The End of My Addiction

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    Letter to the Editor and Reply
    The American Journal of Drug and Alcohol Abuse vol. 34, no. 2, pp. 235–238, 2008 Are the effects of gamma-hydroxybutyrate (GHB) treatment partly physiological in alcohol dependence?
    Olivier Ameisen, M.D.
    Abstract
    It has been hypothesized that the therapeutic effects of gamma-hydroxybutyrate (GHB) in alcohol dependence could be related to ethanol-mimicking action of the drug and that GHB could reduce alcohol craving, intake, and withdrawal by acting as a “substitute” of the alcohol in the central nervous system. Nevertheless, alcohol being the strongest trigger of craving and intake, it is difficult to ascribe reduction of craving and intake to the ethanol-mimicking activity of GHB. I have recently proposed that alcohol/substance dependence could result from a GHB-deficiency-related dysphoric syndrome in which alcohol/substances would be sought to “substitute” for insufficient GHB effect. GHB is the sole identified naturally occurring gamma-aminobutyric acid B (GABA B ) receptor agonist. Here, I propose that exogenous GHB might in fact “substitute” for deficient endogenous GHB and represent true substitutive treatment for GHB deficiency and that baclofen and GHB could both compensate for deficient effect of the physiological GABA B receptor agonist(s).
    Keywords
    alcohol dependence, GABA B , gamma-hydroxybutyrate deficiency
     
    Dr. Nava and colleagues, quoting work that gives fresh significance to Dr. Gessa’s team’s landmark findings on gamma-hydroxybutyrate (GHB), suggest that the “mechanisms of GHB effects on alcohol intake, craving, and withdrawal may be related to the ethanol-mimicking action of the drug…and that GHB may act as a ‘substitute’ of the alcohol in the central nervous system.” 1 An alcohol-like effect is of course certain to be beneficial for withdrawal. But alcohol being the strongest trigger of alcohol craving and intake makes it difficult to ascribe the reducing effects of GHB on alcohol craving and intake to the alcohol-mimicking activity of GHB. A GHB receptor has been recently identified in the human brain. 2 Could exogenous GHB in fact also “substitute” for itself (deficient endogenous GHB)? GHB is currently the sole identified naturally occurring gamma-aminobutyric acid B (GABA B ) receptor agonist. And of all sedative-hypnotics used for the treatment of alcohol dependence, the only two shown to reduce or suppress motivation to consume alcohol—GHB and baclofen—are also the only two that have GABA B receptor-mediated effects. 3 I have recently proposed that alcohol/substance dependence could result from an adaptative phenomenon in response to an underlying GHB-deficiency-related dysphoric syndrome (anxiety, insomnia, depression) in which alcohol and related substances would be sought to “substitute” for insufficient GHB effect. 3 At the later stage of dependence, exogenous GHB could, in addition to “substituting” for the alcohol (as proposed by the authors), also represent true substitutive treatment for GHB deficiency. Interestingly, while baclofen—a synthetic molecule—is characterized as the prototypic GABA B receptor agonist, the physiologic GABA B receptor agonist(s) is (are) yet to be identified (aside from GHB, which possesses such physiologic activity). So baclofen and GHB could in fact both compensate for deficient effect of the physiological GABA B receptor