[gamma]-Hydroxybutyric acid: a medicine or a drug of abuse? (Editorials).

My clinical experience with [gamma]-hydroxybutyrate acid (GHB) for the treatment of substance abuse began in late 1980s after I had met the pharmacologist Professor G. L. Gessa, who was working on neurobiologic mechanisms of drug dependence in animal models. (1) He proposed that I perform some clinical trials with GHB, which had given interesting results in Sardinian alcohol-preferring rats. This substantiated my efforts to look for a rational pharmacologic treatment of addiction in humans.

During that time, I was unsuccessfully trying to cure an alcoholic patient by various treatments, both pharmacologic (disulfiram, S-adenosyl methionine, lithium carbonate, carbamazepine, hydroxyergotamine-thioridazine, tiapride) and psychologic (Alcoholics Anonymous, psychotherapy). Finally, in 1988, I decided to administer GHB to her. The action of GHB was rapid and effective. The patient reported an immediate sense of well-being and a significant decrease of alcohol craving. She was abstinent for the first time in 20 years, saying that it was "so easy." In a week she was completely detoxified. She completed 4 months of treatment with GHB, and to date she is still abstinent.

Given that promising result, my group and I decided to further investigate this drug. In 1989, we provided evidence that GHB was an effective treatment in alcohol withdrawal. In a first randomized double-blind trial, (2) we recruited 23 patients who met the DSM-IIIR criteria for alcohol withdrawal syndrome; 11 of them were treated with GHB, 50 mg/kg/day, and the others with placebo. Those receiving GHB had a significant decrease in Alcohol Withdrawal Score. After a while we realized its potential in the treatment of alcohol craving. A second randomized double-blind study assessed this issue in 82 alcoholic patients. (3) Of the 71 who completed the study and the 3-month follow-up, 36 were in the GI-IB group (50 mg/kg/day), and 35 in the placebo group. The GHB-treated patients significantly reduced the number of drinks they consumed daily and increased the days of abstinence; they also reported a significant reduction in Alcohol Craving Scale scores. No differences were observed in the placebo group.

Today, GHB (ALCOVER) is widely used in Italy for the treatment of alcohol dependence, at the recommended dosage of 50 mg/kg/day in three or more doses. More recently, data were collected about the efficacy of GHB to suppress withdrawal symptoms (4) and to reduce craving (5) in heroin-dependent and methadone-dependent subjects.

The main limitations of GHB are its short half-life (about 40 minutes) and its potential for abuse. In this respect, my group retrospectively assessed 195 patients who met the DSM-IIIR criteria for substance dependence disorder and participated in an integrated treatment program with GHB in a 10-year survey. (6) Twenty-nine of them (15%) used GHB at a greater dosage than prescribed. Only 10 patients (5%) met the criteria of GHB dependence disorder.

For the past 15 years, we treated many patients for drug dependence (alcohol, opiate, cocaine, benzodiazepine, cannabis, and polydrugs), with positive results. [gamma]-Hydroxybutyrate acid has shown great efficacy in the treatment of withdrawal syndrome and in the maintenance of sustained abstinence by reducing the craving for the substance. In our experience, close medical surveillance reduced the side effects (including the potential for abuse) of GHB therapy.

In conclusion, GHB appears to be safe and effective and to have great potential when used either alone or in association with other drugs such as disulfiram, naltrexone, clonidine, and serotonin specific reuptake inhibitors in the treatment of substance abuse. [gamma]-Hydroxybutyrate acid meets 4 of 5 criteria established by the American Psychiatric Association (7) on the efficacy of pharmacotherapies to be used in the treatment of substance use disorder: it is effective for withdrawal treatment, shows anticraving properties capable of diminishing the reinforcing effects of the substance, can be used as a substitute for some substances of abuse, and is effective in alleviating some psychiatric comorbid disorders. The potential for GHB abuse (and its consequences) that alarmed the public and some in the scientific community is not confirmed in my clinical practice from either a psychiatric or a toxicologic point of view. The potential for GHB abuse does not differ from that observed with other drugs commonly u sed in treatment of dependence. The abuse rate observed by my group (less than 15% in subjects treated for 10 years) should not endanger the profile of GHB as a safe and effective medicine.

Luigi Gallimberti, MD

Clinical Toxicology and Addiction Unit

University of Padua 

Padua, Italy

References

(1.) Fadda F, Argiolas A, Melis MR, et al: Suppression of voluntary ethanol consumption in rats by gamma-butyrolactone. Life Sci 1983; 32:1471-1477

(2.) Gallimberti L, Canton C, Gentile N, et al: Gamma-hydroxybutyric acid for treatment of alcohol withdrawal syndrome. Lancet 1989; 2:787-789

(3.) Gallimberti L, Ferri M, Ferrara SD, et al: Gamma-hydroxybutyric acid in the treatment of alcohol dependence, a double blind study. Alcohol Clin Exp Res 1992; 16:673-676

(4.) Gallimberti L, Schifano F, Forza G, et al: Clinical efficacy of gamma-hydroxybutyric acid in treatment of opiate withdrawal. Eur Arch Psychiatry Clin Neurosci 1994; 244:113-114

(5.) Gerra C, Fertonani-Affini G, Caccavari R, et al: Gamma-hydroxy-butyric acid in the treatment of heroin addiction. Clin Neuropharmacol 1994; 8:357-360

(6.) Gallimberti L, Spella MR, Soncini CA, et al: Gamma-hydroxybutyric acid in the treatment of alcohol and eroine dependence. Alcohol 2000; 20:257-262

(7.) American Psychiatric Association: Practice guidelines for the treatment of patients with substance use disorder: alcohol, cocaine, opioids. Am J Psychiatry 1995; 152(suppl)