Psychostimulants Lecture Notes

PS 333 / NE 333: Psychostimulants

Overview of Psychostimulants

• Psychostimulants include:

  • Cocaine

  • Amphetamines

  • Ephedrine

  • Methylphenidate

• These substances mimic activation of the sympathetic nervous system, also known as “sympathomimetics.”

• The main neurotransmitters involved in their effects are monoamines.

Effects of Psychostimulants

• Influence on involuntary movements, motivation, and physical ability, as well as cognitive functions such as knowledge.

Monoamine Neurotransmitters Structure

• Norepinephrine:

  • Structure depicted as HO, HO, OH, HO, NH2 (with molecular configuration).

• Dopamine:

  • Structure consists of OH, NH2, etc.

• Histamine

  • Serotonin

  • The structural components affect their physiological and psychological roles.

Historical Context of Cocaine

• Prehistoric Use:

  • Coca leaf preparations used locally in South America for over 5000 years.

• 19th Century (1800s):

  • Cocaine isolated and named; used medically as a local anesthetic and for treating depression and fatigue;

  • Unrestricted use; popular as an additive in drinks and tonics (e.g., Coca-Cola).

Legal and Usage Evolution

• 1910-1914: Legal restrictions on cocaine initiated.

• 1930s: Increased popularity of amphetamines leads to decreased cocaine usage.

• 1960s: Amphetamine restrictions arise; Cocaine usage increases once more.

• 1980s: The emergence of crack cocaine.

• Present Day: Shift towards lower-cost methamphetamines with stabilized cocaine use levels.

Cocaine: Forms and Routes of Administration

• Coca leaf:

  • Administered orally or bucally.

• Cocaine Hydrochloride Powder:

  • Administered intranasally or intravenously.

• Freebase:

  • Administered via inhalation.

• Crack:

  • Administered via inhalation; easier to make and use.

Addiction Potential

• Routes such as inhalation and injection are more addictive because they provide higher concentrations of the drug more rapidly.

Pharmacokinetics of Cocaine

• Half-life of Cocaine: Approximately 50 minutes. Pharmacokinetics indicate effects last about an hour.

Physiological Effects of Cocaine

1. Local Anesthetic: Used in medical settings for its numbing properties.

2. Vasoconstriction: Constricts blood vessels leading to increased blood pressure.

3. Psychostimulant: Increases:

   • Heart rates

   • Blood pressure

   • Bronchodilation

   • Body temperature

   • Blood glucose levels

   • Blood flow to muscles

   • Pupil dilation

Rewarding Effects

• Increases energy and alertness, reduces fatigue and appetite, enhances activity and libido, prevents sleep, induces euphoria.

Adverse Effects

• Includes increased impulsiveness, anxiety, psychotic-like symptoms, formication, and compulsive behaviors.

Mechanism of Action of Cocaine

• Cocaine acts as a monoamine reuptake inhibitor, affecting:

  1. Dopamine Transporter (DAT)

  2. Norepinephrine Transporter (NET)

  3. Serotonin Transporter (SERT)

• The inhibition of these transporters results in increased concentrations of these neurotransmitters within the synaptic cleft.

Mechanism Details

• Without Cocaine: Dopamine is released into the synaptic cleft, where it interacts with postsynaptic dopamine receptors.

• With Cocaine: Cocaine blocks the reuptake of dopamine, resulting in prolonged action of dopamine in the synaptic cleft.

History of Amphetamines

• 1927: Development of amphetamine as a low-cost alternative to ephedrine for asthma.

• 1935: Market introduction in the US.

• Ephedra: Used traditionally, with ephedrine as the active ingredient.

• Synthesis: Initially complicated, leading to the creation of optimized synthetic pathways for amphetamines.

Amphetamines: Structural Overview

• Amphetamine: NH2, CH3 - structurally resembles monoamines.

• Half-lives of Related Compounds:

  • Adrenaline: 2-3 minutes

  • Ephedrine: 3-6 hours

  • Amphetamine: 9-13 hours

Early Observations and Uses

• First observed uses included:

  • Asthma treatment

  • Weight loss drugs

  • Mood enhancement

  • Increased need for wakefulness

  • Cognitive enhancement during testing

  • Energy boosting

Side Effects of Amphetamines

• Similar to those of cocaine, these include:

  1. Anxiety

  2. Psychosis

  3. Physical dependence

  4. Addiction

Mechanisms of Action of Amphetamines

1. Alters normal uptake mechanisms via DAT and NET.

2. Alters the vesicular monoamine transporter (VMAT).

3. Blocks transporters and reverses their function, leading to massive increases in dopamine and norepinephrine in the synaptic cleft.

Amphetamines: Family of Compounds

• L-amphetamine vs. D-amphetamine: D-amphetamine is known to be more potent.

• Benzedrine: A racemic (1:1) mixture of both isomers.

• Dexedrine: Pure d-Amphetamine.

• Adderall: A mixture with a specific ratio of both isomers.

Methamphetamine

• Similar compound structure with a more stable crystal form suitable for inhalation.

• Results in rapid dopamine and norepinephrine release, leading to pronounced side effects such as euphoria.

Lisdexamfetamine (Vyvanse)

• A prodrug that converts to lysine + d-amphetamine; offers a slow build-up in d-amphetamine levels, intended to reduce side effects.

Dosage and Effects

• Therapeutic Dose: Generally ranges from 5-60 mg daily.

• Lethal Dose: Ranges from 10-20 mg/kg as a single dose.

• Recreational Use: Usually 10-40 mg at a time; heavy users may consume 100-1000 mg daily.

Methamphetamine Dosage Effects

• Different doses can lead to varying manifestations:

  • Anxiety, dysphoria: > 30 mg

  • Elevated body temperature: > 30 mg

  • Talkativeness: > 50 mg

  • Paranoia, hallucinations: > 55 mg

  • Stereotypy and dyskinesia: High doses lead to imbalances in receptor signaling, resultant behavioral and physical manifestations.