Amphetamines

CULTURAL HISTORY OF AMPHETAMINE (AMP)

  • Definition and Context

    • AMP (Amphetamine) is most closely related to two naturally occurring compounds:

      • Cathinone: A stimulant found in khat (plant).

      • Historical significance in conflicts of East Africa and the Arabian Peninsula where it is chewed by soldiers for increased loyalty and compliance.

      • Khat is derived from the plant Catha edulis and is intertwined with ancient traditions (e.g., used by Muslim clerics for study).

  • Economic Impact

    • Khat was Ethiopia’s fourth largest export, earning over $270 million (205 million euros) in 2012-2013.

    • Estimated up to 20 million people in the Horn of Africa and Arabian Peninsula chew khat.

    • However, in economically struggling countries, spending on khat has compounded poverty issues.

  • Legal Status of Khat

    • Khat is classified as a non-narcotic Schedule I controlled substance by the DEA in the U.S.

    • Scheduling is based on perceptions of its role in events in Somalia (1991), especially post-Black Hawk Down incidents.

  • Crackdown Events

    • In the summer of 2006, the DEA arrested a number of suspects in an international narcotics-trafficking organization involving khat.

    • Many charges were eventually dismissed, leading to debates over khat's classification—whether it is akin to an illicit stimulant or merely a mild stimulant.

SIMILAR SUBSTANCES TO AMP

  • Ephedrine

    • Derived from Ephedra sinica, also known as ephedra, contains alkaloids ephedrine and pseudoephedrine.

    • Sympathomimetic properties similar to AMP, phenylpropanolamine, methamphetamine, and epinephrine.

    • Has been used as a herbal remedy in China for over 5,000 years.

    • Current uses include as a bronchodilator and linked to sporting controversies (e.g., three of the first 25 drug-related penalties in the Olympics were for ephedrine).

HISTORICAL USE OF AMPHETAMINE

  • War-Time Distribution

    • Amphetamines, including methamphetamine (MAMP), were distributed extensively to soldiers during WWII to combat sleepiness and reduce appetite.

    • Post-war, AMP use surged among college students (for studying) and truck drivers (for long hauls).

    • Recreational use peaked in the 1970s, followed by a decline as cocaine and smoked MAMP became popular alternatives.

    • Presently, AMP's primary application is in treating ADHD across all age groups.

PHARMACOKINETICS OF AMPHETAMINE

  • Comparative Potency

    • Different forms of AMP have very distinct pharmacokinetics.

    • AMP is less potent than MAMP, resulting in a slower onset of effects.

    • Administration methods: Oral intake, injection, and smoking.

      • Oral: Slow absorption due to AMP being a weak base; effects begin 30 minutes after ingestion.

      • Smoking: Leads to instantaneous effects with peak plasma levels reached in 2-3 hours—known for being fast-acting and long-lasting, contributing to addiction potential.

    • Metabolism: AMP is slowly metabolized in the liver, with some excretion occurring unchanged, influenced by urine acidity affecting AMP reabsorption in the kidneys.

    • Half-life: Ranges from 7 to 30 hours depending on individual metabolism and excretion conditions.

MECHANISM OF ACTION OF AMPHETAMINE

  • Dopamine (DA) and Norepinephrine (NE) Interaction

    • AMP blocks the reuptake of DA and NE.

    • At low doses:

      • AMP enters neurons via transport proteins, displacing DA through the exchange-diffusion model.

    • At higher doses:

      • AMP penetrates vesicles, displacing stored DA, resulting in enhanced release into the synaptic cleft (vesicular release/exchange-diffusion model).

EFFECTS OF AMPHETAMINE

  • Physiological Effects

    • AMP and MAMP are classified as sympatheticomimetic stimulants, triggering a fight or flight response with effects including:

      • Increased blood pressure

      • Bronchodilation

      • Relaxation of gastrointestinal smooth muscle

      • Elevated respiration rates

      • Increased metabolic rate and oxygen consumption

      • Hyperthermia

      • Elevated heart rate

    • Approved medical uses include the treatment of:

      • Narcolepsy

      • Diet control

      • ADHD

NARCOLEPSY

  • Symptoms include:

    • Cataplexy (sudden muscle weakness), sleep paralysis, and hypnagogic hallucinations.

    • Origin is unclear, but DA deficits have been implicated.

    • While both AMP and methylphenidate (e.g., Ritalin) can be effective, high ED50 in cases may lead to dependence and unwanted side effects (e.g., drug-induced anorexia, hypertension).

  • Appetite Suppression

    • AMP and MAMP effectively suppress appetite, impacting hunger ratings among users.

MECHANISM OF ACTION OF METHYLPHENIDATE (MPH)

  • MPH inhibits the reuptake of dopamine and norepinephrine, targeting ADHD symptoms effectively.

TOLERANCE, DEPENDENCE, AND WITHDRAWAL

  • Tolerance

    • Tolerance to AMP is presumed not to be metabolic; distinctions remain unclear between pharmacodynamic and behavioral tolerance.

    • Sensitization may occur with intermittent use, leading to exaggerated responses at low doses.

  • Withdrawal Symptoms

    • Upon cessation, AMP users traditionally experience:

      • Lethargy

      • Inattention

      • Amotivation

      • Increased sleep and dreaming

      • Cravings for the substance

      • Symptoms of depression and dysphoria.

NEUROTOXICITY OF AMPHETAMINE AND METHAMPHETAMINE

  • Neurotoxic Effects

    • Well-established neurotoxic effects of AMP and MAMP, primarily through elevated DA levels leading to free radical formation, which harms neuronal cells.

    • Displacement of DA to the cytoplasm can lead to rapid auto-oxidation and formation of potentially harmful substances (e.g., superoxide radicals, hydrogen peroxide).

    • Normal DA metabolism typically mitigates these toxic effects; however, persistent high DA levels can result in significant brain injury.

    • Research suggests that some brain damage is reversible after prolonged abstinence from the substances.