Table 1.
Pharmacotherapies approved and under development for the treatment of AUD
| Agent | Mechanism of action | Approval status | Preclinical results | Clinical results | Target outcome |
|---|---|---|---|---|---|
| Disulfiram | Aldehyde dehydrogenase inhibitor; dopamine beta-hydroxylase inhibitor | FDA- and EMA-approved for AUD | Mixed results: prevents heavy but not moderate drinking [297]; chronic alcohol induces disulfiram tolerance [298] | Mixed results; drinking outcomes improved with supervised administration [29–33] | Achieve and maintain abstinence |
| Acamprosate | Modulates glutamatergic activity | FDA- and EMA-approved for AUD | Reduced ethanol intake, withdrawal symptoms, place preference [299–302] | Mixed results; Reduced risk of relapse, increased cumulative abstinence duration [36, 44, 49]. Negative studies show no benefit over placebo [37–42] | Achieve and maintain abstinence |
| Naltrexone | Opioid receptor antagonist | FDA- and EMA-approved for AUD | Reduced binge drinking, ethanol preference, motor impairment and sedation [303–305] | Reduced risk of relapse, binge drinking, and craving [52–59]; modest effect sizes [62–64] | Achieve and maintain abstinence and reduce drinking |
| Nalmefene | Opioid receptor antagonist and partial agonist | EMA-approved for AUD; FDA-approved for opioid overdose | Reduced alcohol seeking, relapse and binge-like drinking, neuroinflammation [306–308] | Reduced binge drinking and total alcohol consumption [71–73, 75] | Reduce drinking |
| Baclofen | GABAB agonist | Approved for AUD in France | Reduced ethanol self-administration and motivational properties [309–312] | Mixed results; increased rates of abstinence, time to first relapse, possibly reduced heavy-drinking days [84–86, 91, 92] | Achieve and maintain abstinence |
| Sodium oxybate | Modulates GABA activity | Approved for AUD in Italy and Austria | Reduced ethanol self-administration, withdrawal symptoms, and relapse-like drinking [247, 313] | Effective treatment of alcohol withdrawal syndrome, increased abstinence [99, 100] | Reduce withdrawal symptoms and achieve abstinence |
| Topiramate | Inhibits glutamatergic activity and increases GABA activity | Repurposed | Reduced ethanol intake in rodent models [113–115] | Reduced drinks per day and percent heavy-drinking days and increased percent days abstinent [112, 116–119] | Achieve abstinence and reduce drinking |
| Gabapentin | Modulates GABA activity | Repurposed | Mixed results: reduced or increased ethanol intake [123–125] | Reduced percent heavy-drinking days, alcohol consumption, and abstinence rates and increased time to relapse, with outcomes improved among those with alcohol withdrawal symptoms [126–135] | Achieve abstinence and reduce drinking |
| Varenicline | Nicotinic acetylcholine receptor agonist | Repurposed | Reduced ethanol seeking, intake, and binge-like consumption [138–140] | Reduced percent heavy-drinking days and drinks per day with outcomes improved for those who smoke cigarettes [142–144, 146–149] | Reduce drinking |
| Aripiprazole | Dopamine receptor partial agonist and 5-HT2A receptor antagonist | Repurposed | Reduce ethanol-induced place preference and ethanol consumption [151–153] | Mixed results with outcomes improved for more impulsive individuals; reduced heavy-drinking days and increased days abstinent at rates comparable to naltrexone [154–160] | Reduce drinking |
| Ondansetron | 5-HT3 receptor antagonist | Repurposed | Blocked sensitization to locomotor stimulant effects, reduced voluntary ethanol intake [167–169] | Reduced drinks per day and increased days abstinent in patients with early-onset AUD [170–174] | Achieve abstinence and reduce drinking |
| Mifepristone | Glucocorticoid receptor antagonist | Repurposed |
Reduced ethanol-seeking in rodents [177, 178] Mixed results in primates; reduced chronic voluntary alcohol use but did not prevent relapse [179, 180] |
Reduced alcohol craving and consumption [178, 181, 182] | Reduce drinking |
| Ibudilast | Selective PDE inhibitor and MIF inhibitor | Repurposed | Reduced ethanol intake [188–191] | Reduced craving, odds of heavy drinking, and neural cue-reactivity [192, 193] | Reduce drinking |
| Prazosin and Doxazosin | Adrenergic alpha-1 antagonists | Repurposed | Reduced relapse, ethanol intake, and stress-induced ethanol seeking [201–205] | Mixed results; reduced craving and alcohol consumption. Outcomes improved among those with alcohol withdrawal symptoms [206–211] | Reduce drinking |
| N-Acetylcysteine | Modulates synaptic glutamatergic activity | Repurposed | Reduced ethanol intake and relapse [215–220] | Increased abstinence rates and reduced drinks per week among those with cannabis use disorder [222, 223] | Reduce drinking |
| Suvorexant | Dual orexin antagonist | Repurposed | Reduced ethanol consumption and relapse [229–238] | – | Unknown |
| ABT-436 | Highly selective vasopressin type 1B receptor antagonist | Novel agent | Attenuated ethanol reinstatement and reduced ethanol intake [241, 242] | Increased days abstinent but did not reduce heavy drinking or craving [244] | Achieve and maintain abstinence |
| GET73 | Gamma-hydroxy-butyrate analogue; negative allosteric modulator at mGluR5 | Novel agent | Reduced ethanol intake and suppressed relapse [246] | – | Unknown |
| ASP8062 | Positive allosteric modulator of GABAB receptor | Novel agent | Reduced ethanol self-administration [259] | – | Unknown |
| PF-5190457 | Ghrelin receptor inverse agonist | Novel agent | Reduced ethanol intake and preference [266–270] | Reduced alcohol craving and cue-reactivity [272] | Unknown |
| Cannabidiol | Diverse pharmacological effects | Novel agent | Reduced ethanol administration and relapse-like behavior [279] | – | Unknown |
5-HT3 serotonin receptor 3, 5-HT2A serotonin receptor 2A, AUD alcohol use disorder, EMA European Medicines Agency, FDA United States Food and Drug Administration, GABA gamma-aminobutyric acid, mGluR5 metabotropic glutamate receptor 5, MIF macrophage migration inhibitory factor, PDE phosphodiesterase