Gamma-hydroxybutyrate and ethanol effects and interactions in humans.

Gamma-hydroxybutyrate (GHB) has become a common drug of abuse in the United States and Europe in recent years. GHB was used in the late 1980s by body builders as a nonanabolic steroid performance enhancer and became widely available for sale in health food stores, gymnasiums, and via the Internet. Later, as the reputation for its euphoric effects grew, GHB became popular as a drug of abuse at dance clubs and "rave" parties. More recently, GHB has been used as a drug to facilitate sexual assault. Because of its abuse potential, GHB was classified as a Schedule I controlled substance in 2000, with dual scheduling instituted 2 years later when GHB became Food and Drug Administration approved as the pharmaceutical product Xyrem. In recent years, GHB has been a major cause of emergency department visits for drug-induced central nervous system depression.1–5 In overdose, GHB produces coma, often associated with hypothermia, bradycardia, hypotonia, myoclonus, and seizure-like activity.1,2 In very high doses, respiratory depression and death can occur.3–5 At lower doses, the primary effects of GHB are drowsiness, alcohol-like inebriation, dizziness, and induction of sleep.6,7 Gamma-hydroxybutyrate was previously studied as an anesthetic agent, and has also been studied as a medication for the treatment of cataplexy, a symptom of narcolepsy. Some effectiveness for this indication has been demonstrated, and GHB is currently Food and Drug Administration approved for use as a Schedule III drug for the treatment of narcolepsy.8 In addition, GHB has been marketed in Italy for the treatment of alcoholism since 1994. Psychomotor performance has been studied in healthy volunteers receiving GHB 12.5 and 25 mg/kg, and no significant effects of GHB were observed.6 Gamma-hydroxybutyrate is found naturally in the human body as a degradation product of the neurotransmitter, gamma-aminobutyric acid. GHB is extensively metabolized, in part to succinic acid, then through the tricarboxylic acid pathway, and in part by beta oxidation.9,10 Alcohol dehydrogenase has been postulated to contribute to GHB metabolism in animal and human liver.11 There is evidence of dose-dependent metabolism. The disposition kinetics of GHB in humans have been described in 3 published studies using doses of 12.5 to 50 mg/kg orally.12–14 The average elimination half-life after single doses ranged from 30 to 50 minutes, and the time to peak concentration averaged 30 to 40 minutes, consistent with rapid gastrointestinal absorption. In recreational use, GHB is frequently ingested with other drugs, including most commonly ethanol, which has sedative effects similar to those of GHB. There is a concern that these drugs may interact synergistically in producing sedation. However, this has not been well studied in doses of GHB that are relevant to therapeutic dosing or to recreational use. One study of the combination of GHB and low-dose ethanol showed significant impairment of reaction time with the combination.15 There have been no human studies conducted on the pharmacokinetic interactions between GHB and ethanol. We examined the effects of ethanol on the pharmacokinetics of GHB, and the pharmacodynamic interactions between ethanol and GHB in healthy human volunteers. We used a 50-mg/kg dose of GHB, which is comparable to doses used in the treatment of narcolepsy. We administered 0.6-g/kg dose of ethanol, which was projected to produce blood alcohol concentrations of about 50 mg/dL. Our objectives were to (1) identify any significant pharmacokinetic interactions that exist between these 2 sedative-hypnotic drugs; (2) determine if coingestion of ethanol and GHB produces greater cognitive, hemodynamic, and subjective mood effects than either GHB or ethanol alone; and (3) explore differences in response to GHB and ethanol between men and women, and people of different races. In this article, we report our findings on the pharmacokinetics and the hemodynamic effects of GHB and ethanol. Subjective drug effects, effects of race and sex, and cognitive testing will be reported separately.