Cocaine, Amphetamine, and Non-Amphetamine Stimulants – Comprehensive Study Notes

Cocaine: Plant Sources & Common Forms

• Erythroxylon coca leaf
  • About $1\%$ cocaine by weight
  • Traditional chewing produces mild stimulant effect
• Cocaine hydrochloride (HCl)
  • Purified, water-soluble powder (“crystal,” “snow”)
  • Typical intranasal dose: $25\,\text{mg}$ per line; users often take $50\text{–}100\,\text{mg}$ per session
  • Can also be taken orally or IV
• Free-base cocaine
  • Alkaloid form liberated from the HCl salt; volatilised and inhaled
  • Requires hazardous organic-solvent extraction
• Crack cocaine
  • Prepared by mixing cocaine base with baking soda & water, heating, then drying
  • Smoked; average unit (“rock”) ≈ $250\,\text{mg}$

Cocaine Pharmacokinetics

• Absorption & Onset (Table 7-1 highlights)
  • Oral (leaf chew): onset $300\text{–}600\,\text{s}$; “high” $45\text{–}90\,\text{min}$; bioavailability $\approx 0.5\text{–}1\%$
  • Oral (HCl): onset $600\text{–}1800\,\text{s}$; duration $100\text{–}200\,\text{min}$; dose $150\text{–}200\,\text{mg}$
  • Intranasal: onset $120\text{–}180\,\text{s}$; duration $30\text{–}45\,\text{min}$; $20\text{–}80\%$ absorbed
  • IV: onset $30\text{–}45\,\text{s}$; duration $10\text{–}20\,\text{min}$; peak plasma > $200\,\text{ng/mL}$
  • Smoking (paste, free-base, crack): onset $8\text{–}10\,\text{s}$; intense “rush”; duration $5\text{–}10\,\text{min}$; bioavailability $60\text{–}90\%$
• Distribution
  • Rapid brain penetration; brain concentrations exceed plasma
  • Crosses placental barrier → foetal exposure
• Metabolism
  • Primary enzyme: butyryl-cholinesterase → benzoylecgonine (inactive)
  • Half-life of cocaine in plasma: $\sim 30\text{–}60\,\text{min}$
• Interaction with Ethanol
  • Transesterification in liver produces cocaethylene (ethyl ester of benzoylecgonine)
  • Cocaethylene: active indirect dopamine agonist, $t_{1/2}\approx 2.5\,\text{h}$; ↑ cardiotoxicity, ↑ euphoria
  • Alcohol inhibits cocaine metabolism → ↑ blood cocaine + ↑ cocaethylene
  • $85\text{–}90\%$ of cocaine users meet criteria for alcohol-use disorder—synergistic dependence hypothesis

Cocaine: Core Pharmacodynamic Actions

1. Local anaesthetic (blocks voltage-gated Na⁺ channels)
2. Potent vasoconstrictor (sympathomimetic action on peripheral NE)
3. Psychostimulant (blocks monoamine re-uptake, esp. DA)

Dopamine Transporter (DAT) Blockade Mechanism

• Under normal conditions, DAT recovers synaptic DA → vesicular storage via VMAT2
• Cocaine binds to DAT → re-uptake blockade →
  • ↑ synaptic DA, NE, 5-HT
  • Postsynaptic receptor overstimulation (esp. D1 & D2 in nucleus accumbens)
• No direct release of transmitter (contrast with amphetamine)

Acute Pharmacological & Subjective Effects

Low / Typical dose ($25\text{–}75\,\text{mg}$)

• Physiological: ↑ HR, BP, body temperature, blood glucose
• Subjective: ↑ energy, alertness, talkativeness, libido; “freeze” (intranasal numbness) or “rush” (IV/smoke)
• Duration: $10\text{–}20\,\text{min}$, followed by “comedown” (mild dysphoria)

High / Repeated dosing

• Intensified autonomic activation; agitation, anxiety, paranoia
• Formication (“coke bugs”) → compulsive skin-picking, infections
• Acute tolerance to euphoria develops within a session → “coke runs” (continuous redosing)

Toxicity & Overdose

• Acutely toxic dose ≈ 2\,\text{mg·kg}^{-1} → $\approx 150\,\text{mg}$ for $70\,\text{kg}$ adult (but wide variability)
• Lethality linked to rapid spike, not absolute amount
• Symptoms: muscle weakness, hyperthermia, seizures, respiratory depression, cardiac arrhythmia/failure
• Seizures treatable with benzodiazepines or other tranquillizers

Cocaine-Induced Psychosis

• Hallucinations (auditory/visual), persecutory or grandiose delusions
• Clinically indistinguishable from paranoid schizophrenia; can occur in individuals with no prior psychosis

Tolerance, Dependence, Withdrawal

• Tolerance: rapid for euphoric effects; inverse (sensitization) for paranoia & stereotypy
• Dependence: strong psychological craving; physical component less pronounced than opioids
• Withdrawal trajectory
  1. Crash (days): exhaustion, hypersomnia/insomnia, dysphoria
  2. Intense craving & anhedonia (weeks)
  3. Extinction (months–years): cue-induced cravings episodic; classical conditioning plays a role

Pregnancy & Neonatal Outcomes

• Placental transfer leads to continuous foetal exposure via amniotic fluid
• Early pregnancy: ↑ spontaneous abortion rate
• Later outcomes: low birth weight, congenital anomalies, neonatal withdrawal, feeding difficulty, higher infant morbidity, later cognitive/behavioural issues; elevated risk of neglect/abuse

The Amphetamines: Historical Context

• Synthesised late 1800s; medical uses (asthma, obesity, narcolepsy, depression) by 1920s
• WWII: military stimulant; post-war epidemics in Japan, Sweden, Europe
• 1960s US recognition of danger → production controls; methamphetamine trialled for heroin detox
• Users’ motto “speed kills” + legal restriction → decline; search for “natural” alternative contributed to Cocaine Epidemic 2.0

Amphetamine Chemistry & Variants

• Core structure: phenethylamine backbone resembling dopamine
• Isomers
  • d-amphetamine (Dexedrine) – more potent
  • l-amphetamine – less potent
  • Mixed salts (Adderall)
• Methamphetamine: N-methyl substitution ↑ lipophilicity, BBB penetration, & half-life
• Other analogues: MDMA, MDA, cathinone, ephedrine, khat alkaloids

Amphetamine vs. Cocaine (Key Pharmacological Differences)

• Cocaine triad (local anaesthetic + vasoconstrictor + stimulant); amphetamine mainly stimulant
• Cocaine half-life minutes; methamphetamine $\approx 12\,\text{h}$ (smoked “ice”)
• Amphetamines associated with longer dosing runs, potential irreversible neurotoxicity

Amphetamine Mechanism of Action

Low–Moderate Doses

• Enters DA & NE terminals via DAT/NET
• Displaces vesicular monoamines via VMAT2
• DAT/NET reverse transport → non-exocytotic release into synapse
  High Doses
• Inhibits MAO → ↓ metabolic degradation
• Massive synaptic DA & NE ↑

Dose-Dependent Physiological & Behavioural Effects

Low doses

• ↑ BP/HR, bronchodilation, modest CNS arousal
  Moderate (20–50 mg)
• Respiration stimulation, tremor, restlessness, insomnia
  High / Chronic (>20 mg to >400 mg depending on tolerance)
• Stereotypies (pacing, picking), weight loss, skin sores
• Paranoid psychosis (“speed bugs”), potential violence, homicidal behaviours

Toxicity & Neurotoxicity

• Methamphetamine particularly neurotoxic: damages DA & 5-HT axon terminals; associated with Parkinsonian motor slowing, memory deficits
• Acute risks: stroke, aortic dissection, cardiac arrest

Dependence, Tolerance & Withdrawal (Amphetamines)

• Acute tolerance: “flash” diminishes while plasma level still high → cycles of binge/run
• Withdrawal
  1. Crash: sleep, hunger, depression
  2. Prolonged dysphoria, anhedonia, intense craving
  3. Extinction: episodic cue-triggered craving may persist
• Pharmacotherapy: antidepressants, antipsychotics, mood stabilizers sometimes used symptomatically

Methamphetamine Specifics

• 35 % of US supply from clandestine “home labs” (pseudoephedrine precursor)
• Crystalline “ice” smoked, snorted, or injected; users may dose 3–4× daily, >20 days month
• Physical sequelae
  • “Faces of Meth”: accelerated ageing, facial muscle/fat loss, acne, sores
  • “Meth mouth”: xerostomia + bruxism + poor hygiene → rampant caries & tooth loss

Non-Amphetamine Stimulants

• Plant-derived / OTC
  • Ephedrine (Ma-huang), khat (cathinone), pseudoephedrine
• Prescription
  • Modafinil (Provigil): wake-promoting; mechanism likely ↑ glutamate, ↓ GABA; used for narcolepsy, shift-work disorder
  • DMAA (nasal decongestant re-emerged in sports supplements)
  • Methylphenidate (Ritalin), pemoline (Cylert) — ADHD treatments; methylphenidate is a DAT/NET blocker similar to cocaine but slower kinetics

ADHD Pharmacotherapy Snapshot

Stimulants (Schedule II, FDA Black-Box Warning)

• Short-acting: methylphenidate (Ritalin, Methylin), dexmethylphenidate (Focalin), mixed amphetamine salts (Adderall), dextroamphetamine (Zenzedi), methamphetamine HCl (Desoxyn)
• Extended-release: Concerta, Adderall XR, Vyvanse (lisdexamfetamine), Mydayis, etc.
  Non-stimulants
• Atomoxetine (Strattera) – selective NET inhibitor
• Viloxazine (Qelbree)
• Alpha-2 agonists: clonidine (Kapvay), guanfacine (Intuniv)
  Ethical/Clinical issues
• Potential for abuse/diversion; cognitive “enhancement” debate (“smart drugs”)

Psychostimulant Withdrawal Stages (Unified Model)

1. Crash (days): intense craving, hypersomnolence or insomnia, depression, agitation
2. Withdrawal (weeks): anhedonia, moderate–severe depression, strong cue-induced cravings
3. Extinction (months–years): intermittent cravings; extinction therapies target conditioned cues

Practical, Ethical & Societal Considerations

• Evolving perception of “hardest” drugs: cocaine & meth often cited due to rapid dependence & neurotoxicity, yet prescription stimulants carry similar pharmacology under medical oversight
• Co-use patterns (e.g., cocaine + alcohol) produce novel toxic entities (cocaethylene) → public-health implications
• Prenatal exposure raises ethical concerns regarding maternal autonomy vs. foetal harm
• Pharmacological enhancement (“smart drugs”) blurs line between therapy & performance-boosting

Key Numerical / Statistical References & Formulae

• Toxic cocaine dose: 2\,\text{mg·kg}^{-1} \times 70\,\text{kg} = 140\,\text{mg} (≈ $150\,\text{mg}$ reported)
• Cocaethylene half-life: $t_{1/2} \approx 2.5\,\text{h}$ (vs. cocaine $\sim 0.5\,\text{h}$)
• Methamphetamine half-life: $\sim 12\,\text{h}$; cocaine smoked “high” lasts $5\text{–}10\,\text{min}$
• $85\text{–}90\%$ comorbidity of alcohol dependence among cocaine users

Connections to Broader Neuroscience & Clinical Concepts

• Dopaminergic reward pathway (VTA → nucleus accumbens) common site for cocaine & amphetamine action → shared liabilities for addiction
• Sensitization vs. tolerance dichotomy explains escalating compulsive use alongside heightened psychosis risk
• DAT knockout mice show reduced cocaine self-administration → confirming transporter’s central role
• Amphetamine neurotoxicity parallels pathophysiology of Parkinson’s disease (loss of nigrostriatal DA)

Study Tips & Integrative Questions

• Compare mechanisms: Why does amphetamine—but not cocaine—cause reverse transport of DA?
• Predict outcomes: What happens to blood pressure when a cocaine user drinks alcohol? (synergistic ↑ via NE + vasoconstriction + cocaethylene)
• Clinical scenario: Managing a pregnant patient with stimulant-use disorder—what risks to discuss?
• Ethical debate: Should modafinil be allowed for cognitive enhancement in healthy students?