UPDATE ON NEUROPHARMACOLOGICAL TREATMENTS FOR ALCOHOLISM: SCIENTIFIC BASIS AND CLINICAL FINDINGS

Abstract

The past decade has seen an expansion of research and knowledge on pharmacotherapy for the treatment of alcohol dependence. The Food and Drug Administration (FDA)–approved medications naltrexone and acamprosate have shown mixed results in clinical trials. Oral naltrexone and naltrexone depot formulations have generally demonstrated efficacy at treating alcohol dependence, but their treatment effect size is small, and more research is needed to compare the effects of different doses on drinking outcome. Acamprosate has demonstrated efficacy for treating alcohol dependence in European trials, but with a small effect size. In U.S. trials, acamprosate has not proved to be efficacious. Research continues to explore which types of alcohol-dependent individual would benefit the most from treatment with naltrexone or acamprosate. The combination of the two medications demonstrated efficacy for treating alcohol dependence in one European study but not in a multi-site U.S. study. Another FDA-approved medication, disulfiram, is an aversive agent that does not diminish craving for alcohol. Disulfiram is most effective when given to those who are highly compliant or who are receiving their medication under supervision. Of the non-approved medications, topiramate is among the most promising, with a medium effect size in clinical trials. Another promising medication, baclofen, has shown efficacy in small trials. Serotonergic agents such as selective serotonin reuptake inhibitors and the serotonin-3 receptor antagonist, ondansetron, appear to be efficacious only among certain genetic subtypes of alcoholic. As neuroscientific research progresses, other promising medications, as well as medication combinations, for treating alcohol dependence continue to be explored.

INTRODUCTION

Alcohol dependence is a common disorder. Globally and in the U.S., alcohol dependence ranks 5th and 3rd, respectively, on the list of preventable causes of morbidity and mortality [1]. In 2000, the U.S. had 20,687 alcohol-related deaths, excluding accidents and homicides, with an overall estimated cost to the nation of about $185 billion [1].

Alcohol dependence is a chronic relapsing medical disorder [2]. Notwithstanding its psychological and social ramifications, once established, alcohol dependence is essentially a brain disorder that bears many of the characteristics of other medical relapsing disorders such as diabetes and hypertension. Indeed, without a pharmacological adjunct to psychosocial therapy, the clinical outcome is poor, with up to 70% of patients resuming drinking within one year [3,4].

Alcohol dependence is a treatable disorder when efficacious medicines are added to enhance the effects of psychosocial treatment. The development of these medicines has been facilitated by advances in the neurosciences that have implicated several target neurotransmitter systems, such as those within the cortico-mesolimbic dopamine (CMDA) pathway, which mediate alcohol’s reinforcing effects associated with its abuse liability. Additionally, it is now known that some alcoholics may possess a biological predisposition to the disease. These biologically vulnerable alcoholics can be expected to benefit from specific adjunctive medication targeted toward correcting or ameliorating the underlying abnormalities. Further, we are now better at controlling the “dose” of psychosocial treatments through a manual-guided treatment approach, thereby enabling the optimization of how particular medicines can be combined with adjunctive psychosocial treatment.

Recently, the treatment of alcohol dependence has been advanced by development of new models as well as broader therapeutic objectives. An important model is that with appropriate pharmacotherapy it is possible to initiate treatment for alcohol dependence while the individual is still drinking heavily and at the point of maximum crisis and help-seeking behavior [5]. To broaden access to treatment, effective but brief and standardized behavioral treatment has been developed to accompany medication delivery; thus, these medicines can now be provided more readily in the general practice setting [6,7]. Finally, it is now better recognized that although abstinence remains the ultimate goal in treating alcohol-dependent individuals, reducing the frequency of heavy drinking has the major impact of decreasing alcohol-related consequences and improving quality of life [5].

In this review, I focus on the development of those medications for which there is clinical information and that have been designed to reduce the desire to drink, to promote abstinence, or both. Basically, of the numerous neurotransmitter systems that have been identified for the development of new medicines, the most promising compounds appear to be those that modulate the function of opioids, glutamate with or without gamma-aminobutyric acid (GABA), and serotonin (5-HT). Other putative therapeutic medications including direct modulators of dopamine function and enzyme inhibitors also shall be discussed. Each subsection of this article provides an overview of the basic science, clinical studies, and future directions for the development of specific promising medications from these neurobiological systems. Emphasis is made in places where the development of a particular medicine has advanced the development of a new treatment model or broadened therapeutic objectives. I conclude the article with remarks pertaining to current barriers to treatment and how they might be overcome.

OPIOIDS: MU RECEPTOR ANTAGONIST — NALTREXONE

Basic science and human laboratory studies

The endogenous opioid system, particularly through its interactions with the CMDA system, is involved in the expression of alcohol’s reinforcing effects [8-14] (Fig. 1). Obviously, opioid receptors also have interactions with other neurotransmitters, including those in the glutamate [15], GABA [16], 5-HT [17], cannabinoid [18] and perhaps glycine [19] systems, that contribute to its effects on ethanol intake.

Fig. 1.

Schematic representation of opioid interactions with the cortico-mesolimbic dopamine reward pathway. Functional activity of beta-endorphin pathways primarily originating from the nucleus arcuatus can lead to increased dopamine release in the nucleus accumbens via two mechanisms. First, beta-endorphins can disinhibit the tonic inhibition of gamma-aminobutyric acid (GABA) neurons on dopamine cells in the ventral tegmental area [10-12]. Second, beta-endorphins can stimulate dopamine cells in the nucleus accumbens directly. Both mechanisms may be important for alcohol reward. Alcohol stimulates beta-endorphin release in both the nucleus accumbens and ventral tegmental area [13]. Mu receptor antagonists such as naloxone and naltrexone block these central effects of beta-endorphins [9,13]. Embellished from Gianoulakis [13]. Reprinted from Figure 1 in Johnson and Ait-Daoud [14], with the kind permission of Springer Science and Business Media.

Even though naltrexone has some affinity for the kappa-opioid receptor [20], its principal pharmacological effect on alcohol consumption is through blockade of the mu-opioid receptor as mice that lack the mu-opioid receptor do not self-administer alcohol [21]. Further, alcohol intake increases beta-endorphin release in brain regions such as the nucleus accumbens [22-24], an effect that is blocked by naltrexone [25]. Mu receptor antagonists such as naltrexone and naloxone also suppress ethanol intake across a wide range of animal paradigms [26-36] cf. [37-39]. More recently, there also has been interest in elucidating the role of the hypothalamic-pituitary-adrenocortical axis in stress-induced ethanol consumption and sensitivity and how this might be influenced by naltrexone treatment [40].

Ethanol has complex neurobiological interactions that affect the production, secretion, and binding of opioids to their receptors [41], thereby hinting at a fundamental mechanistic process linking the two. This relationship does, however, remain imperfectly understood. For example, animals bred for high ethanol preference exhibit an exaggerated reactive rise in beta-endorphin level following ethanol intake [42]. Yet, naltrexone’s ability to suppress ethanol-associated increases in beta-endorphin level appears greater in animals bred for low rather than high preference for alcohol [25]. Indeed, from a group of animals in the beta-endorphin-deficient mutant mouse line — C57BL/6-Pomc1(tm1Low) — the highest ethanol consumption occurred in the heterozygotes (50% beta-endorphin deficient) and not the homozygotes (no beta-endorphin) or control group of sibling wild type mice from the same strain [43]. These findings do, however, suggest that molecular genetic differences that alter beta-endorphin expression, not simply its plasma levels, modulate the level of response to naltrexone. Nevertheless, there is growing evidence in humans that differences in the OPRM1 mu-opioid receptor gene are associated with differential therapeutic response to naltrexone — a theme that is explored in detail later in this review.

Human laboratory studies that have evaluated naltrexone’s effects on alcohol-induced positive subjective mood and craving have yielded mixed results. Although it has been shown that naltrexone can reduce alcohol-induced positive subjective mood, albeit with increased sedation [44], and increase the latency to consume alcohol among social drinkers [45], others have reported no effect [46]. It does, however, appear that a positive familial loading for alcoholism might predict the potential anti-drinking and anti-craving effects of naltrexone in human laboratory studies. For example, King et al. [47] showed that social drinkers with a familial loading for alcoholism were more likely than those without it to exhibit a decrease in the stimulant effects of alcohol following naltrexone treatment. Nevertheless, they also reported concomitant negative mood exemplified by increased tension, fatigue, and confusion and decreased vigor, as well as notable adverse events such as nausea and vomiting following naltrexone. More recently, Krishnan-Sarin et al. [48] have shown that individuals with a family history of alcoholism, compared with their family history-negative counterparts, consumed less alcohol in a laboratory paradigm. Obviously, these results would lead to the speculation that a genetic explanation for differential response to naltrexone’s effects on craving and alcohol consumption among alcohol-dependent individuals is being studied in the human laboratory. Nevertheless, even here, what has been demonstrated is that naltrexone increases the urge to drink among alcohol-dependent individuals who are aspartate (Asp) carriers of the OPRM1 gene but has no effect on their homozygote, i.e., asparagine-carrying, counterparts in a cue-reactivity laboratory paradigm [49]. Despite the dissimilarities between studies, including the subject’s motivation toward seeking treatment, experimental set, setting, expectations, and paradigm, these results do appear to be in contrast with the report that naltrexone preferentially protected against relapse in Asp-carrying alcohol-dependent individuals [50]. The implications of these findings are discussed in the clinical subsection below.

In sum, basic science studies support the finding that naltrexone can reduce ethanol drinking and related behaviors in animals. Naltrexone appears most effective in suppressing the expected ethanol-induced increase in beta-endorphin level among animals that exhibit an exaggerated beta-endorphin response. The molecular genetic construct for understanding preferential response to naltrexone is not well understood and is even contrary to expectations. Generally, human laboratory studies provide some support for naltrexone as a medication that can reduce craving for alcohol as well as its consumption; however, these effects appear to be more readily demonstrable among individuals with high familial loading for alcoholism. An initial molecular genetic exploration did not demonstrate that naltrexone’s anti-drinking effect is greatest among non-treatment-seeking, alcohol-dependent individuals who carry the Asp variant of the OPRM1 gene.

Clinical studies with oral naltrexone

In 1994, the Food and Drug Administration (FDA) approved naltrexone for the treatment of alcohol dependence based on data from two relatively small (total N = 167) studies [51,52]. In those studies, recently abstinent, alcohol-dependent individuals who received naltrexone (50 mg/day), compared with their counterparts who got placebo, were less likely to relapse during the treatment period of 12 weeks. Nevertheless, 5 months after treatment, the relapse rates for the naltrexone and placebo groups were similar. The anti-alcohol-craving effects that were ascribed to naltrexone were based on three findings. First, individuals with the highest level of baseline craving appeared to benefit the most from naltrexone [53]. Second, abstinent individuals who had received naltrexone had less of an impulse to initiate drinking [54]. Third, even among those who sampled alcohol, less pleasure was derived from the beverage [55]. These earlier studies were limited by the fact that only male veterans were tested in one of the studies [52], and either there was no biomarker used to corroborate the self-reported data [51] or when the liver enzyme gamma-glutamyl transferase (GGT) was used as a biomarker the results were not contributory [52] — presumably due to the relative insensitivity of this measure to capture transient drinking patterns.

Notably, in two large meta-analytic studies [56,57], naltrexone has been demonstrated to be efficacious at reducing the risk of relapse among recently abstinent, alcohol-dependent individuals. What emerged from this literature review was that naltrexone’s effect size was small, with a corresponding number needed to treat (i.e., the number of individuals who need to be treated to prevent relapse in a single individual) of 7. Another threat to demonstrating efficacy for naltrexone is not having quite high enough levels of medication compliance. Indeed, in a 3-month follow-up and systematic replication of their study, Volpicelli et al. [58] only found a significant effect of naltrexone treatment compared with placebo recipients if the pill taking rate exceeded 90%; even here, the difference in the percentage of drinking days between the naltrexone and placebo groups was small — 3% and 11%, respectively. Perhaps because of this small effect size, some studies have failed to demonstrate naltrexone’s efficacy in treating alcohol dependence. For instance, in the UK collaborative trial led by Chick et al., no overall difference was found between the naltrexone 50 mg/day and placebo groups on any of the endpoint measures; however, when individuals with less than 80% pill-taking compliance were excluded from the analysis, naltrexone was associated with a lower percentage of days drinking compared with placebo — 12% vs. 20%, respectively [59,60]. With naltrexone treatment, reduced pill-taking compliance is typically the result of adverse events such as nausea that can be reported as significant in up to 15% of trial participants [61]. Therefore, new technologies that aim to improve compliance by delivering naltrexone in depot form might possess a therapeutic advantage to the oral formulation. These technologies are discussed later in this section. Importantly, the recent publication of the results of the NIAAA-sponsored COMBINE study (N = 1383) has served to underscore that naltrexone (100 mg/day) plus medication management to enhance compliance compared with placebo reduced the risk of a heavy drinking day (hazard ratio = 0.72; 97.5% CI = 0.53–0.98; p = 0.02) [62]. Uniquely, this study used a higher naltrexone dose (i.e., 100 mg/day vs. 50 mg/day), and the high compliance rate of pill-taking — 85.4% — improved clinical outcome.

Recently, it has been proposed that individuals with the Asp variant of the OPRM1 gene exhibited preferentially higher relapse prevention rates when receiving naltrexone treatment [50]. As described previously, a similar response to naltrexone treatment on cue-elicited craving was not observed among non-treatment-seeking, alcohol-dependent individuals in a human laboratory study [49]. Further, a recent clinical trial did not find a preferential effect of naltrexone treatment on any of the variants of the OPRM1 gene [63]. Notably, the functional importance of variation in the OPRMI gene is still being elucidated. Although earlier studies in transfected cells suggested that the OPRM1-Asp⁴⁰ variant had a 3-fold higher affinity for beta-endorphin than OPRM1-Asn⁴⁰, which would suggest enhanced function [64], this has not been corroborated by others [65,66]. Recent in vitro transfection studies have, however, suggested that the G118 allele might be associated with lower OPRM1 protein expression than the A118 allele [67]. A further complication to estimating the general clinical significance of the effects of the Asp⁴⁰ allele on pharmacotherapeutic response to naltrexone is that its frequency can vary considerably between populations — from as low as 0.047 in African Americans to 0.154 in European Americans, and as high as 0.485 among those of Asian descent [68,69]. More molecular genetic studies are, therefore, needed to elucidate fully the mechanistic effects of the Asp⁴⁰ allele, and to establish whether or not naltrexone response varies by variation at the OPRM1 gene.

Certain clinical characteristics have, however, been associated with good clinical response to naltrexone, and these include a family history of alcohol dependence [53,70,71] or strong cravings or urges for alcohol [71].

In sum, the majority of the data confirm that naltrexone is an efficacious medication for treating alcohol dependence. The therapeutic treatment effect size is, however, small, and poor pill-taking compliance can be associated with poor clinical outcome. There remains a dearth of published studies on the effects of different doses of naltrexone on drinking outcome. Further research is needed to establish whether naltrexone’s therapeutic efficacy in treating alcohol dependence differs among individuals who have variants of the OPRM1 gene. Alcohol-dependent individuals with a positive family history for the disease and individuals with strong cravings for alcohol appear to benefit the most from naltrexone treatment.

Clinical studies with depot naltrexone

Three extended-release formulations of naltrexone for deep intramuscular injection have been developed — Vivitrol^® (Alkermes, Inc., Cambridge, MA, USA), Naltrel^® (Drug Abuse Sciences, Inc., Paris, France), and Depotrex^® (Biotek, Inc., Woburn, MA, USA). The premise for developing these depot formulations of naltrexone is three-fold. First, a well formulated depot preparation can maintain relatively constant plasma levels by producing a slow but regular release of naltrexone. Individuals who take oral naltrexone and have notable adverse events such as nausea that can lead to study discontinuation probably experience this phenomenon due to the rapid rise in plasma levels following initial doses of oral naltrexone. Hence, a depot formulation might be expected to decrease these initial adverse events if it provided a more gradual rise in naltrexone plasma levels. Second, by providing a monthly depot preparation, compliance with receiving the medication is optimized and should be greater than reliance on remembering to take tablets. Third, because plasma levels should remain relatively constant throughout the month following the administration of a depot preparation, there should be relatively greater exposure to the therapeutic dose, thereby facilitating good clinical outcome. Information pertaining to the three depot preparations of naltrexone that are being tested is provided below.

Vivitrex^® or Vivitrol^®

Vivitrex^®, or Vivitrol^® as it is known now, is naltrexone formulated into poly-(lactide-co-glycolide) [72], small-diameter (<100 μm), injectable microspheres that contain other proprietary active moieties, which lead to its extended-release properties lasting for several weeks [73]. In 2004, Johnson et al. [74] published the initial safety, tolerability, and efficacy trial of Vivitrex^® for treating alcohol dependence. The design of the study was a 16-week randomized, placebo-controlled, double-blind clinical trial. Of the 25 alcohol-dependent individuals who participated in the trial, five of them got placebo and the remainder (n = 20) got 400 mg of Vivitrex^®. Results of that trial showed the safety of Vivitrex^®, with the most common adverse events being non-specific abdominal pain, nausea, pain at the injection site, and headaches. None of the placebo recipients dropped out due to adverse events; in contrast, two of those who got Vivitrex^® discontinued for that reason. Due to the unbalanced design and small subject numbers, any inferences regarding efficacy had to be viewed quite cautiously. Nevertheless, there was a trend for those on Vivitrex^®, compared with placebo, to have a lower percentage of heavy drinking days — 11.7% vs. 25.3%. Later, in a large placebo-controlled, double-blind, randomized, multi-site, 24-week clinical trial, Garbutt et al. [75] showed that high-dose Vivitrex^® (380 mg) recipients had a significantly lower percentage of heavy drinking days than those who got placebo (hazard ratio = 0.75; 95% CI = 0.60–0.94; p = 0.02). Recipients of low-dose Vivitrex^® (190 mg) had outcomes similar to those who got placebo. The treatment response signal in the high-dose Vivitrex^® recipients came from the male participants as the effect of both Vivitrex^® doses was no different from that in women who took placebo (hazard ratio = 1.23; 95% CI = 0.85–1.78; p = 0.28). The lack of efficacy for Vivitrol^® in women has been ascribed to greater subclinical affective symptoms, less of a family history of alcoholism (which is meant to be associated with good clinical outcomes to naltrexone), more responsiveness to placebo, and more clinical heterogeneity in the sample. In contrast with the premise for developing depot preparations, the dropout rate of 14.1% in the high-dose Vivitrex^® group was similar to that reported in studies with oral naltrexone. The chosen objective biomarker to corroborate the self-reported data — GGT — did not show a difference between any of the Vivitrex^® doses and the placebo group. The common reasons for study discontinuation were injection site reactions, headaches, and nausea. Serious adverse events were reported in two participants taking active medication that resulted in an interstitial pneumonia and an allergic-type eosinophilic pneumonia, both of which resolved after medical treatment. Thus, the evidence remains that Vivitrol^® appears to be efficacious in preventing heavy drinking in men; however, it was approved by the FDA for treatment of both men and women based on the extant literature on naltrexone as a treatment for alcohol dependence. The expected advantage of Vivitrol^® to increase compliance did not materialize quickly although this might become more manifest in generic treatment settings rather than a closely monitored clinical trial. The potential for hypersensitivity reactions to Vivitrol^®, while small, does require post-marketing evaluation by the FDA.

Naltrel^®

Naltrel^® consists of naltrexone incorporated into microspheres of poly-(DL-lactide) polymer. These microspheres, stored in single-dose vials, are suspended in a diluent that contains carboxymethylcellulose, mannitol, polysorbate 80, and water for injection. The polylactide polymer is metabolized to water and carbon dioxide. Then, as the microspheres degrade, naltrexone is released. In 2004, Kranzler et al. [76] studied the safety and efficacy of Naltrel^® in treating male and female alcohol-dependent individuals receiving monthly motivation enhancement-based therapy in a double-blind, placebo-controlled, 3-month randomized controlled trial (N = 157). The initial dose of Naltrel^® (150 mg) was delivered as a deep intramuscular injection into each buttock, and subsequent monthly doses were just 150 mg. Placebo injections were provided at the same frequency and constitution but lacked the active compound. Adverse events reported significantly more frequently in the Naltrel^® group than in the placebo group included injection site reactions, chest pain, and upper abdominal pain. Placebo recipients were, however, more likely to report irritability than those who got Naltrel^®. While 6 (3.8%) of the placebo recipients dropped out, 13 (8.2%) of those who got Naltrel^® discontinued treatment. Naltrel^® was superior to placebo at increasing the mean number of cumulative abstinent days (52.8 days, 95% CI 48.5–57.2 days, vs. 45.6 days, 95% CI 41.1–50.0 days, respectively; p = 0.018) and having a longer median time to first drink (5 days, 95% CI 3–9 days, vs. 3 days, 95% CI 2–4 days, respectively; p = 0.003). The effects of gender on treatment outcome were not examined.

Somewhat in contrast, a single-site, 6-week trial of 16 alcohol-dependent individuals who received one intramuscular dose of Naltrel^® (300 mg) [77] suggested low tolerability, with 198 adverse events being reported. Of these, 17 were considered to be severe and included fatigue, gastrointestinal pain, irritability, nausea, somnolence (two reports), headache (four reports from three subjects), injection site pain, injection site mass, lethargy, depression, increased level of GGT (an index of heavy drinking [78]), back pain, and flatulence. No serious adverse events were reported. Drinking outcomes showed an improving trend over the duration of the trial.

Nevertheless, further studies on the safety and efficacy of the Naltrel^® formulation are warranted. Additional data are needed to determine whether, as with Vivitrol^®, there is a differential response on drinking outcomes between men and women who get Naltrel^®.

Depotrex^®

Rather little public information is available on the Depotrex^® depot formulation. Like the other depot formulations, Depotrex^® appears to provide steady increases in plasma naltrexone levels [79] and is an effective mu-opioid receptor antagonist [80,81]. Pharmacokinetic data from 12 heroin-dependent individuals who received low and high doses of Depotrex^® — 192 mg and 384 mg, respectively — showed that both doses maintained plasma naltrexone levels above 1 ng/ml for up to 4 weeks [82]. Average peak levels for the low and high doses of Depotrex^® were 3.8 ng/ml and 8.9 ng/ml, respectively. Plasma beta-naltrexol, the major metabolite of naltrexone, was greater proportionately but could not be detected 5 weeks following Depotrex^® administration. Both doses of Depotrex^® antagonized the positive subjective effects of heroin. Reported adverse events were minimal and included mild discomfort at the injection site, with no irritation or erythema. The promising earlier study by Kranzler et al. [79] of Depotrex^® (206 mg) in the treatment of alcohol dependence needs to be followed up.

In sum, depot formulations of naltrexone may offer some advantages such as increased compliance over the oral formulations. This advantage has, however, been difficult to demonstrate in randomized controlled trials but might become more apparent when these depot formulations are used in generic practices. Depot formulations do not appear to be more efficacious than the oral formulations, and with one of these — Vivitrol^® — no therapeutic effect in women has been demonstrated. The adverse events profiles of depot formulations of naltrexone that have been reported in randomized controlled trials appear similar in frequency and intensity to those observed for the oral formulation. The different depot formulations do appear to be similar in characteristics and profile, and more clinical information about which one to select to treat a particular alcohol-dependent patient, if all are approved by the FDA, shall be needed.

GLUTAMATE

Metabotropic glutamate receptor-5 (mGluR5) modulator and N-methyl-D-aspartate (NMDA) antagonist — acamprosate

Acamprosate’s principal neurochemical effects have been attributed to antagonism of NMDA glutamate receptors [83,84], which restores the balance between excitatory and inhibitory neurotransmission that is dysregulated following chronic alcohol consumption [85]. Recently, however, it also has been proposed that acamprosate modulates glutamate neurotransmission at metabotropic-5 glutamate receptors (mGluR5) [86]. Evidence that acamprosate modulates a novel site of action at mGluR5 comes from the finding that it inhibits the binding and neurotoxic effects of ±-1-aminocyclopentane-trans-1,3-dicarboxylic acid [86]. Acamprosate has been shown to decrease: a) ethanol consumption in rodents [87-89], but this effect may not be specific in food-deprived C57BL/6J mice as both ethanol and water were reduced in a schedule-induced polydipsia task [90]; b) dopamine hyperexcitability in the nucleus accumbens during alcohol withdrawal [91,92]; c) general neuronal hyperexcitability [93,94]; d) glutamatergic neurotransmission in alcohol-dependent rats [91,95]; e) voltage-gated calcium channel activity, and f) the expression of brain c-fos, an immediate early gene associated with alcohol withdrawal [96,97]. Nevertheless, it is acamprosate’s ability to suppress alcohol-induced glutamate receptor sensitivity [98], as well as conditioned cue responses to ethanol in previously dependent animals even after prolonged abstinence [99-102], that has been linked with its therapeutic effect in humans — dampening negative affect and craving post-abstinence [14,103] (Fig. 2).

Fig. 2.

Schematic representation of acamprosate’s effects. Acamprosate has four principal effects: A) reducing post-synaptic excitatory amino acid neurotransmission at N-methyl-D-aspartate (NMDA); B) diminishing Ca²⁺ influx into the cell, which interferes with expression of the immediate early gene c-fos; C) decreasing the sensitivity of voltage-gated calcium channels, and D) modulating metabotropic-5 glutamate receptors (mGluR5). mGluR5 are post-synaptic and are coupled to their associated ion channels by a second messenger cascade system (not shown). Also shown in this representation is synthesis of c-fos and c-jun in the endoplasmic reticulum, which can bind with DNA to alter the transcription of late effector genes. Late effector genes regulate long-term changes in cellular activity such as the function of receptors, enzymes, growth factors, and the production of neurotransmitters. Embellished from Spanagel and Zieglgansberger [103]. Adapted from Figure 2 in Johnson and Ait-Daoud [14], with the kind permission of Springer Science and Business Media.

Interestingly, there has been a paucity of human laboratory studies that have examined the potential effects of acamprosate on alcohol-related behaviors associated with its abuse liability. Evidence from a human magnetic resonance imaging study does, however, support acamprosate’s ability to modulate glutamate neurotransmission as it decreases activity in brain regions rich in N-acetylaspartate and glutamate [95]. Human laboratory studies in both volunteers [104] and alcohol-dependent individuals [105] also have shown that acamprosate — i.e., calcium acetyl homotaurinate — is relatively safe, with the most important adverse events being diarrhea, nervousness, and fatigue, especially at a relatively high dose (3 g/day). Since acamprosate is excreted unchanged in the kidneys, there is no risk of hepatotoxicity, but it should be used with caution in those with renal impairment [104,105]. Acamprosate has no significant clinical interaction with alcohol. Recently, it was shown that acamprosate can reduce heart rate response but not the increase in cortisol or subjective craving following the presentation of alcohol cues — a finding that suggests utility for acamprosate in managing autonomic dysregulation in abstinent alcoholics exposed to a high risk for relapse situations [106].

Most of the clinical evidence for the efficacy of acamprosate in the treatment of alcohol dependence comes from a series of European studies. In 2004, Mann et al. [107] wrote a meta-analysis of 17 published studies that included 4087 alcohol-dependent individuals. In that report, continuous abstinence rates at 6 months were greater than for those who got placebo (acamprosate, 36.1%; placebo, 23.4%; relative benefit, 1.47; 95% CI = 1.29–1.69; p < 0.001). The overall pooled difference in success rates between acamprosate and placebo was 13.3% (95% CI = 7.8–18.7%), and the number needed to treat was 7.5. Similar results were obtained from another meta-analysis conducted at about the same time [56]. Generally, the effect size of acamprosate is small — 0.14 for increasing the percentage of non-heavy drinking days [108] and 0.23 for reducing the relapse to heavy drinking [109]. Early studies also had some methodological problems, including non-standardization of diagnostic criteria and the psychosocial adjunct to the medication, which were resolved in later trials.

Despite approval by the FDA on July 29, 2004, for the use of acamprosate in the treatment of alcohol dependence, largely based on the data from European studies, the results of U.S. studies have been disappointing. In the U.S. multi-site trial by Lipha Pharmaceuticals, Inc., there was no overall clinical evidence that acamprosate was superior to placebo among a heterogeneous cohort of alcohol-dependent individuals; however, post-hoc analysis suggested that a subgroup of alcoholics with a treatment goal of abstinence might derive benefit [110]. Further, in 2006, the multi-site COMBINE project also failed to find any therapeutic benefit of acamprosate compared with placebo on any drinking outcome measures [62]. Obviously, the findings of these U.S. studies have reduced the enthusiasm for using it by addiction specialists in the U.S. From a scientific perspective, these findings do beg the questions as to what type of alcohol-dependent individual benefits the most from acamprosate and why there is an important discrepancy between the results of U.S. and European studies.

From the European studies, acamprosate appears to benefit alcohol-dependent individuals with increased levels of anxiety, physiological dependence, negative family history, late age of onset, and female gender [111].

There are at least four possible explanations for the discrepancy between U.S. and European studies. First, the populations sampled differ, with European, compared with U.S., studies having alcohol-dependent individuals with more prolonged drinking histories and alcohol-related neurological and psychosocial impairments. Thus, it is tempting to speculate that European studies might have included individuals with greater neuroplasticity and, therefore, higher response to the ameliorating effects of anti-glutamatergic agents such as acamprosate. Second, U.S., compared with European, studies have tended to have higher levels of standardized psychosocial intervention as an adjunct to acamprosate, thereby masking the effect of the medication. Third, the therapeutic effect of acamprosate is small; hence, by chance, some trials can be expected to fail, especially those conducted in a multi-site rather than a single-site environment due to the greater heterogeneity and variability of the cohort and research settings. Fourth, it is possible that future research might uncover other important differences between U.S. and European cohorts to explain the discrepant findings such as potential differences in patient subtype, stage of the alcoholism disease, or bio-molecular constitution.

In sum, European studies have clearly demonstrated efficacy for acamprosate as a treatment for alcohol dependence. Acamprosate was FDA approved in the U.S. largely based on the results of the European studies. Acamprosate’s therapeutic effect is small, but it is well tolerated, with the most prominent adverse events being diarrhea, nervousness, and fatigue, especially at a relatively high dose (3 g/day). In contrast, U.S. studies have, to date, been unable to find efficacy for acamprosate among a heterogeneous group of alcohol-dependent individuals. The reason for this discrepancy between the results of U.S. and European studies has not been established. Perhaps, however, this discrepant finding might be due to differences in patient selection, subtype, stage of the alcoholism disease, or bio-molecular constitution that are yet to be determined. Future studies are needed to delineate more clearly what type of alcohol-dependent individual can benefit the most from acamprosate treatment.

Other N-methyl-D-aspartate (NMDA) receptor antagonists

Other NMDA receptor antagonists such as memantine and neramexane are being studied for the treatment of alcohol dependence. Both compounds have been shown in animal models to suppress ethanol-induced NMDA receptor up-regulation, thereby reducing ethanol sensitization and the propensity for subsequent drug use (for a review, see Nagy [112] and Kotlinska et al. [113]). In a human laboratory study, memantine reduced alcohol craving prior to but not after the experimental administration of alcohol. This would suggest that memantine might have the effect of reducing post-cessation craving for alcohol [114]. This finding is supported by a later report that memantine might have comparable effects to diazepam at ameliorating alcohol withdrawal symptoms [115]. Nevertheless, despite the early preliminary findings, a recent pilot clinical trial comparing memantine with placebo for the treatment of alcohol dependence reported that the greater therapeutic effect at reducing the percentage of heavy drinking days and increasing the percentage of days abstinent [116] occurred among the placebo group. Although this pilot study did not provide support for memantine as an efficacious treatment for alcohol dependence, further studies are needed to make a final determination of memantine’s therapeutic potential for this indication. No human study on the therapeutic effects of neramexane in treating alcohol dependence has been published.

Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and kainate glutamate receptor antagonist — topiramate

Topiramate, a sulfamate-substituted fructopyranose derivative, has six important mechanisms of action. Additional to its ability to antagonize alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors and kainate glutamate receptors [117-119], topiramate also facilitates inhibitory GABA_A-mediated currents at non-benzodiazepine sites on the GABA_A receptor [120,121], inhibits L-type calcium channels and limits calcium-dependent second messenger systems [122], reduces activity-dependent depolarization and excitability of voltage-dependent sodium channels [123], activates potassium conductance [124], and is a weak inhibitor of carbonic anhydrase isoenzymes, CA-II and CA-IV [125], which are found in both neuronal and peripheral tissues. In renal tubules, carbonic anhydrase isoenzyme inhibition reduces hydrogen ion secretion and increases secretion of Na⁺, K⁺, ${\mathrm{HCO}}_3^{-}$, and water, thereby enhancing the likelihood of acidosis and renal stone formation [125,126].

Johnson [127,128] has proposed a neuropharmacological model by which topiramate can decrease alcohol reinforcement and the propensity to drink (Fig. 3). Nevertheless, few studies on the effects of topiramate on ethanol consumption in animals have been published. An initial animal study had shown complex effects of topiramate on ethanol drinking in C57BL/6 mice. In that study, high-dose (50 mg/kg) but not low-dose (1, 5, and 10 mg/kg) topiramate suppressed ethanol intake 2 hours after it was injected into the animal. Topiramate also decreased saccharin preference, but its ability to suppress ethanol preference was associated with some increase in water intake [129]. Notably, in an elegant, recent animal study, Nguyen et al. [130] demonstrated that topiramate can suppress ethanol drinking in C57BL/6 mice; additionally, in contrast with the effects of naltrexone and tiagabine in the same animals, the mice treated with topiramate did not develop any tolerance to its anti-drinking effects. Further, topiramate also has been shown to suppress alcohol drinking moderately in both alcohol-preferring (P) and Wistar rats [131]. Additional to its ethanol-suppressing effects, there is evidence that topiramate can reduce alcohol withdrawal symptoms in a model of handling induced convulsions [132]. Hence, the preponderance of the animal literature does support topiramate as a promising medication for the treatment of alcohol dependence. Nevertheless, the effect of topiramate on ethanol drinking in animals appears to be less striking than that on drinking outcomes in humans, which are presented below. This challenges the notion that animal models can predict directly treatment response in humans, especially when a variety of models have not been used or been available to characterize or “fingerprint” response [133]. The results of additional animal experiments examining topiramate’s mechanistic effects on ethanol consumption or related behaviors in animals are, therefore, awaited eagerly.

Fig. 3.

Schematic illustration of the hypothesized effects of acute and chronic alcohol, both with and without topiramate, on the cortico-mesolimbic dopamine (DA) reward circuit [127]. (Upper left) Acute alcohol suppresses the firing rate of ventral tegmental area (VTA) gamma-aminobutyric acid (GABA) neurons, which leads to less suppression of VTA DA neuronal activity. This disinhibition leads to VTA DA neuronal firing and DA release in the nucleus accumbens (N Acc.) [127]. (Lower left) With chronic drinking, VTA GABA neurons are hyperexcitable, mainly because of increased glutamatergic input, less GABA tone from the N Acc., and rebound firing of GABA neurons because of their long-term suppression from repeated alcohol ingestion. This leads to VTA DA hypofunction and decreased release (compared with the acute condition) of DA in the N Acc. [127]. (Upper right) During acute drinking, the GABAergic influence of topiramate probably predominates, particularly in the N Acc. This leads to greater inhibition of N Acc. DA neurons, and greater GABA tone from the N Acc. to the VTA suppresses VTA DA cell firing. Topiramate concomitantly inhibits the excitatory effects of glutamatergic neurons on DA neurons in the VTA and N Acc. These combined actions of topiramate should lead to profound suppression of DA neuronal activity and DA release in the N Acc. Hence, topiramate reduces the DA-mediated reinforcing effects of acute alcohol [127]. (Lower right) During chronic drinking, the predominant neuronal activity resides with the hyperexcitable state of VTA GABA neurons. Because of GABA-mediated inhibition and glutamatergic blockade of these neurons, topiramate “normalizes” VTA GABA neuronal activity. Although this would, at first, suggest that DA release in the N Acc. would be enhanced, this does not occur, and DA release in the N Acc. is most likely reduced because these N Acc. terminals are contemporaneously inhibited by GABA inhibition and blockade of glutamate (GLU). In the chronic drinker, the anti-glutamatergic and L-type calcium channel effects of topiramate to block sensitization might predominate. Hence, topiramate would make it easier for a chronic alcoholic to withdraw from alcohol because rebound DA release would not occur (if drinking were ceased abruptly), and topiramate would aid in relapse prevention because alcohol’s reinforcing effects would be decreased [127]. Line weights represent relative strengths of neuronal activity (heavy, medium, and light). The broken line represents decreased tone. VP, ventral pallidum. Reprinted from Figure 1 in Johnson [127], with the permission of Blackwell Publishing, Inc.

Recently, Johnson et al. [5,134] and Ma et al. [135] showed in a double-blind, randomized clinical trial that topiramate (up to 300 mg/day), compared with placebo, improved all drinking outcomes, decreased craving, and improved the quality of life of alcohol-dependent individuals who received 12 weeks of weekly brief behavioral compliance enhancement treatment [6]. The improvements in self-reported drinking outcomes were confirmed by plasma GGT, an objective biochemical measure of alcohol consumption [78]. The therapeutic effect size for the primary efficacy variable — percentage of heavy drinking days — was 0.63.

In a 6-week experimental study of 76 heavy drinkers who were not seeking treatment, Miranda et al. [136] showed that low- and high-dose topiramate — 200 mg/day and 300 mg/day, respectively — were significantly better than placebo at decreasing the percentage of heavy drinking days.

Further, in a subsequent 17-site (N = 371) U.S. trial, topiramate (up to 300 mg/day) was again superior to placebo at improving all self-reported drinking outcomes, GGT level, and some measures of quality of life among alcohol-dependent individuals who received 14 weeks of weekly brief behavioral compliance enhancement treatment. Topiramate’s therapeutic effect size for the reduction in percentage of heavy drinking days was 0.52, and the number needed to treat was 3.4 [137].

Taken together, these clinical studies provide strong evidence that topiramate is a promising medication for the treatment of alcohol dependence. Encouragingly, topiramate’s therapeutic effect size is in the moderate range, and the clinical effects appear to increase with greater length of time on the medication.

Generally, topiramate has a favorable adverse event profile, with most reported symptoms being classified as mild to moderate [138]. The most common adverse events are paresthesia, anorexia, difficulty with memory or concentration, and taste perversion. Slow titration to the ceiling dose (up to 300 mg/day) for 6 to 8 weeks is critical to minimizing adverse events and improving tolerability; however, about 10% of individuals taking topiramate may experience some cognitive difficulty irrespective of the dose titration schedule [139]. Topiramate use has been linked with acute but rare visual adverse events. As of January 2005, there had been 371 spontaneous reports of myopia, angle-closure glaucoma, or increased intraocular pressure, for a rate of 12.7 reports per 100,000 patient-years exposure. Usually, the syndrome of acute bilateral myopia associated with secondary angle-closure glaucoma presents as the acute onset of visual blurring, ocular pain, or both. Associated bilateral ophthalmologic findings can include myopia, shallowing of the anterior chamber, conjunctival hyperemia, and raised intraocular pressure. This syndrome resolves within a few days of discontinuing topiramate administration [138].

In sum, predicated upon a neuropharmacological conceptual model, there is now strong clinical support for topiramate as a promising medication for the treatment of alcohol dependence. Topiramate’s therapeutic effects appear to be robust, with a medium effect size, thereby potentially ushering in a new era of a reliably efficacious medicine for the treatment of alcohol dependence. Intriguingly, although the animal data do provide support for topiramate’s anti-drinking effects, more research is needed to characterize fully or “fingerprint” the pattern of response. Such preclinical studies should enable us to elucidate more clearly the basic mechanistic processes that underlie topiramate’s efficacy as a treatment for alcohol dependence.

SEROTONIN (5-HT)

For almost three decades, there has been intense interest in the effects of serotonergic agents in the treatment of alcohol dependence. Encouraged by increased knowledge about the various 5-HT receptor subtypes, researchers have examined the effects of various medications that bind to specific receptor sites. Here, I provide a synopsis of the preclinical and clinical studies that have been done on these 5-HT function-altering medications in the treatment of alcohol dependence.

Serotonin reuptake inhibitors

For decades, it has been known that pharmacological manipulations that deplete the brain of 5-HT decrease the preference for ethanol [140,141]. Using preference paradigms, pharmacological agents that inhibit 5-HT reuptake from the synapse reduce the voluntary consumption of ethanol solutions using the preference paradigm [142-147]. Knockout mice at the 5-HT transporter do, however, exhibit a general decrease in ethanol preference and consumption [148]. Thus, there is ample preclinical support for the notion that selective serotonin reuptake inhibitors (SSRIs) suppress ethanol consumption in animals.

Although these preclinical studies have shown that SSRIs can reduce ethanol consumption, the selectivity of this effect on reinforcement as opposed to general consummatory behaviors has been questioned [149-151].

The inhibition of 5-HT reuptake function has complicated the effects on food intake and fluid consumption [152]. SSRIs do suppress food intake [153,154] and fluid consumption [152] and decrease palatability [155]. Yet, motivational factors exert some control on the expression of these behaviors [156]. For instance, SSRIs enhance satiety [150] but selectively reduce preference for certain macronutrients (i.e., sweet items and carbohydrates) [ 157-159] cf. [160,161] that increase the palatability and rewarding effects of food [162-164]. Hence, SSRIs might decrease ethanol consumption via the suppression of non-specific general consummatory behaviors and specific anti-reinforcing effects.

Studies conducted using operant techniques have also supported a role for SSRIs in the suppression of ethanol consumption. Haraguchi et al. [165] showed that same-day pretreatments with fluoxetine dose-dependently reduced ethanol responding. Nevertheless, whereas the chronic administration of SSRIs to C57BL/6J male mice produced an initial suppression of lever pressing for ethanol, there was a later rebound to baseline levels of responding for ethanol and ethanol consumption [166]. These results are somewhat similar to those of Murphy et al. [167], who observed that fluoxetine administered to rats in a single daily infusion produced a significant reduction in ethanol-reinforced responding that started on the first day of treatment and increased on subsequent days of the 7-day treatment regimen. Responding for ethanol returned to pretreatment levels following cessation of fluoxetine treatment. Food intake, while somewhat suppressed initially, appeared to return to baseline levels on subsequent treatment days. Again, these results demonstrate that the suppression of ethanol intake by SSRIs follows a pattern of initial suppression of consummatory behavior followed by a reduction in reinforcement; thus, when the SSRIs are discontinued, there is an extinction-like pattern of a return to the baseline behavior.

Despite the promise of these preclinical results, there is, at present, little support for the proposal that SSRIs are an efficacious treatment for a heterogeneous group of alcohol-dependent individuals. Initial studies of small sample size reported that SSRIs can produce short-term (1–4 weeks) decreases in alcohol consumption among problem drinkers [168-172]. Nevertheless, these studies were limited by at least three factors. First, most of the studies were conducted in men, thereby limiting the generalizability of the results to the general population [168-170]. Second, the adjunctive psychosocial treatment, which can decrease the apparent efficacy of the putative therapeutic medication because this too can have an important effect on drinking outcomes, was not standardized. Third, the treatment periods were short; thus, it was not possible to determine whether these initial effects, which could be due to non-specific factors, would be sustained. Indeed, the problem with studies of short duration that focus on a chronic relapsing disorder such as alcohol dependence was highlighted in a later study by Gorelick and Paredes [173], who found that there also was an effect for fluoxetine, compared with placebo, to decrease alcohol consumption by about 15% in the first 4 weeks of the trial but not over the entire length of the trial. Also, Naranjo et al. [174] did not demonstrate that citalopram (40 mg/day) was superior to placebo in a 12-week treatment trial. Further, neither Kabel and Petty [175] nor Kanzler et al. [176] in two separate 12-week studies found fluoxetine (60 mg/day) to be superior to placebo for the treatment of alcohol dependence.

There has been renewed understanding about how the administration of functionally different serotonergic agents can lead to different drinking outcomes among various subtypes of alcoholic (for a review, see Johnson [177]). Adapted from Cloninger’s classification scheme [178], two methods for subtyping alcoholics have been used in these pharmacotherapy studies. Basically, a particular type of alcoholic (i.e., Type A-like or late onset) characterized by a later age of onset of problem drinking (typically over the age of 25 years), a preponderance of psychosocial morbidity, and low familial loading can experience improved drinking outcomes after SSRI treatment.

Although early human laboratory studies showed that Type B-like or early-onset alcoholics, characterized by an early age of problem drinking onset (i.e., before the age of 25 years), high familial loading for alcohol dependence, and a range of impulsive or antisocial traits, might be centrally deficient in the major metabolite of 5-HT, 5-hydroxyindoleaceteic acid [179-181], the implications of this finding were, perhaps, oversimplified. At a cursory glance, it would appear that an SSRI, by increasing 5-HT turnover, would compensate for this dysfunction; thus, these Type B-like or early-onset alcoholics would then be expected to experience improved drinking outcomes following SSRI treatment. Remarkably, the literature has demonstrated quite the opposite. For instance, Kranzler et al. [182] observed that fluoxetine treatment appeared to worsen the clinical benefit of the adjunctive cognitive behavioral treatment and there was no difference from placebo. Actually, Type A-like or late-onset alcoholics, with presumably more normative 5-HT function, have been observed to experience improved drinking outcomes from sertraline both during active treatment [183] and at 6-month follow-up [184]. Also, Chick et al. [185] have shown that early-onset or Type B-like alcoholics were more likely to relapse than their late-onset or Type A-like counterparts following fluvoxamine treatment.

Obviously, the relationship between serotonergic dysfunction and Type B-like or early-onset alcoholism is not the simple result of a deficiency state. Indeed, Johnson [177] has hypothesized that an explanation for this effect might be allelic variation at the 5-HT transporter, which leads to the differential expression of 5-HT function. Of course, other bio-molecular explanations are possible, and further research is needed to elucidate this important area of research.

While outside the scope of this review, it has been proposed that SSRIs might be of therapeutic benefit in the treatment of alcohol-dependent individuals with suicidal tendencies and severe comorbid depression [186]. Nevertheless, a recent study did not find that sertraline treatment was more beneficial than placebo to depressed alcohol-dependent individuals irrespective of the severity of depression [187]; nor has it been shown that the reduction in dysphoria in depressed alcoholics is associated with concomitant decreases in alcohol consumption [188,189]. Hence, the only conclusion that can be drawn at present is that except for a subtype of depressed alcoholic with suicidal tendencies, there is not much evidence to recommend SSRIs over placebo for the treatment of depressed alcoholics.

In sum, despite strong animal data that would support the use of SSRIs as a promising treatment for alcohol dependence, there is no evidence that they are of therapeutic benefit to a heterogeneous group of alcohol-dependent individuals. Notably, however, there is growing confirmation that SSRIs can improve the drinking outcomes of Type A-like or late-onset alcoholics. Rather than being a cause for discouragement, this finding might a) open up the possibility of identifying important bio-genetic or pharmacological mechanisms that underlie the alcoholism disease and b) improve understanding about which type of alcohol-dependent individual can benefit the most from specific serotonergic treatment. Further, there is no current evidence that providing SSRIs to depressed alcoholics without severe depressive symptoms and suicidal tendencies is of therapeutic benefit. Hence, what is clear is that clinicians should be cautious in prescribing SSRIs to alcohol-dependent individuals for the treatment of minor depressive or affective symptoms. Not only is this strategy unlikely to be a therapeutic benefit over placebo, and perhaps appropriate psychosocial management, but drinking outcomes can actually be worsened, especially if the alcohol-dependent individual is Type A-like or of late onset.

Serotonin-1 (5-HT₁) partial receptor agonist

Preclinical studies have suggested that the 5-HT_1A partial agonist, buspirone, may be effective at reducing ethanol consumption. Buspirone decreased volitional alcohol consumption from 60% to 30% in macaque monkeys, but there was considerable inter-individual variation [190]. In Sprague-Dawley rats, buspirone significantly reduced ethanol intake in animals induced to drink by repeated brainstem injection of tetrahydropapaveroline. In a group of medium alcohol-preferring rats, buspirone (0.0025–0.63 mg/kg) reduced, while buspirone (>2.5 mg/kg) increased, alcohol consumption without affecting water consumption [191]. While buspirone is a partial 5-HT_1A agonist, the net effect of its repeated administration is to enhance 5-HT function via facilitation of the post-synaptic receptor, which is more sensitive than the autoreceptor, and down-regulation of autoreceptor function [192]. Nevertheless, this preclinical evidence would have been strengthened by operant studies examining the dose-response characteristics of buspirone as a function of ethanol concentration.

Buspirone has not been demonstrated to be an efficacious medication for the treatment of alcohol-dependent individuals without comorbidity. In a review of five published trials, buspirone was without a convincing effect in non-comorbid alcoholics; however, alcoholics with comorbid anxiety experienced some benefit [193,194]. Hence, buspirone’s anxiolytic effects might translate to those who also are dependent on alcohol.

In sum, there is no current evidence that would suggest a role for buspirone in the treatment of alcohol dependence without comorbid anxiety disorder.

Serotonin-2 (5-HT₂) receptor antagonist

Preclinical studies have suggested that the 5-HT₂ receptor antagonist, ritanserin, can reduce ethanol consumption in animals [195,196] cf. [197]. Also, the 5-HT₂ antagonists, amperozide [198-201] and FG5974 [202,203], significantly suppress ethanol intake without affecting water consumption. The exact mechanism by which 5-HT₂ receptor antagonists might reduce ethanol consumption is unknown. It has, however, been suggested that they might exert their effects by acutely substituting for alcohol’s pharmacobehavioral effects by facilitating burst firing in CMDA neurons [204], or by the suppression of dopamine neurotransmission following their chronic administration.

In the clinical setting, ritanserin is not an efficacious treatment for alcohol dependence. In a rigorously conducted, 12-week, multi-center clinical trial (N = 423) of ritanserin (2.5 or 5 mg/day) vs. placebo as an adjunct to weekly cognitive behavioral therapy, none of the ritanserin doses were superior to placebo [205]. In a later study using similar methodology, ritanserin (2.5, 5.0, or 10.0 mg/day) was not superior to placebo at improving drinking outcomes [206]. Although higher doses of ritanserin might be of therapeutic benefit, testing these doses is precluded by ritanserin’s potential to cause dose-dependent prolongation of the QTc interval on the electrocardiogram, thereby increasing the potential for life-threatening cardiac arrhythmias.

In sum, there is no clinical evidence that would support the use of ritanserin as a treatment for alcohol dependence.

Serotonin-3 (5-HT₃) receptor antagonists

Preclinical studies provide strong support for the role of the 5-HT₃ receptor in mediating alcohol’s important neurochemical effects, and for 5-HT₃ receptor antagonists to be promising treatment for alcohol dependence.

In neurophysiological experiments, ethanol potentiates 5-HT₃ receptor-mediated ion currents in NCB-20 neuroblastoma cells [207,208] and in human embryonic kidney 293 cells transfected with 5-HT₃RA cDNA [209]. 5-HT₃ receptor antagonists block these effects [210]. Thus, the 5-HT₃ receptor is a site of action for ethanol in the brain [211,212].

Pharmacobehavioral studies show that many of alcohol’s reinforcing effects are mediated by 5-HT₃ and dopamine interactions in the cortico-mesolimbic system [9,213-216].

5-HT₃ receptor antagonists have three principal effects that demonstrate their ability to modulate ethanol consumption and related behaviors. First, 5-HT₃ receptor antagonists suppress hyperlocomotion in the rat induced by dopamine or ethanol injection into the nucleus accumbens [217]. Second, 5-HT₃ receptor antagonists inhibit DiMe-C7 (a neurokinin)-induced hyperlocomotion, which also is reduced by the dopamine antagonist, fluphenazine [218,219]. Third, 5-HT₃ receptor antagonists reduce ethanol consumption in several animal models and across different species [191,213,220-228] cf. [229].

Human laboratory studies have generally supported a role for the 5-HT₃ antagonist ondansetron in reducing preference and craving for alcohol. In two distinct experiments, Johnson and Cowen [214] and Johnson et al. [224] showed that ondansetron pretreatment attenuated low-dose alcohol-induced positive subjective effects (including the desire to drink). Swift et al. [230], using much higher alcohol and ondansetron doses, also discovered that ondansetron compared with placebo pretreatment reduced alcohol preference; however, a mixture of both stimulant and sedative interactions between ondansetron and alcohol also was observed. Whereas Doty et al. [231] did not find an effect of ondansetron on alcohol-induced mood, their experimental model of using a group rather than individual experimental setting could have decreased the sensitivity of their assessments.

Three clinical studies have provided evidence that ondansetron is a promising treatment for alcohol-dependent individuals, particularly those with an early-onset or Type B-like subtype.

First, in a 6-week, double-blind, placebo-controlled study of 71 non-severely alcohol-dependent males, Sellers et al. [232] observed that the 0.5-mg dose but not the 4-mg dose of ondansetron was associated with a non-significant trend (p = 0.06) toward a reduction in alcohol consumption. Post-hoc analysis that eliminated 11 subjects who consumed less than 10 drinks/drinking day rendered the difference in drinking outcomes between the ondansetron 0.5 mg and placebo groups to be significant statistically (p = 0.001). Despite the limitations of this initial trial, which included a relatively short treatment period, the inclusion of just males, and the small number of subjects, the results of this study provided general support for ondansetron’s promise in treating alcohol dependence. Also, these results show that ondansetron may exhibit a non-linear dose-response effect in the treatment of alcohol dependence.

Second, in a large-scale (N = 321), 12-week, randomized, double-blind clinical trial in which alcohol-dependent individuals received weekly cognitive behavioral therapy, Johnson et al. [233] showed that ondansetron (1, 4, and 16 μg/kg b.i.d.) was superior to placebo at improving drinking outcomes of those of the early onset or Type B-like subtype but not the late onset or Type A-like subtype. The self-reported decreases in alcohol consumption were corroborated by the concomitant reduction in carbohydrate-deficient transferrin level — a biomarker of transient alcohol consumption.

Third, Kranzler et al. [234] provided replication of the results by Johnson et al. [233] by showing that early-onset (Type B-like) alcoholics had a significantly greater improvement in drinking outcomes compared with their late-onset (Type A-like) counterparts following 8 weeks of ondansetron (4 μg/kg b.i.d.) treatment.

Intriguingly, these results demonstrate a differential effect of ondansetron treatment by subtype of alcohol-dependent individual. Indeed, the contrast is striking when compared with the effects of SSRIs on different subtypes of alcohol-dependent individuals as described above. Basically, early-onset or Type B-like alcoholics with apparent serotonergic deficiency respond best to a medication that blocks the 5-HT₃ receptor, whereas late-onset or Type A-like alcoholics with apparently normal serotonergic function derive the most benefit from a medication that can increase 5-HT turnover and function. As mentioned earlier, Johnson [177] has proposed a bio-molecular explanation for these effects; however, other plausible possibilities exist. Although elaboration of this concept is beyond the scope of this review, the key feature is that polymorphic variation at the 5-HT transporter allele is affected differentially by the history of drinking behavior and, perhaps as a consequence, the expression of 5-HT turnover in these different polymorphic types modulates present drinking behavior. Further studies are needed to test this and other proposals that can explain the differential effect of various serotonergic agents among alcohol-dependent individuals of different subtype. Obviously, a molecular genetic explanation for this effect, if proven, may enable a pharmacogenetic approach to treatment whereby the appropriate medication can be provided to the particular subtype of alcohol-dependent individual who would benefit the most from such treatment.

In sum, preclinical data support an important role for 5-HT₃ receptors in mediating alcohol’s important reinforcing effects associated with its abuse liability. Ondansetron is a promising medication for the treatment of early-onset or Type B-like alcohol dependence. Further studies are needed to determine whether treatment with various serotonergic agents can best be applied using a pharmacogenetic approach.

DOPAMINE

Dopamine receptor antagonists

CMDA neurons have been implicated as the principal pathway by which alcohol and most other abused drugs express their reinforcing effects associated with abuse liability [9,215,216]. Yet it has been difficult to show evidence that direct dopamine receptor antagonists have a role in the treatment of alcohol dependence. Presumably, direct opposition of dopamine pathways is associated with neuroadaptive changes that tend to reverse the initial effects of the blockade [128]. No traditional dopamine receptor blocker has been demonstrated to be an efficacious treatment for alcohol dependence. With the advent of atypical neuroleptics, there has been renewed interest in testing these medications as potential treatment for alcohol dependence. Indeed, medications such as aripiprazole and quetiapine are currently in clinical testing, and the results are awaited eagerly. Other medications that are selective for dopamine-3 receptor antagonism also are under development.

Dopamine receptor agonists

At low doses, dopamine-2/dopamine-3 agonists such as bromocriptine and 7-OH DPAT can reduce ethanol consumption in animals [235-237]. Although this might appear paradoxical to the dopamine theory of reinforcement for most abused drugs, it is possible that low-dose dopamine agonists preferentially augment autoreceptor function, thereby decreasing dopamine turnover.

Although an earlier report proposed that bromocriptine can decrease alcohol craving, subsequent studies have found no effect on alcohol drinking or related behaviors [238-240]. Nevertheless, perhaps due to the high addictive potential of dopamine agonists, this research approach has largely been abandoned in the clinical setting. Currently, dopamine receptor agonists do not hold promise as a treatment for alcohol dependence.

GABA-B RECEPTOR AGONIST — BACLOFEN

Animal studies have demonstrated that the GABA_B receptor agonist, baclofen [beta-(4-chlorophenyl)-GABA], causes decreases in voluntary ethanol intake [241], the ethanol-deprivation effect [242], and morphine-induced stimulation of ethanol consumption [243].

Clinical trials have bolstered the findings of animal studies that suggest a role for baclofen in treating alcohol dependence. In an open-label, 4-week study, 9 alcohol-dependent men were given baclofen (up to 30 mg/day). Seven of the 9 subjects achieved abstinence, while the other 2 participants improved their self-reported drinking outcomes during the study period, according to self-reports corroborated by family members. Several objective biological markers of alcohol intake also showed significant reductions between the beginning and end of the study. Furthermore, craving, as measured by median Alcohol Craving Scale scores, decreased in the first study week and remained stable thereafter [244].

In a 4-week, randomized, placebo-controlled, double-blind clinical trial with 39 alcohol-dependent patients, 14 of 20 (70%) patients treated with baclofen (up to 30 mg/day) achieved abstinence, compared with 4 of 19 (21.1%) in the placebo group (p < 0.005). Baclofen treatment improved significantly drinking outcomes, state anxiety scores, and craving measures. Baclofen generally was well tolerated and had no apparent abuse liability. Adverse events, none of which were serious, consisted of nausea, vertigo, transient sleepiness, and abdominal pain [245].

These findings, which indicate that baclofen is safe and efficacious, with no addictive properties, suggest a potential role for baclofen in treating alcohol-dependent individuals. Additional studies of larger sample size and longer duration would help to establish the efficacy of baclofen in the treatment of alcohol-dependent individuals.

DISULFIRAM

Disulfiram is an FDA-approved medication that has been used for treating alcoholism since the 1940s and is perhaps still the most widely used such medication in the U.S. today. Its principal mode of action is as an aversive agent. Disulfiram inhibits aldehyde dehydrogenase and prevents the metabolism of alcohol’s primary metabolite, acetaldehyde. In turn, the accumulation of acetaldehyde in the blood causes unpleasant effects to occur if alcohol is ingested; these include sweating, headache, dyspnea, lowered blood pressure, flushing, sympathetic overactivity, palpitations, nausea, and vomiting. The association of these symptoms with drinking discourages further consumption of alcohol [246]. Serious side effects also have been reported, including hepatitis, hepatotoxicity, depression, and psychotic reactions [247,248]. Disulfiram also has been shown to reduce norepinephrine synthesis by inhibiting dopamine beta-hydroxylase [249], a mode of action that has been proposed to support early reports of its potential efficacy as a treatment for cocaine dependence. While a review of disulfiram’s potential effects on cocaine taking are outside the scope of this review, the reader is referred to recent studies by Petrakis et al. [249], Carroll et al. [250], and Baker et al. [251].

A 52-week, multi-site, randomized, controlled trial with 605 alcohol-dependent men found that disulfiram might help prevent relapse in compliant patients yet be ineffective at promoting continuous abstinence or a delay in the resumption of drinking [252].

Disulfiram has no significant effect on craving for alcohol. Hence, patients must be highly motivated to maintain disulfiram treatment, whereas those who wish to drink can simply stop taking the medication. The efficacy of disulfiram generally is limited to those who are highly compliant or who receive their medication under supervision — i.e., the type of alcohol-dependent individuals who might be likely to abstain on their own, without adjunctive pharmacotherapy. Including a supportive spouse or partner in a disulfiram treatment plan helps to improve outcome [246,253].

POTENTIAL TREATMENTS ON THE HORIZON

Cannabinoid-1 (CB₁) receptor antagonists

Endocannabinoid receptors are found ubiquitously in the central nervous system, particularly in the cortex, hippocampus, basal ganglia, and cerebellum. Endogenous cannabinoids include anandamide and 2-arachidonylglycerol, which are metabolized by fatty acid amide hydrolase [254].

In C57BL/6J mice, cannabinoid-1 (CB₁) receptor blockade reduced ethanol consumption to the amounts ingested by CB₁ receptor null mutant mice [255]. Endocannabinoids may be involved in the neurochemical expression of susceptibility to the effects of ethanol. For instance, ethanol exposure can increase levels of brain 2-arachidonylglycerol and anandamide and down-regulate CB₁ receptors [256,257]. In pharmacobehavioral studies, CB₁ receptor antagonists suppress ethanol intake in rats with a chronic history of alcohol administration [258,259], reduce ethanol drinking in alcohol-preferring sP rats [260,261], and decrease operant responding and cue-induced reinstatement of ethanol consumption [262,263]. It is plausible, however, that an important method by which CB₁ receptors influence ethanol taking is via their extensive connections to modulate other neuronal systems including monoamine pathways and their metabolism [264-266]. Figure 4 shows the interactions between CB₁ and other neuronal systems [267].

Fig. 4.

Neuronal pathways involved with the reinforcing effects of alcohol and other abused drugs. Cholinergic inputs that arise from the caudal part of the pedunculopontine tegmental nucleus (PPTg) and laterodorsal tegmental nucleus (LDTg) can stimulate ventral tegmental area (VTA) dopamine neurons. The VTA dopamine neuron projection to the nucleus accumbens (nACC) and cortex, the critical substrate for the reinforcing effects of abused drugs (including alcohol), is modulated by a variety of inhibitory [gamma-aminobutyric acid (GABA) and opioid] and excitatory [nicotinic (NIC-R), glutamate (GLU), and cannabinoid-1 receptor (CB1-R)] inputs. The GLU pathways include those that express alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors. Serotonin-3 receptors (5-HT3-R) also modulate dopamine release in the nACC. Adapted and embellished by Bankole A. Johnson, DSc, MD, PhD, from an original drawing by Dennis Twombly, PhD, at the National Institute on Alcohol Abuse and Alcoholism. Reprinted from the figure in Johnson [267]. Copyright © 2006, American Medical Association. All rights reserved.

In Europe, initial human studies of the effects of cannabinoid receptor blockade on the drinking outcomes of alcohol-dependent individuals have been completed, and the results are awaited eagerly. Nevertheless, the recent finding that the CB₁ receptor antagonist (rimonabant) can increase mood disturbance and suicidality in smokers, which precluded the FDA from granting approval for that indication, might also impact the development of similar compounds for the treatment of alcohol dependence.

Other neurochemicals and small molecules

Presently, there are a host of other neurochemicals with potential benefit in treating alcohol dependence. At this stage, testing remains within the animal literature and other preclinical models, and it would, therefore, be beyond the scope of this review to discuss them in detail. These compounds include antagonists at mGluR5, mGluR2/3 agonists, stress-related neuropeptides such as corticotropin releasing factor antagonists and modulators of neuropeptide Y, and nociceptin (for a review, see Heilig and Egli [254]).

COMBINATION TREATMENTS

Combination treatments offer the promise of augmenting the effects of single medications by engaging multiple neuronal networks associated with the expression of alcohol’s reinforcing effects associated with its abuse liability. While this idea is alluring, medication combinations do create the potential for reduced compliance (due to the need to take additional tablets), heightened or new treatment emergent adverse events, or even inefficacy if the medications counteract one another.

Perhaps the best studied medication combination so far has been that of naltrexone and acamprosate. This combination has been proposed to be of potential added therapeutic benefit for three reasons. First, naltrexone, by its action on endogenous opioids, modulates CMDA activity, thereby reducing the reinforcing effects of alcohol [215,268]. Acamprosate modulates alcohol withdrawal-induced increases in extracellular glutamate in the cortico-mesolimbic system [91,269]. Thus, the combined effect of both naltrexone and acamprosate may be to modulate both the neurochemical effects responsible for triggering drinking and those associated with conditioned responses to drink even after a prolonged period of abstinence. Second, while naltrexone decreases positive craving for alcohol [55], acamprosate attenuates negative or conditioned craving post-drinking cessation [103]. It is, therefore, tempting to speculate that the combination of naltrexone and acamprosate would make it easier both to abstain and to prevent a “slip” from turning into a relapse. Third, acamprosate can increase blood levels of naltrexone, thereby augmenting its neurochemical effects [104,105].

In a European study, Kiefer et al. [270] showed that the combination of naltrexone and acamprosate was clinically additive at improving the drinking outcomes of alcohol-dependent individuals, but only the effect of the combination vs. acamprosate achieved statistical significance. Nevertheless, the recently completed COMBINE project in the U.S. did not find any therapeutic advantage to combining the two medications [62]. Hence, at present, it is not possible to advise practitioners to combine naltrexone and acamprosate. Further research may, however, provide a definitive answer as to the utility of the combination.

Mechanistically, there are many other medication combinations that are possible, some of which are being pursued. It is, however, noteworthy that preliminary clinical evidence suggests that the combination of ondansetron and naltrexone may result in added or synergistic therapeutic effects on alcohol drinking [271,272]. The results of definitive confirmatory trials are, however, awaited.

In sum, medication combinations may afford the opportunity to augment the treatment effects of single medications for the treatment of alcohol dependence. Such studies should, however, be conducted where there is a compelling pharmacological rationale for combining the medicines. This is because there also is the potential for reduced compliance, heightened or new treatment emergent adverse events, and inefficacy. Further, there are important issues that must be determined for all medication combinations, such as optimal dosing, sequencing of the medications, duration of treatment, and the increased complexity of managing such protocols.

CONCLUSIONS

Recently, there has been renewed interest in developing efficacious medicines for the treatment of alcohol dependence. Naltrexone and its depot formulations have demonstrated utility, but their therapeutic effect size is small. Despite FDA approval of acamprosate based upon the positive results of European studies, there has, as yet, not been a clear demonstration of its efficacy in U.S. studies. Even in the European studies, the therapeutic effect size of acamprosate is small. These discrepant findings might be the result of different populations of alcohol-dependent individuals, selection criteria, chronicity of the alcoholism disease, bio-molecular differences, different methodologies between U.S. and European studies, or sampling error due to the small effect size. For both naltrexone and acamprosate, research is ongoing to determine what type of alcohol-dependent individual benefits the most from using either medication. There also is the possibility that a pharmacogenetic approach may make it possible to improve the therapeutic outcome for those who receive naltrexone. At present, the combination of naltrexone and acamprosate cannot be recommended to be of therapeutic benefit, but this conclusion might change with future research. Topiramate is a promising medication for the treatment of alcohol dependence. Based on two studies, its therapeutic effect size appears to be in the medium range. Future research is needed to extend these results to other subpopulations of alcohol-dependent individuals. Serotonergic medications need to be administered with care to ensure that they are provided to the subtype of alcohol-dependent individual who will benefit the most from such treatment. While SSRIs benefit late-onset or Type A-like alcohol-dependent individuals, the 5-HT₃ receptor antagonist, ondansetron, has efficacy in treating early-onset or Type B-like alcohol-dependent individuals. Molecular genetic studies are ongoing to understand the underpinnings of this differential response among various subtypes of alcoholic to different serotonergic agents. Although disulfiram is also FDA approved for the treatment of alcohol dependence, it is perhaps best utilized under supervised conditions. Given the explosion in neuroscientific ideas, the future holds promise for many new and efficacious medicines in the treatment of alcohol dependence.