and methamphetamine

Amphetamine

Methamphetamine

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 cocaine use: Cocaine products

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

What are two forms of synthetic amphetamines?

Amphetamine and methamphetamine

When did medical use of amphetamines develop?

1920-30s

What was the purpose of the Benzedrine inhaler?

For congestion

First use for narcolepsy - 1935

narcolepsy

When did the peak use of 'speed' occur?

Early 1970s

During which major event was there widespread adoption of amphetamines?

1940s World War II

History of amphetamine use

Mood and weight control Amphetamines used for narcolepsy wake-promoting

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

History of MDMA

Never used clinically

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

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)

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

Current medical uses for amphetamines

(DEA schedule II):

1) Narcolepsy

2) Attention deficit disorder (ADD, ADHD)

MDMA use

Club drug during 1980s-90s

DEA Schedule I

Most addictive drug(s) and/or route of administration

Cocaine Extremely rapid absorption of cocaine with smoking or IV

How is cocaine absorbed when smoked or injected?

Extremely rapid absorption

What is the peak subjective effect time for crack cocaine?

~1-2 minutes

What is the half-life of cocaine?

0.5-1.5 hours

Amphetamines metabolism and excretion

Half-life is 7-30 hrs.

MDMA

Orally; long half-life (8 hrs).

What is the inactive major metabolite of cocaine that is detectable in urine?

Benzoylecgonine

How long can benzoylecgonine be detected in urine after cocaine use?

Several days

What active metabolite is formed when cocaine and ethanol are ingested simultaneously?

Cocaethylene

Does cocaethylene have a longer or shorter half-life than cocaine?

Longer half-life

Amphetamines metabolism and excretion

Amphetamines have a slower metabolism and elimination as compared to cocaine

Stimulants: Major effects

- Behavioral and subjective effects of cocaine and amphetamines in humans

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

MDMA effects at low doses

Behavioral: Increased energy and sociability/empathy; mild euphoria

Autonomic: Increased heart rate and temperature;

MDMA effects at high doses

Behavioral: Mild hallucinogenic effects

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

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

Reinforcing/rewarding effects

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

What is a potential effect of amphetamines on the nervous system?

Neurotoxicity

What substances can cause depletion of monoamines and degeneration of nerve terminals?

Amphetamine, meth, and MDMA

What long-lasting effect does methamphetamine have on dopamine transporters in humans?

Long-lasting decrease in DAT availability

What is the average period of abstinence for users studied regarding methamphetamine's effects?

3 years

What are the most acute adverse effects of MDMA?

Dehydration and hyperthermia

Is overdose common in adults using MDMA?

No, it is rare

What cognitive effect has been reported in regular MDMA users?

Subtle cognitive deficits

What long-lasting effect does chronic MDMA use have on serotonin transporters in humans?

Long-lasting decrease in SERT availability

Amphetamine/methamphetamine neurotoxicity:

- high doses

- high extracellular DA necessary

What type of neurotoxicity does MDMA primarily affect?

5-HT terminals

What type of neurotoxicity does amphetamine primarily cause?

Damage to DA terminals

What type of neurotoxicity does methamphetamine cause?

Damage to both DA and 5-HT terminals

Methamphetamine neurotoxicity

Humans: Long-lasting decrease in DAT availability

abstinent methamphetamine and methcathinone users (average period of abstinence: 3 years).

MDMA neurotoxicity

Most acute adverse effects of MDMA reflect dehydration and hyperthermia,

not overdose (rare in adults).

However, several reports of subtle cognitive deficits in regular MDMA users

Humans: Long-lasting decrease in SERT

availability after chronic MDMA

Therapeutics for stimulant addiction

No clinically licensed therapeutics for cocaine/amphetamine treatment.

Best treatments currently available:

• Psychosocial treatment

• Cognitive behavior therapy

• Relapse prevention therapy

What is the primary action of cocaine in pharmacodynamics?

Cocaine blocks reuptake of monoamines: dopamine, norepinephrine, and serotonin.

What role does dopamine play in the effects of cocaine?

Dopamine is important for stimulating, reinforcing, and addictive properties.

What additional effect does cocaine have at high concentrations?

Cocaine blocks voltage-gated Na+ channels.

What is one mechanism by which amphetamines affect dopamine?

Amphetamines block reuptake of monoamines.

What are the three types of monoamines affected by amphetamines?

Dopamine (DA), norepinephrine (NE), and serotonin (5-HT).

How do amphetamines cause dopamine release?

By entering nerve terminals via the dopamine transporter (DAT) and causing vesicles to release dopamine.

What is another way amphetamines promote dopamine release?

By reversing the dopamine transporter (DAT) so that dopamine is transported out of the cell.

What effect do high doses of amphetamines have on monoamine oxidase (MAO)?

High doses of amphetamines inhibit monoamine oxidase (MAO).

What type of agonists are cocaine and amphetamines?

Indirect agonists of monoamine systems

What do cocaine and amphetamines block?

Monoamine transporters

Which monoamines does cocaine affect?

5-HT, DA, NE

How does cocaine cause dopamine release?

By blocking monoamine transporters and causing DA release via release from vesicles and reverse transport

Which monoamines do amphetamines affect?

DA, NE

Which monoamines does methamphetamine affect?

DA, NE

Which monoamine does MDMA primarily affect?

5-HT

Cocaine in the human brain

Distribution of cocaine binding matches the distribution of DAT (densest in striatum

Which neural systems are involved in drug-induced behavioral effects?

DA is critical for the reinforcing and locomotor effects of amphetamine and cocaine.

Evidence from many studies

Pharmacological studies: Antagonists

DA antagonists, but not NE antagonists, disrupt amphetamine reinforcement (self-administration).

Pharmacological studies: Transporter blockers

Other drugs that block DAT are also self-administered by animals

Not readily self-administered by animals or abused by people:

Selective blockers of NET

Selective blockers of SERT

Other local anesthetics (Na+ channel blockers)

Therefore, DAT blockade appears to be the core mechanism by which cocaine and

amphetamine are reinforcing.

What substance is used to lesion dopamine (DA) in lesion studies?

6-OHDA

What effect does lesioned dopamine (DA) have on cocaine reinforcement?

Disrupts cocaine reinforcement (self-administration)

What does VNAB/DNAB lesion target?

Norepinephrine (NE)

What does a nucleus accumbens lesion target?

Dopamine (DA)

Neurochemical studies

Similar time course for amphetamine effects on

• DA release in striatum and

• locomotor effects

Neurochemical studies

sensitization of locomotor

and reinforcing effects, as well as

sensitization of DA levels in striatum.

Which neural systems are involved in drug-induced behavioral effects?

DA is critical for the reinforcing and locomotor effects of amphetamine and cocaine.

What is the effect of stimulant-induced dopamine in the nucleus accumbens?

Locomotion and reinforcement

What is the effect of stimulant-induced dopamine in the dorsal striatum?

Stereotypies

What do reward-associated cues (conditioned stimuli) elicit?

Dopamine release

What is the role of dopamine release from reward-associated cues?

Drive motivation for the reward

Cocaine cues drive dopamine and craving

addicted individuals shows dopamine

release related to viewing cocaine cue vs. neutral cue.

Cue-induced dopamine release in dorsal striatum correlates with craving

Genetic studies: Knockout

DAT knockout mice (DAT -/-) are spontaneously

hyperactive, showing increased locomotion

Genetic studies: Knockin

DAT knock-in mice (DATki) have a mutation that

makes DAT insensitive to cocaine but normal

otherwise. They show loss of cocaine reinforcement

(self-administration).

Cocaine cues drive craving in animals

In rats, cocaine-associated cues also trigger

drug seeking

Methamphetamine neurotoxicity- Animal studies

Baboons: Long-lasting decrease in DAT availability

after meth

Rats: Long-lasting decreases in TH and DAT after meth

MDMA neurotoxicity- Animal studies

Squirrel monkeys: Loss of serotonin axons

after MDMA

Fine 5-HT axons destroyed in cortex,

hippocampus, striatum