1,4-Butanediol

GHB produces dose-dependent respiratory depression as its primary mechanism of lethality. Individuals with pre-existing respiratory conditions (COPD, sleep apnea, restrictive lung disease) face elevated overdose risk even at common doses.

GHB can modulate seizure threshold, and abrupt cessation in dependent individuals precipitates seizures. Individuals with epilepsy or seizure history face elevated risk both during use and especially during withdrawal.

Carriers of the ADH1B G143A variant allele (particularly prevalent in East Asian populations) show a four-fold reduction in 1,4-BD oral clearance (CL/F 151.5 vs 598.8 mL/min·kg), predicting delayed onset, higher 1,4-BD accumulation, and prolonged or unpredictable GHB effects from a given dose.

No human or animal reproductive toxicity data have been published for 1,4-BD or exogenous GHB. Given the compound's steep dose-response curve, CNS depressant effects, and lack of any safety characterization, use during pregnancy cannot be considered safe.

Ethanol competitively inhibits ADH (Ki ~0.56 mM), blocking 1,4-BD → GHB conversion and causing 1,4-BD accumulation. When ethanol clears, rapid conversion of the accumulated pool produces a delayed, massive GHB surge. This creates a deceptive pattern: minimal initial effects during co-ingestion, followed by sudden severe CNS depression hours later. This interaction has been implicated in multiple fatalities. Additionally, ethanol and GHB produce synergistic CNS and respiratory depression.

Combination of 1,4-BD (via GHB metabolite) with opioids produces additive CNS and respiratory depression. Multiple documented fatalities involve GHB/1,4-BD combined with opioids across Australasian and Nordic case series.

Benzodiazepines combined with active 1,4-BD/GHB intoxication produce additive CNS and respiratory depression. This is pharmacologically paradoxical: benzodiazepines are used therapeutically to manage GHB withdrawal, but combining them during active intoxication is life-threatening.

barbiturates, antipsychotics, ketamine, other sedative-hypnotics

All CNS depressants carry risk of additive sedation and respiratory depression when combined with 1,4-BD/GHB. This is a GABAergic class-level contraindication.

1,4-BD/GHB produces motor control impairment, sedation, and amnesia that preclude safe operation of vehicles or machinery. Effects may persist for 6+ hours after ingestion.

Diclofenac inhibits monocarboxylate transporters (MCT1) that transport GHB across the blood-brain barrier and in renal tubules. In rats, diclofenac reduced brain GHB concentrations and attenuated respiratory depression. The clinical significance in humans is not established, but altered GHB pharmacodynamics are possible.