Elsevier

Alcohol

Volume 20, Issue 3, April 2000, Pages 257-262
Alcohol

Articles
Gamma-hydroxybutyric acid in the treatment of alcohol and heroin dependence

https://doi.org/10.1016/S0741-8329(99)00089-0Get rights and content

Abstract

We briefly review two double-blind, placebo-controlled surveys conducted in this laboratory with the aim of evaluating the efficacy of gamma-hydroxybutyric acid in the treatment of alcohol withdrawal syndrome as well as alcohol craving and consumption in alcoholics. In the first study, acute administration of 50 mg/kg gamma-hydroxybutyric acid, a nonhypnotic dose in alcoholic patients, resulted in a rapid and significant reduction of the severity score of alcohol withdrawal signs and symptoms that lasted as long as 7 hours. In the second study, treatment with 50 mg/kg/day gamma-hydroxybutyric acid for 3 consecutive months (1) reduced the number of daily drinks by approximately 50%, (2) increased the days of abstinence approximately threefold, and (3) reduced the alcohol craving score by up to 60%. These results feature gamma-hydroxybutyric acid as an effective agent for the treatment of alcohol dependence. Data on the effect of gamma-hydroxybutyric acid on opiate withdrawal syndrome also are reviewed. Administration of 25 mg/kg induced a marked reduction of opiate withdrawal score in both heroin- and methadone-dependent subjects. Finally, we report the cases of adverse reactions to and abuse of gamma-hydroxybutyric acid revealed in a retrospective analysis of patients recruited in this laboratory over a 10-year period.

Introduction

Gamma-hydroxybutyricacid (GHB) was synthetized in the late 1950s by Henri Laborit with the intent of discovering a gamma-aminobutyric acid (GABA) analogue capable of crossing the blood–brain barrier (Laborit et al., 1960a). Gamma-hydroxybutyric acid accomplished the aim of penetrating the blood–brain barrier but exerted a number of central effects not mediated by the GABA receptors. So it was that this drug started down a road that, after more than 40 years, still seems to be far from the end.

Gamma-hydroxybutyric acid was initially used as a general anesthetic (Laborit et al., 1960b) and hypnoinducer (Laborit & Weber, 1965). Moreover, the anxiolytic (De Couedic & Voisse, 1964) and antidepressive (Rinaldi et al., 1967) properties of GHB were soon recognized. Gamma-hydroxybutyric acid was also tested for the treatment of (1) schizophrenia Levy et al. 1983, Schuls et al. 1981, Tanaka et al. 1966, (2) acute alcohol intoxication Benda et al. 1960, Langlois et al. 1960, and (3) opiate (De Couedic & Voisse, 1964) and barbiturate (Appia, 1967) dependence. Because of its ability to stimulate REM sleep, GHB was also used to “shorten” the psychoanalytical approach in psychotherapy (Appia, 1967).

In the late 1970s, in view of the proved hypnoinducing effect of GHB, Broughton and Mamelak (1979) tested its efficacy in the treatment of narcolepsia. Administration of GHB restored the cytoarchitectonics of narcoleptic sleep (characterized by scarce and fragmented REM and reduced percentage of slow-wave deep sleep). Subsequently, Snead and colleagues Snead 1977, Snead 1978, Snead 1990, Snead & Bearden 1980, Snead & Liu 1993, Snead et al. 1980 showed that, in rhesus monkeys, GHB was capable of evoking a clinical picture resembling that of petit mal epilepsy in human beings. Further studies in the same laboratory featured GHB-induced absence seizures as a suitable experimental model for testing potentially effective antagonists for petit mal epilepsy (Snead, 1992). According to this hypothesis, the antiepileptic agent valproate sodium was reported to normalize the GHB-induced petit mal picture in monkeys. Interestingly, valproate sodium is a drug routinely used in the treatment of alcohol withdrawal syndrome (Rosenthal et al., 1998) and is capable of enhancing brain levels of GHB (Snead & Bearden, 1980).

In the 1980s, data obtained by our group (reviewed herein) provided evidence that GHB is an effective treatment in alcohol dependence. More recent data suggest that GHB may be effective in opiate dependence. Owing to its low toxicity (Palatini et al., 1993), rapid metabolism (Laborit, 1964), and antioxidant properties (Mamelak, 1977), GHB is currently being reevaluated as an anesthetic agent in cases of (1) compromised renal and hepatic functionality, (2) cerebral edema, and (3) ischemia, as well as in (4) hypovolemic states (Kleinschmidt & Mertzlufft, 1995).

Section snippets

Gamma-hydroxybutyric acid and alcohol dependence

Different lines of experimental evidence have demonstrated the effectiveness of GHB in animal models of alcoholism. Briefly, (1) the acute administration of GHB to rats rendered physically dependent on alcohol reduced the intensity of alcohol withdrawal signs; and (2) nonsedative doses of GHB, administered acutely, produced a dose-dependent reduction (as much as 70% compared with findings in saline-treated controls) of voluntary alcohol intake in selectively bred alcohol-preferring (P) and

Gamma-hydroxybutyric acid and heroin dependence

The first observation on the efficacy of GHB in the treatment of opiate dependence dates to 1964, when De Couedic and Voisse reported “at least two cases in which GHB seemed to have replaced morphine-like drugs … by placating the state of need typical of the drug addict” (DeCouedic & Voisse, 1964). By using GHB in the management of alcohol withdrawal syndrome in a number of alcoholics who concomitantly abused heroin, we observed that GHB suppressed not only the alcohol withdrawal symptoms, but

Gamma-hydroxybutyric acid and adverse reactions

In the past 10-year period of GHB use in the treatment of dependence on alcohol and different psychoactive substances, we have observed a number of adverse reactions, largely induced by an inadequate use of the drug. These reactions include vertigo, nausea, vomiting, asthenia, epileptic-like tonic-clonic seizures, confusion, agitation, hallucinations, respiratory insufficiency, and loss of consciousness. These reactions, often occurring after combined intake of GHB and other substances such as

Gamma-hydroxybutyric acid and abuse

Of the aforementioned 195 patients, 29 cases (14.9%) showed GHB abuse. It should be pointed out that, although several episodes of GHB abuse have been reported in the scientific literature (Galloway et al., 2000), the events described by us occurred within an integrated treatment for alcohol, heroin, or polydrug dependence.

We adopted a rather broad definition of abuse—namely, any use of GHB greater than the dose prescribed by the physician. According to this definition, three groups of GHB

Conclusions

Gamma-hydroxybutyric acid appears to meet at least four of the five criteria established by the American Psychiatric Association on the efficacy of pharmacotherapies to be employed in the treatment of alcohol and opiate dependence (American Psychiatric Association, 1995). Indeed GHB (1) is effective in the treatment of withdrawal (criterion 1), (2) possesses anticraving properties capable of diminishing the reinforcing effects of the drug (criterion 2), (3) can be used as a substituting drug

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