Butanediol and Ethanol: A Reverse Mickey Finn?

Lewis Nelson, M.D.
Director, Fellowship in Medical Toxicology
New York City Poison Control Center

Int J Med Toxicol 2000; 3(1):2

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In 1990, in response to several deaths and considerable morbidity, the Food and Drug Administration issued an advisory in an attempt to limit the availability of gamma-hydroxybutyrate.(1)  Its success was limited, however, by slow Congressional movement to ban the drug (Hilary J Farias and Samantha Reid Date-Rape Drug Prohibition Act of 1999) and the counterproductive passage of the Dietary Supplement Health and Education act, which actually created certain protections for "natural" products such as gamma-hydroxybutyrate. Regardless, the FDA ban on its over-the-counter sale reduced access by removing it from retail outlets. However, since possession of gamma-hydroxybutyrate is not proscribed on a Federal basis, illicit Internet sales remained strong for several years.

One of the odd effects of this regulatory process is the development of substitute drugs that skirt the existing regulatory issues. This process is similar to what occurred when the amphetamine congeners kicked-off the designer drug craze of the 1970’s. During this period, the mere substitution of a functional group onto a controlled substance, such as amphetamine, produced a compound that was temporarily legal. However, the loophole that permitted marketing of illicit drug analogues was closed in 1986 with the passage of the Controlled Substance Analogue Enforcement Act, known familiarly as the Designer Drug law. In the current instance, the residual demand for gamma-hydroxybutyrate following its removal by the FDA motivated suppliers to market gamma-butyrolactone and later butanediol, both legal-to-sell precursors of gamma-hydroxybutyrate. These agents unfortunately do not fall under existing controlled substance laws since the parent compound, gamma-hydroxybutyrate, is not yet scheduled as a controlled substance by the Drug Enforcement Administration.

Although analogue drugs often introduce unanticipated problems, they are typically expected to have clinical effects and toxicity similar to those of the parent compound; this is essentially a "class effect". For example, virtually all amphetamines predictably produce autonomic stimulation and this is, therefore, considered a class effect of amphetamines. However, the increased frequency of the serotonin syndrome and symptomatic hyponatremia associated with the use of methylenedioxymethamphetamine (i.e. Ecstasy) are not predicted by the class effect. Similarly, the majority of our initial experience with the management of patients intoxicated by gamma-butyrolactone and butanediol was highly reminiscent of gamma-hydroxybutyrate. This was not surprising, since once again the expected pharmacodynamic profile of the new agents were predictably following the class effect.(2)  However, the expectation of a relationship in the pharmacokinetics of gamma-hydroxybutyrate, its precursors, and ethanol may have been misguided. Interestingly, the contrasting pharmacokinetic effects of ethanol on each of these agents was predicted many years ago by experimental science.(3)

Gamma-butyrolactone, essentially the ring form of gamma-hydroxybutyrate undergoes spontaneous hydrolysis following absorption to form gamma-hydroxybutyrate (Figure 1). This subsequently invokes sedative/euphoric effects that appear to be at least additive with ethanol. Alternatively, butanediol requires enzymatic oxidation to gamma-hydroxybutyrate by alcohol dehydrogenase. This critical distinction between the two agents explains the unique clinical effects and altered pharmacologic profiles that may occur in patients who concomitantly consume ethanol. The case reported here (4), if accurate, suggests that ethanol does indeed interfere with the metabolism of butanediol. The result, rather than or in addition to potentiated toxicity, is delayed toxicity. That ethanol inhibits the oxidation of butanediol, likely in a competitive fashion, is not at all surprising; this, of course, is the basis for the use of ethanol in the management of ethylene glycol-poisoned patients. The presumed lack of a pharmacokinetic effect of ethanol on the metabolism of gamma-hydroxybutyrate and gamma-butyrolactone is predictable, yet represents another example of the difficulties in broadly applying the class effect.

Butanediol is easily available on the Internet, and often sold by confusing chemical names such as 1,4-butylene glycol; 1,4-dihydroxybutane; and 1,4-tetramethylene glycol. It is sold for the same "indications" for which gamma-hydroxybutyrate and gamma-butyrolactone had become notorious; i.e. euphoria, muscle building, and chemical submission. Of interest is the dichotomous effect of ethanol on two diols used historically as "date rape" drugs: butanediol and chloral hydrate. Although alcohol dehydrogenase is responsible for the reductive conversion of chloral hydrate to its active metabolite, trichloroethanol, ethanol in moderate doses accelerates this conversion. Thus, rather than inhibiting or delaying the onset of sedation, as with butanediol, ethanol speeds the onset of action of chloral hydrate. This, of course, is the basis for the Mickey Finn effect (Figure 2).

Clearly the Internet is a new and complex world for patients and for regulators. However, the unchecked sale of dangerous compounds such as butanediol, with still undefined clinical effects, is unfortunate. It is critical for those in authority to modernize existing regulations or author new legislation to limit the availability of these hazardous chemicals. Until such time, the medical community should be anticipating the unanticipated.

Figure 1. (Above) The structure and metabolic conversions of gamma-butyrolactone and butanediol to gamma-hydroxybutyrate.

Figure 2. (Above) The structure and metabolic conversions of chloral hydrate to trichloroethanol. Ethanol increases the rate of conversion by supplying, through its metabolism, reducing equivalents (NADH) for the alcohol dehydrogenase mediated reduction of chloral hydrate.


  1. Food and Drug Administration. Gamma-hydroxybutyrate. Nov 8, 1990 (www.fda.gov)
  2. Rambourg-Schepens MO, Buffet M, Durak C, Mathieu-Nolf M. Gamma-butyrolactone poisoning and its similarities to gamma-hydroxybutyric acid: two case reports. Vet Hum Toxicol 1997;39:234-5.
  3. Poldrugo R, Snead OC. 1,4 Butanediol, gamma-hydroxybutyric acid and ethanol: Relationships and interactions. Neuropharmacology 1984;23:109-113.
  4. Schneidereit, T,  Burkhart, K, Donovan, JW. Butanediol toxicity delayed by preingestion of ethanol internet. J Toxicol 2000;3(1): 1.


Int J Med Toxicol 2000; 3(1):2

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