CNS Stimulants and Hallucinogenics: Cocaine, Amphetamines, & Psilocybin

Drug Scheduling of Controlled Substances

  • Definition and Classification System:

    • Schedule I:

      • Definition: Drugs with no currently accepted medical use and a high potential for abuse.

      • Examples: Heroin, LSD, marijuana, MDMA (3,4-methylenedioxy-methamphetamine), peyote, methaqualone. Note: The absence of therapeutic properties for these drugs is a subject of debate.

    • Schedule II:

      • Definition: Drugs with a high potential for abuse, with use potentially leading to severe psychological or physical dependence.

      • Examples: Combination products with less than 15 mg15\,\text{mg} of hydrocodone per dosage unit (Vicodin), cocaine, methamphetamine, PCP (phencyclidine), methadone, hydromorphone (Dilaudid), meperidine (Demerol), oxycodone (OxyContin), fentanyl, Dexedrine, Adderall, and Ritalin.

    • Schedule III:

      • Definition: Drugs with a moderate to low potential for physical and psychological dependence.

      • Examples: Products containing less than 90 mg90\,\text{mg} of codeine per dosage unit (Tylenol with codeine), ketamine, anabolic steroids, and testosterone.

    • Schedule IV:

      • Definition: Drugs with a low potential for abuse and low risk of dependence.

      • Examples: Xanax, Soma, Darvon, Darvocet, Valium, Ativan, Talwin, Ambien, and Tramadol.

    • Schedule V:

      • Definition: Drugs with lower potential for abuse than Schedule IV; consist of preparations containing limited quantities of certain narcotics. These are generally used as antidiarrheals, antitussives, and analgesics.

      • Examples: Cough preparations with less than 200 mg200\,\text{mg} of codeine per 100 mL100\,\text{mL} (Robitussin AC), Lomotil, Motofen, Lyrica, and Parepectolin.

CNS Stimulants

  • General Characteristics:

    • A group of psychoactive drugs that accelerate brain and body processes.

    • Functions include increasing alertness, attention, energy, and physical activity.

  • Clinical Utility:

    • Clinically useful for treating Attention Deficit Hyperactivity Disorder (ADHD), narcolepsy, and obesity.

  • Commonly Abused CNS Stimulants:

    • Cocaine

    • Amphetamines

    • Methamphetamine

    • Methylphenidates

    • Modafinil

Hallucinogenics

  • General Characteristics:

    • A group of psychoactive drugs that alter a person's perception of reality, thought processes, and mood.

    • Primary Mechanism: These drugs primarily alter serotonin levels.

  • Clinical Utility:

    • Useful for treatment-resistant depression, Major Depressive Disorder (MDD), Post-Traumatic Stress Disorder (PTSD), substance use disorders, existential anxiety, and cluster headaches.

  • Common Hallucinogens:

    • Psilocybin

    • DMT / Ayahuasca

    • Mescaline (Peyote)

  • Disassociatives:

    • Phencyclidine (PCP)

    • Ketamine

    • Salvia

Cocaine: Prevalence and Pharmacology

  • Prevalence of Use in the US:

    • Total Users: Approximately 25,000,00025,000,000 people aged 12 and older.

    • Past Year Prevalence: 1.8%1.8\% of the population.

    • Overdose Impact: 11 in 55 overdose deaths involve cocaine.

    • Gender Gap: Men use cocaine at double (2×2\times) the rate of women.

    • Cocaine Use Disorder: Affects 1.3 million1.3\,\text{million} people.

    • Substance Use Disorder (SUD) Rate: 20%20\% of people who used cocaine met the criteria for a SUD.

  • Pharmacology and Reinforcement:

    • Primary Mechanism: Reinforcing properties correlate with effectiveness in inhibiting the dopamine transporter (DAT).

    • Result: This leads to increased concentrations of dopamine (DA) at sites mediating reward.

    • Additional Transporters: Cocaine also inhibits norepinephrine (NE) and serotonin (5-HT5\text{-HT}) transporters, thereby inhibiting reuptake.

  • Physiological and Psychological Effects:

    • Produces a dose-dependent increase in heart rate and blood pressure.

    • Accompanied by increased arousal, improved performance on tasks associated with vigilance and alertness, and a sense of self-confidence and well-being.

  • Kinetics and Metabolism:

    • Half-life: The half-life of cocaine is approximately 50 min50\,\text{min}.

    • Administration: Inhaled (crack) cocaine produces a "high" within 10−30 min10-30\,\text{min}.

    • Metabolite: Cocaine is largely metabolized into benzoylecgonine, which is excreted in the urine and can be detected for up to 10 days10\,\text{days} after heavy use.

  • Effects of Chronic and Repeated Use:

    • Repeated doses may lead to involuntary motor activity, stereotyped behaviors, and paranoia.

    • Chronic users exhibit increased irritability and an increased risk of violence.

Cocaine and Ethanol Coadministration

  • Abuse Pattern: Cocaine is frequently abused concurrently with ethanol.

    • Purpose: Ethanol is used to reduce the irritability associated with cocaine use; dual addiction is common.

  • Formation of Cocaethylene:

    • Coadministration produces the compound cocaethylene.

    • Potency: It is equipotent to cocaine.

    • Half-life: It has an increased half-life of 3−5 hours3-5\,\text{hours}.

    • Cardiac Risks: Acts as a potent cardiac sodium (Na+Na^+) channel blocker. It prolongs the heart's recovery time, induces arrhythmias, and directly depresses myocardial function.

    • Fatality Risk: Results in an 18- to 25-fold18\text{- to }25\text{-fold} increase in the risk of immediate death compared to taking cocaine alone.

Cocaine Withdrawal: Data and Stages

  • Comparison of Male and Female Users (Sample N=554N=554):

    • Demographics: Average age is approximately 33.8 years33.8\,\text{years} (Standard Deviation 7.77.7).

    • Usage History: Average history of 11.0 years11.0\,\text{years}. Males spent significantly more money per week (US$439US\$439) compared to females (US$350US\$350, p=0.04p=0.04).

    • Craving: Males reported significantly higher cravings for cocaine (90%90\%) compared to females (83%83\%; p=0.04p=0.04).

    • Common Withdrawal Symptoms (Aggregate Sample):

      • Psychomotor agitation: 90%90\%

      • Depressed mood: 84%84\%

      • Fatigue: 82%82\%

      • Insomnia: 76%76\%

      • Psychomotor retardation: 74%74\%

      • Increased appetite: 63%63\%

      • Hypersomnia: 62%62\%

      • Vivid, unpleasant dreams: 49%49\%

  • Withdrawal Timeline:

    • Hours 1-40: Symptoms begin.

    • Up to 10 Weeks: Side effects come and go.

  • Three Phases of Cocaine Withdrawal:

    • Stage 1 - "The Crash": Occurs in Week 1.

    • Stage 2 - "The Withdrawal": Occurs during Weeks 1-4.

    • Stage 3 - "Recovery": Occurs from Week 5 onwards.

  • Withdrawal Factors: Physical/mental health, duration of use, use of other substances, and the quality of the cocaine.

  • Cocaine Detox:

    • Professional detox is medically supervised and almost always an inpatient process.

    • It is considered the safest and most comfortable method to detox as part of an overall recovery plan.

Amphetamines

  • Prevalence in the US:

    • Total Users (12 and older): 7,400,0007,400,000

    • Methamphetamine Users: 1.4 million1.4\,\text{million}

    • Amphetamine Misuse: 4 million4\,\text{million}

    • Overdose Data: 70%70\% of stimulant-involved overdose deaths co-involve opioids.

    • Stimulant Use Disorder: Affects between 1.8−2 million1.8-2\,\text{million} people.

    • College Statistics: 11%11\% of college students abuse "study aids."

  • Amphetamine Use Disorder Definition:

    • A medical condition characterized by a compulsive, uncontrollable pattern of amphetamine or methamphetamine use that leads to significant clinical distress, impairing daily functioning, and ongoing use despite severe physical, psychological, and social consequences.

  • Pharmacology:

    • Increases synaptic DA, NE, and 5-HT5\text{-HT} by stimulating the presynaptic release of stored neurotransmitters.

  • Clinical Utility:

    • Used for ADHD, sleep apnea, shift work sleep disorder, and narcolepsy.

    • Mechanism in ADHD: Stimulants optimize neurotransmitters in the Prefrontal Cortex (PFC), promoting attention and arousal and reducing impulsivity and hyperactivity.

    • Example Medication: Methylphenidate (Ritalin).

  • Methamphetamine Details:

    • Slang: Meth, crystal, ice.

    • Form: Synthetic powder or crystal; highly lipophilic.

    • Administration: Frequently smoked; can be snorted, injected, administered orally, or rectally.

    • Effects: Increased alertness, talkativeness, decreased appetite, and euphoria.

    • Health Hazards: Postmortem studies link use to diseases associated with aging, specifically coronary atherosclerosis and pulmonary fibrosis.

  • Amphetamine Withdrawal Symptoms:

    • Irritability and depression.

    • Fatigue.

    • Gastrointestinal (GI) symptoms: Abdominal pain, cramping, and nausea.

Psilocybin

  • Prevalence in the US:

    • Total Users (12 and older): 36,000,00036,000,000

    • Demographics: 18−2518-25 year olds are 1.4×1.4\times more likely to use it.

    • Past Year Prevalence: 2.8%2.8\%

    • Microdosing: Approximately 10 million10\,\text{million} people.

  • General Properties:

    • Chemical Name: 4-phosphoryloxy-N,N-dimethyltryptamine.

    • A naturally occurring psychedelic compound found in over 200200 species of fungi ("magic mushrooms").

    • Found in tropical/subtropical regions of South America, Mexico, and the US.

    • Consumption: Raw, mixed with food, or brewed into tea.

    • Legal Status: Therapeutic use legalized in Oregon.

  • Pharmacology:

    • Metabolism: Psilocybin (pro-drug) undergoes Phase I and Phase II metabolism to become Psilocin.

    • Mechanism: Serotonergic psychedelic acting as an agonist at serotonin receptors in the CNS.

    • Cellular Effect: Stimulates glutamate release and excites cortical pyramidal cells.

    • Key Receptors:

      • 5HT1A5HT_{1A}

      • 5HT2A5HT_{2A}: A partial agonist (<40\% efficacy). Effects can be blocked by the antagonist Ketanserin.

      • 5HT2C5HT_{2C}

      • TrkB and mTOR: Signaling pathways mediating neuroplastogenic effects (neuritogenesis and increased neurogenesis).

    • Neurochemical Increases:

      • Dopamine increases in the nucleus accumbens (linked to euphoria).

      • Serotonin increases in the medial PFC (linked to mood elevation).

  • Effects:

    • Physiological: Moderately elevates autonomic functions (increased HR and BP).

    • Psychological/Perceptual: Altered time perception, euphoria, visual hallucinations, perceptual disturbances, and greater depersonalization.

  • Clinical Potential:

    • Rarely addictive; however, it may trigger mental health disorders like schizophrenia in predisposed individuals.

    • Clinical Trials Targeted Towards:

      • Major Depressive Disorder (MDD) and Treatment-Resistant Depression.

      • Post-Traumatic Stress Disorder (PTSD).

      • Substance Use Disorders (SUD).

      • Anorexia.

      • Cancer-related existential distress.

      • Postpartum depression.

      • Chronic back pain.

      • Parkinson's disease-associated depression.