Cocaine
TL;DR — Triple monoamine reuptake inhibitor (DAT/NET/SERT). Acute HR spike +11–20 bpm, same-night REM suppression, crash from D2 autoreceptor redistribution (not simple DA depletion). Cocaethylene (cocaine + alcohol) is 18–25× more cardiotoxic; ~92% of users co-use alcohol. No FDA-approved treatment — 30+ agents tested over decades, all failed. BChE polymorphisms (D70G atypical, rs1803274) affect metabolism and toxicity risk. Retatrutide (GLP-1 RAs) associated with reduced cocaine use disorder risk (BMJ 2026, n=524,817).
Key Facts
| Intoxicating compound | Cocaine HCl / freebase |
| Primary mechanism | DAT blockade — DAT > NET > SERT; also blocks voltage-gated Na⁺ channels |
| Key metabolite | Cocaethylene (with ethanol); norcocaine (hepatotoxic) |
| Acute HR effect | +11–20 bpm (cocaine alone); +20–40 bpm with ethanol |
| Route with highest addiction risk | Smoked (crack) — fastest onset, most reinforcing |
| FDA-approved treatment | None (as of March 2026) |
| Stack conflict flag | Cocaine peptide interactions — additive appetite suppression risk |
Pharmacokinetics
BChE Polymorphisms
| Variant | Effect | Clinical Significance |
|---|---|---|
| BChE D70G (atypical) | 10× reduced cocaine affinity | Prolonged high plasma → greater toxicity risk |
| rs1803274 AA genotype | Altered metabolism | OR=4.36 for crack preference (n=1436) |
| BChE knockout | Cannot clear cocaine via plasma | Markedly prolonged toxic effects |
CES1 polymorphisms (dominant hydrolysis enzyme): prevalence and clinical impact poorly characterised — information gap.
Failed Pharmacotherapies (30+ years)
No FDA-approved treatment exists as of March 2026. The FDA published its first guidance for stimulant use disorder in October 2023. Previous failed trials: disulfiram (inconsistent), topiramate (2/5 positive), modafinil (2/7 positive), bupropion+naltrexone (modest signal), psychostimulants (RR 1.36), vigabatrin (initial positive → subsequent negative), amantadine (1/3 positive), antidepressants (consistently negative), antipsychotics (consistently negative). 2019 meta-analysis conclusion: “No strong or consistent evidence that any drug class was effective.”
| Route | Onset | Tmax | Half-life | Bioavailability |
|---|---|---|---|---|
| IV | 1–5 min | Immediate | ~0.6 h (~36 min) | 100% |
| Smoked (crack) | 3–5 min | 5–10 min | ~0.9 h (~54 min) | 30–70% |
| Intranasal | 5–15 min | 30–60 min | ~1.3 h (~78 min) | 25–60% |
| Oral | 15–30 min | 50–90 min | ~0.9 h | 32–45% |
Brain:plasma ratio ~4:1 — highly lipophilic, rapid BBB crossing. Volume of distribution ~1.3–4.2 L/kg. Non-linear PK at oral abuse doses (bioavailability increases with dose). CES1 (liver) → benzoylecgonine (BZE); CES2 (intestine/liver) → ecgonine methyl ester (EME). BChE (plasma) is a minor pathway. Ethanol inhibits both CES1 and CES2, redirecting metabolism toward Cocaethylene formation.
Mechanisms
- DAT blockade: Primary euphoriant — blocks DAT/NET/SERT → synaptic monoamine accumulation → nucleus accumbens DA surge. Also blocks voltage-gated Na⁺ channels → local anaesthetic + cardiac arrhythmia risk.
- Cocaethylene: Ethanol + cocaine via hepatic CES1 → transesterification → cocaethylene (not hydrolysis). Half-life 2–3× longer than cocaine. 18–25× increased sudden death risk.
- Cocaine crash: Not simple DA depletion. D2 autoreceptor-mediated vesicular redistribution + PKC-mediated DAT dysregulation + HPA axis disruption + neuroinflammation (TLR4 → TNF-α/IL-1β/IL-6 via NF-κB/NLRP3). Timeline: hours (single) → weeks (binge) → months (chronic).
Biometric Phases
Acute (0–3 h)
- HR ↑ 11–20+ bpm; BP ↑ via ↑ myocardial O₂ demand
- HRV ↓ (sympathetic predominance from catecholamine surge)
- REM suppressed same night
- Hyperthermia risk with physical activity
Crash/Overnight (6–24 h)
- Anhedonia from functional DA deficit
- Possible hypotension/bradycardia rebound after tachycardia
- Insomnia from residual CNS stimulation
Abstinence/Recovery (days–weeks)
- D2R downregulation persists; D2R recovery possible with sustained abstinence (weeks-months)
- REM rebound (↑ REM time, ↓ REM latency, SOREMPs) — most pronounced first 2 weeks
- Elevated cortisol stress responses during withdrawal predict relapse
- Neuroinflammation (TNF-α, IL-1β) persists 10+ days even after acute withdrawal
Risks
- Cardiovascular: Cocaine risk profile — dose-dependent tachycardia/hypertension; 4 arrhythmia mechanisms (Na⁺ channel block + K⁺ channel block + catecholamine surge + MI/myocarditis); pro-arrhythmic positive feedback via use-dependent Na⁺ channel blockade worsened by high HR
- Cocaethylene: Cocaethylene — unique to cocaine + ethanol co-use; prolonged cardiotoxicity; ~92% of cocaine users co-consume alcohol
- Neuropsychiatric: Cocaine crash — anhedonia, impaired executive function, potential relapse driving
Detection
Cocaine detection model — Primary wearable features: acute HR spike (11–20 bpm above baseline), HRV suppression during intoxication, same-night REM reduction. Next-day patterns (HRV suppression, cognitive impairment) are corroborating signals but less specific.
Interactions
Cocaine peptide interactions — BPC-157 is the most relevant peptide (dopamine stabiliser from amphetamine literature); Retatrutide additive appetite suppression risk; GHK-Cu likely safe; TB-500 cardiac repair mechanism may not apply (cocaine cardiomyopathy ≠ ischemic MI).