Chapter 6B Comprehensive Study Guide on Amphetamines: Pharmacology, History, and Clinical Applications

Historical Context and Origins of Amphetamines

• Medicinal Tea and Ma Huang: The Chinese historically utilized a medicinal tea derived from ma huang (Ephedra).

  • Ma Huangs Active Ingredient: The active ingredient identified in ma huang is ephedrine, discovered in $1887$.

  • Physiological Effect: Ephedrine stimulates the sympathetic branch of the autonomic nervous system.

  • Drug Classification: It is classified as a sympathomimetic drug.

  • Historical Medical Use: Originally used as a treatment for asthma.

Chemical Classification and Molecular Variations

• Dextroamphetamine: A form of amphetamine known to be more potent than other variations.

• Levoamphetamine: This form is typically combined with d-amphetamine to create the medication known by the brand name Adderall.

• Methamphetamine:

  • Molecular Modification: This is a modified form of d-amphetamine achieved by substituting a methyl group ($CH_3$) for a hydrogen atom ($H$).

  • Effect of Modification: This structural change allows for a quicker passage across the blood-brain barrier.

  • Common Names: Often referred to as meth, speed, or crank.

  • Prevalence: Recognized as the primary form of amphetamine abuse.

Evolutionary History and Market Availability

• Amphetamine Synthesis: Amphetamine is a synthesized chemical structure similar to ephedrine.

• Patent and Availability: It was patented in $1932$ and subsequently became globally available.

• Early Medical Indications:

  • Asthma

  • Narcolepsy

  • Hyperactivity in children

  • Appetite suppressant

  • General stimulant purposes

• Wartime Applications: Used during wars to increase overall efficiency and reduce feelings of fatigue among personnel.

• The 1960s "Speed Scene":

  • Many intravenous (IV) drug users consumed amphetamines alone or in combination with heroin, a mixture known as a speedball.

  • During this era, most street amphetamines were sourced through legal prescriptions.

• Regulatory Shift: As amphetamines became more tightly controlled, the market saw an increase in cocaine use and the illicit manufacture of methamphetamine.

• Abuse Cycles: Injectable abuse peaked in $1967$, declined, and later resurfaced in the $1990\text{s}$.

Pharmacological Mechanism of Action in the Central Nervous System

• Neurotransmitter Interaction: Amphetamines possess a close molecular resemblance to dopamine and norepinephrine.

• Brain Activity: They increase activity levels of dopamine, norepinephrine, and serotonin.

• Specific Mechanism: Amphetamines increase the release of neurotransmitters at the terminal and simultaneously slow down the reuptake process.

• Dopamine Focus: High activity is seen in regions of the brain associated with positive reinforcement.

  • Euphoric Effects: Directly tied to the dopamine surge.

  • Cravings: Long-term neurochemical changes lead to intense cravings.

• Comparison to Cocaine:

  • Shared Mechanism: Both cocaine and amphetamines share a common neurochemical mechanism regarding dopamine.

  • Gastrointestinal Absorption: Amphetamines are more easily absorbed into the nervous system from the gastrointestinal tract than cocaine.

  • Duration: The effects of amphetamines are much longer-lasting than those of cocaine.

Pharmacokinetics: Absorption, Elimination, and Tolerance

• Peak Effect Timelines:

  • Oral Ingestion: Peak effects occur after $1.5$ hours.

  • Intranasal Administration: Peak effects occur within $5-20$ minutes.

  • Intravenous Injection or Smoking: Peak effects occur within $5-10$ minutes.

• Half-life: The drug has a half-life of range $5-12$ hours.

• Elimination: Complete elimination from the body takes approximately $2-3$ days.

• Tachyphylaxis: A rapid tolerance known as tachyphylaxis can occur following high doses.

Clinical and Societal Effects: Acute and Chronic Consequences

• Acute Effects:

  • Closely resemble cocaine effects but are extended over an $8-24$ hour period of increased sympathetic activation.

  • Benefits (Short-term): Boost in alertness, energy, euphoria, and a sense of invincibility.

  • Adverse Changes: Can lead to convulsions, chest pains, stroke, and is potentially lethal.

• Chronic Effects:

  • Formication: Heavy users experience the sensation of bugs crawling under the skin.

  • Stereotypy: Compulsive or repetitive behaviors fixed on trivial aspects of life.

  • Physical Indicators: Compulsive jaw movements and teeth grinding.

• Amphetamine Psychosis:

  • Symptoms: Paranoia, delusions, hallucinations, and violent behaviors.

  • Prevalence: Displayed by up to $50\%$ of heavy users.

  • Context: Often occurs after periods without sleep for $3-5$ days.

  • Similarity: Closely resembles paranoid schizophrenia.

  • Dopamine Hypothesis: Suggests the psychosis is caused by elevated dopamine levels in the frontal cortex.

Evolution and Patterns of Methamphetamine Abuse

• 1960s Distribution: Widely distributed via prescriptions for weight control and combating drowsiness.

• 1980s Decline: Abuse became less prominent in the public mind as emphasis shifted toward cocaine.

• 1990s Resurgence: Reemerged as the use of crack and powder cocaine decreased.

• Prevalence Statistics (2009 Data):

  • Lifetime use ($12+$): $12.8 \times 10^6$ people.

  • Past year use: $1.2 \times 10^6$ people.

  • Past month use: $500,000$ people.

  • Comparison: These numbers are approximately $\frac{1}{3}$ of powder cocaine use and similar to crack cocaine levels.

• National Institute on Drug Abuse (2017 Survey): Indicated that for those over the age of $26$, $5.6\%$ had used amphetamines within their lifetime.

• Clandestine Manufacturing:

  • Homegrown Labs: Emerged in the late $1990\text{s}$ in mobile homes, campers, vans, and farm sheds.

  • Environmental Hazards: Manufacturing creates $5\,lb$ of toxic waste for every $1\,lb$ of methamphetamine produced. Waste seeps into soil and fumes pose risks of fire and explosion.

  • Regulation: Laws now limit the sale of cold medicines containing pseudoephedrine and farm fertilizers such as liquid anhydrous ammonia used in production.

• Crystal Meth: The smokable form of the drug characterized by high purity and efficient delivery to the system.

• Usage Frequency: Methamphetamine users typically dose at $2-4$ hour intervals throughout the day, whereas cocaine users often binge during evening and night hours.

Clinical Treatment for Methamphetamine Dependency

• Approaches: Treatment is similar to cocaine protocols, including inpatient and outpatient programs and self-help groups.

• Barriers to Recovery: Users find it extremely difficult to become drug-free due to the perception that they are in control of their use.

• Relapse Rates: Methamphetamine has one of the highest relapse rates of all illicit drugs.

• Withdrawal:

  • Initial "crash" occurs $2-4$ hours post-drug behavior.

  • Symptoms: Depression, high anxiety, hunger, and agitation.

  • Full withdrawal process takes approximately $6-8$ weeks.

Approved Medical Therapeutics and ADHD Treatment

• Common Use: Treatment of Attention-Deficit Hyperactivity Disorder (ADHD).

• Primary Medications:

  • Methylphenidate (Brand name: Ritalin).

  • Atomoxetine (Brand name: Strattera).

  • Dextroamphetamine/Levoamphetamine (Brand name: Adderall): Noted for longer duration.

  • Dextroamphetamine/Lysine (Brand name: Vyvanse).

• Efficacy: These drugs improve learning and ability in $60-80\%$ of correctly diagnosed patients.

• Mechanism in ADHD:

  • Low Arousal Theory: Suggests stimulants may amplify environmental stimulation while reducing background firing of neurons.

  • Salience: Heightens motivation for tasks by enhancing the salience and interest in the task.

  • Safety: Slow absorption and action of dopamine avoid an emotional high.

• Other Beneficial Uses:

  • Depression: Choice treatment in the $1950\text{s}-1960\text{s}$; now used as an adjunctive therapy due to rapid antidepressant effects.

  • Weight Control: Used to reduce food intake; methamphetamine remains FDA-approved for this, though long-term efficacy is unclear.

  • Narcolepsy: Used to prevent uncontrolled daytime muscle weakness and sleep episodes.

  • Smart Pills: At low arousal levels, they may improve performance; at high levels, they may decrease it.

  • Athletics: May produce slight improvements in performance under specific circumstances.

Methamphetamine Effects on Performance

• Simple Task (Reaction Time): As dose increases, reaction time decreases (improves).

  • $0\,mg/70\,kg \approx 960\,msec$

  • $50\,mg/70\,kg \approx 800\,msec$

• Complex Task (False Alarms): As dose increases, the proportion of false alarms increases (performance quality decreases).

  • $0\,mg/70\,kg \approx 0.0$

  • $50\,mg/70\,kg \approx 0.4$