Gamma hydroxybutyric acid (GHB) was synthesized in 1960 in an attempt to create an analogue of the ubiquitous inhibitory brain neurotransmitter gamma-aminobutyric acid (GABA) that would cross the blood-brain barrier [1–3]. GHB was first developed as a central nervous system depressant [4,5] and used as an anesthetic adjuvant for minor surgical procedures in laboratory as well as in clinical settings [6–11]. The use of GHB as an anesthetic is now decreasing, even though it is still approved in Germany for intravenous anesthesia [1]. In the 1970s, GHB was found to be effective in the treatment of narcolepsy [12–15]. In particular, nightly doses of GHB were shown to improve the structure of sleep in narcoleptic patients, reducing the number of nocturnal awakenings and daytime attacks of cataplexy [16–18]. In the United States, through a limited distribution program, the FDA approved GHB as a Schedule III Controlled Substance to treat a small subset of patients with narcolepsy who have episodes of weak or paralyzed muscles (i.e. cataplexy) [19]. In addition, since 1992, GHB has been approved in Italy and Austria as a treatment for alcohol dependence [20].

GHB occurs naturally in mammalian brain tissue [21]. The primary precursor of GHB in the brain is GABA, which is transformed into succinic semialdehyde (SSA) through a GABA-transaminase and then converted into GHB via a specific succinic semialdehyde reductase (SSR). GHB can be reconverted to SSA via a GHB dehydrogenase, and then SSA can be converted back to GABA (Figure 1); SSA can also be transformed by succinic semialdehyde dehydrogenase (SSADH) into succinic acid and then further metabolized via the Krebs Cycle in mitochondria (Figure 1). GHB is primarily eliminated by the liver, and only a modest quantity of it remains unmodified (2–5%) and eliminated with urine and/or by a still not fully ascertained process of beta-oxidation (Figure 1) [21].

Exogenous GHB is rapidly absorbed by the gastro-intestinal tract; its peak plasma concentration appears after 15–45 minutes, and its clinical effects after 15–20 minutes. This drug has a dose-dependent elimination half-life; in healthy subjects this can vary from 20 to 53 minutes [22].

In the central nervous system, GHB binds to GHB and GABA_B receptors with high and low affinity, respectively [21]. The endogenous neurobiological activity of GHB is mediated through the GHB receptor, while many of the pharmacological and clinical effects of exogenously administered GHB appear to be mediated through the GABA_B receptor, where GHB may act both directly, as a partial GABA_B receptor agonist, and indirectly through GHB-derived GABA [1,21]. Irrespective of the brain GHB concentration, it is far from certain that GHB interacts directly with the GABA_A receptors [1,21,22]. However, the conversion of exogenously administered GHB to GABA induces an activation of GABA_B receptor and GABA_A receptors too [1,21,22] and this is responsible of GHB sedative and anxiolitic effects.

Physiologically, the mesocorticolimbic dopaminergic neurons (DA) are involved in reward-dependent learning (Figure 2a). DA have their cell bodies in the ventral tegmental area (VTA) and project into the basal forebrain structures, such as the nucleus accumbens (NAc), amygdala, and frontal and limbic cortexes [21]. Activation of DA, with a resultant increase in the output of dopamine in innervated projection structures, has been reported with virtually all major drugs of abuse. It is supposed that the alcohol-mimetic effect of GHB appears to be related to the effects of the dopamine increase mediated by GABA_B receptors in mesocorticolimbic circuitry [21].

Both endogenous and exogenous forms of GHB have a dual action on the GHB receptors and the GABA_B receptors. GHB that binds with high affinity to the pre-synaptic GHB receptors decreases the release of GABA, while GHB that binds with a low-affinity site on the GABA_B receptors increases activation of cell-surface receptors. Therefore, the administration of exogenous GHB is primarily able to decrease the release of GABA from the pre-synaptic GABA-ergic neurons through effects mediated by a direct activation of GHB receptors [21]. The result would be disinhibition of DA of the VTA with increased dopamine within that circuitry, and this is responsible of the alcohol mimic effect of GHB (Figure 2b) [21]. Finally, GHB has been recently shown to decrease the activity of neurons in the locus ceruleus (LC), providing yet another route by which GHB could disinhibit mesocorticolimbic DA (Figure 2b) [21].

In summary, data indicate that sedative effect of exogenously administered GHB (high dose) may be due to a direct effect on GABA_B and indirect on GABA_A receptors: mainly 100 mg/kg/day to suppress alcohol withdrawal syndrome (AWS) and from 4 to 9 g/day to treat cataplexy in narcoleptic patients. On the other hand, the alcohol-mimic mechanism of exogenously administered GHB (low dose) may be due to a decrease in the release of GABA through the effects mediated by GHB receptors on pre-synaptic GABA-ergic and noradrenergic neurons, with a resultant disinhibition of DA and increase in dopaminergic activity in the mesocorticolimbic circuitry (Figure 2b) [21]: mainly 50 mg/kg/day to suppress craving for alcohol intake.

AWS is mediated by a reduced GABA-ergic activity in the central nervous system [25–27]. Exogenous GHB suppresses AWS symptoms in humans by an indirect activation of GABA_A receptors due to the conversion of GHB to GABA [21]. Such a GABA-ergic activity triggers chloride transport across the neuronal membrane, thus inducing a decreased neuronal excitability [28] with consequent resolution of AWS symptoms.

In the clinical area, the efficacy of a non-benzodiazepine GABA-ergic compound such as GHB in suppressing AWS is well demonstrated [29]. After the first pilot study [30], a single-blind trial comparing GHB versus diazepam did not show a significant different efficacy of these drugs in suppressing AWS [31], even though GHB reduced anxiety, agitation and current depression more rapidly than diazepam [31]. A more recent study, however, demonstrated that GHB was even more effective than diazepam in treating AWS [32]. GHB has also been found to be equally efficient as clomethiazole [33], and its efficacy was further confirmed by treating AWS in almost three hundred hospitalized patients affected by different conditions, such as for medical, neurological or psychiatric diseases, trauma or surgery [34]. In all these studies, GHB was employed at the dose of 50–100 mg/kg divided into three or four daily administrations, and no serious side effects were reported.

Craving for and abuse of GHB remains one of the crucial points during the use of this drug. However, episodes of craving for GHB in alcoholics, when manifested, are a very limited phenomenon (about 10%) [53]; on the other hand, it is to be hoped that better manageability and safety of GHB can probably be improved with the identification of groups of alcoholics more predisposed to develop this unfavorable effect. A study investigating the risk of developing craving for and abuse of GHB among different types of alcoholics was, therefore, performed [54]. In this study, indeed, 47 patients were enrolled and divided into four different sub-types of alcoholics, and treated with an oral dose of GHB (50 mg/kg of body weight fractioned into three daily administrations) for three months. At the end of the study, besides a general efficacy of GHB in maintaining alcohol abstinence in all four groups of patients, craving for GHB was statistically significantly higher in those alcoholics with previous cocaine dependence than in “pure” alcoholics (patients with a diagnosis of alcohol dependence without other addictive disorders) (90% vs 14.3%, P < 0.001), with 60% abuse of it [54]; however, craving for GHB did not differ between “pure” alcoholics and alcoholics with previous heroin dependence except for the fact that all alcoholics with previous heroin dependence abused GHB, while none of the “pure” alcoholics manifested this addiction. The greater incidence of craving for and abuse of GHB in alcoholics with a previous diagnosis of cocaine or heroin dependence is an interesting finding and may be putatively explained by the alteration of dopamine system [55]. It has been clearly described that patients with previous chronic exposure to heroin or cocaine may present a down-regulation of D₁ and D₂ receptors, and only high doses of GHB (> 50 mg/kg/die) may exert a reward effect [56,57]. Moreover, imaging studies with positron emission tomography have shown that chronic exposure to cocaine, alcohol or opiates down regulates D₂ receptors in striatum, and these adaptations may persist for a long time after substance cessation [58]. In addition, chronic exposure to cocaine reduces GABA_B receptor activity in the meso-cortico-limbic area [59,60]. The consequence is a reduction in dopamine release, which persists after cocaine cessation. As GHB acts on GABA_B receptors, it is likely that alcoholics with previous cocaine addiction present a down-regulated GABA_B system and are more predisposed to develop craving and episodes of abuse of GHB. Thus, GHB, a GABA_B receptor agonist, may act as a substitutive drug, so that alcoholics with previous cocaine or heroin addiction tend to become predisposed to misuse of the drug. Interestingly, in the above mentioned study [54], alcoholics following a methadone maintenance treatment (MMT) program did not develop craving for GHB. As some recent studies have shown that MMT may induce a μ-opioid receptor desensitization in rats [61] and a long-lasting striatum dopamine neuron impairment in heroin users [62], a dopamine independent pathway may be responsible for these results; the low percentage of subjects who failed to maintain abstinence for alcohol in the MMT group may confirm this hypothesis.

Available studies have demonstrated that GHB appears to be effective both in the management of AWS and in the maintenance of long-term abstinence from alcohol [63,64]. Moreover, it is worth noting that all the cited clinical trials have clearly demonstrated that GHB discontinuation is not followed by withdrawal syndrome, irrespective of its use for treating AWS or maintaining abstinence from alcohol; therefore, the discontinuation of GHB does not require a tapering procedure [65]. None of the above-mentioned trials reported serious side effects during the treatment of GHB; in addition, the fractioning of the GHB doses, from three to six daily administrations, avoided the occurrence of additive sedative effects in patients who voluntarily use alcohol during the treatment with this drug [44–46]. Moreover, due to its short half-life (4–6 hours) [23], GHB may be also safe in patients with decompensated liver disease with ascites effusion [24]; however, this data needs to be confirmed by further clinical trials. Furthermore, even though rare and transitory episodes of sedation due to GHB abuse have been reported, no cases of intoxication, coma or deaths have occurred when the drug is administered under a medical supervision [40,54]. On the other hand, when GHB is used as a recreational drug of abuse (non-clinical use), several cases of intoxication and even death after a single and self-administered dose of the “street” formulation have been reported [66–68].

In conclusion, we believe that specialists in the treatment of alcohol addiction should be less concerned by the risk of GHB intoxication when this drug is employed for treating alcoholism under close medical surveillance. They should not be discouraged from using GHB in the treatment of alcohol addiction, as long as some rules are followed during its administration: a) not exceeding 50–100 mg/kg fractioned into three to six daily administrations; b) using GHB only for the treatment of pure alcoholics, and avoiding this drug for those alcoholics with previous cocaine or heroin dependence; c) planning strict medical surveillance (weekly visits) and designating a family member to whom GHB should be entrusted [69]. The safety and efficacy of GHB, thus, need to be emphasized, as this drug represents a most useful tool for treating alcohol dependence [70,71].