Mifepristone , a glucocorticoid receptor antagonist, works on the stress system by regulating the amygdala. Preclinically, both systemic and central amygdala injections of mifepristone were shown to suppress yohimbine stress-induced reinstatement of alcohol seeking, indicating that the central amygdala plays an important role in mifepristone’s effects on ethanol-seeking. Recent preclinical research in primates has shown mixed results, such that mifepristone was shown to decrease chronic voluntary alcohol consumption in rhesus macaques at doses of 30 and 56 mg/kg per day, but had no effect on alcohol-seeking or self-administration in baboons at slightly lower doses of 10–30 mg/kg per day. Of note, in the former study, cessation of mifepristone treatment resulted in a rapid return to baseline intake levels, and mifepristone was not effective in preventing a relapse during early abstinence. In a human laboratory study with 56 alcohol-dependent participants, mifepristone was effective in reducing alcohol craving and consumption relative to placebo, improved liver-function markers, and was overall well tolerated. A two-week Phase 4 RCT examining the effects of mifepristone on cognition in AUD was recently conducted, but recruitment challenges rendered the results inconclusive. Of note,vertical grow rack system in this trial, participants who received mifepristone had higher Beck Depression Inventory scores compared to placebo at 4 weeks post-randomization despite similar scores at baseline between the two groups, indicating a greater severity of depression symptoms caused by the medication. Additional clinical research on mifepristone as a treatment for AUD and its potential side effects is warranted.Ibudilast is an inhibitor of phosphodiesterases -3, -4, -10, and -11 and macrophage migration inhibitory factor.

Ibudilast has been shown to dose-dependently suppress pro-infammatory cytokines, such as interleukins IL-1β, IL-6, and tumor necrosis factor alpha , and to increase the anti-infammatory cytokine IL-10 and neurotrophic factors.As increases in infammation are seen in AUD, the effects of ibudilast in treating AUD are thought to be driven by its anti-infammatory and proneurotrophic qualities. Preclinically, ibudilast was demonstrated to reduce alcohol intake in two rat models, and decreased drinking selectively in alcohol-dependent mice in comparison to nondependent mice. These preclinical findings align with prior rodent studies in which pharmacological inhibition of PDE also reduced alcohol intake. In a 7-day human laboratory crossover trial , ibudilast was well tolerated and decreased tonic craving in comparison to placebo. Additionally, ibudilast improved mood during exposure to alcohol and stress cues, and reduced the mood-altering and stimulant effects of alcohol among participants with more severe depressive symptoms. Another recent 2-week RCT enrolling 52 participants found that ibudilast also significantly decreased the odds of heavy drinking during the trial by 45% compared to placebo and attenuated neural response to alcohol cues in the ventral striatum. Ibudilast appears to be well tolerated, with common adverse side effects including gastrointestinal symptoms , headaches, and depression. In the aforementioned 2-week RCT, no significant differences in side effects were seen between groups. In summary, early findings from clinical studies of ibudilast for AUD treatment appear promising and warrant further clinical investigation.Prazosin and doxazosin are alpha-1 adrenergic receptor antagonists with similar chemical structures that can readily cross the blood-brain barrier and block noradrenergic excitation of the mesolimbic dopaminergic system . Both medications are used for the treatment of hypertension and benign prostatic hyperplasia. While these medications show good safety and tolerability, doxazosin appears to have a better clinical profile, such as improved absorption profile and a longer half-life, leading to less frequent dosing.

Adrenergic receptors regulate sympathetic nervous system activity through activation of the neurotransmitter norepinephrine. Stress physiology is disrupted with chronic alcohol use, particularly during early alcohol abstinence. In early abstinence, individuals with AUD experience more emotional dysregulation, stress, and alcohol cravings, all of which can increase the risk of relapse. Thus, alpha-1 blockers like prazosin and doxazosin may help to normalize these stress system changes seen in AUD. Preclinical work found that prazosin reduced ethanolrelated operant responding in acute withdrawal for dependent, but not non-dependent rodents. In addition, prazosin treatment prevented yohimbine stress-induced reinstatement of ethanol seeking and attenuated ethanol intake during relapse in alcohol-preferring rats. Doxazosin decreased voluntary alcohol intake in alcohol-preferring rats in a dose-dependent manner, and this effect was likely not due to general motor impairment. Further, doxazosin significantly reduced voluntary ethanol intake in a rodent model of AUD and stress exposure. In humans, an early 6-week pilot study with 24 randomized participants with AUD revealed that prazosin treatment was associated with fewer drinking days per week and fewer drinks per week than placebo. More recently, 92 participants with AUD completed a 12-week double-blind study with prazosin and medication management. Results from intent-to-treat analyses showed that prazosin participants had greater reductions in heavy drinking and rates of drinking over time, although these effects were modest. A 10-week RCT comprising 41 individuals with AUD showed no significant effect of doxazosin over placebo on quantity of alcohol consumption. However, further examination of clinical moderators revealed that doxazosin significantly reduced drinks per week and heavy-drinking days among individuals with higher family history of AUD and higher standing diastolic blood pressure. Similarly, moderator analyses from a 12-week RCT of prazosin found that one’s degree of alcohol withdrawal symptoms predicted clinical response, such that participants with high levels of withdrawal symptoms benefited the most from treatment. A small meta-analysis of 6 studies with a total of 319 participants tested the effectiveness of drugs acting on adrenergic receptors for AUD and found a significant treatment effect of prazosin and doxazosin on alcohol consumption but not abstinence.

In summary, prazosin and doxazosin show some early promise as a treatment for AUD and may be particularly beneficial as a harmreduction approach and for individuals with significant alcohol withdrawal symptoms or family history of AUD as well as comorbid post-traumatic stress disorder .Alcohol use has been shown to alter the glutamate system. Chronic and binge drinking inhibit glutamate levels and transmission through blockade of NMDA receptors, subsequently leading to elevated glutamate levels during alcohol withdrawal . N-Acetylcysteine is a cysteine prodrug that works to restore glutamatergic tone in reward circuitry by improving the expression and function of the cysteine-glutamate exchanger and normalizing glial glutamate transporters. Preclinically, NAC has been shown to reduce withdrawal effects , block the development of behavioral sensitization to alcohol, and attenuate biological adaptations induced by alcohol cessation. Additionally, NAC reduced ethanol-seeking and self-administration in rodents. NAC and aspirin co-administration also reduced ethanol intake and relapse binge drinking in ethanol-preferring rats. In a recent meta-analysis of seven RCTs with a total of 245 participants, NAC compared to placebo was shown to reduce craving symptoms across a number of substance use disorders. A secondary analysis of a 12-week, multisite RCT of NAC to treat cannabis use disorder in 277 participants found that NAC increased odds of between-visit abstinence, and reduced alcohol consumption by 30%. However,clone rack a recent 5-day human laboratory study found that NAC did not attenuate alcohol self-administration. Additional clinical trials will also examine the effectiveness of NAC in adolescent and adult samples of AUD . These trials include samples with comorbid psychopathology and will use neuroimaging methods to examine the neural circuitry underlying NAC’s modulation of relevant metabolites and neural reactivity to alcohol cues. Orally-administered NAC appears to be well tolerated, with the most common adverse effects being nausea and diarrhea. Of note, NAC is currently being tested in adolescent AUD, a unique prospect as no other AUD pharmacotherapies are yet approved for adolescents. In summary, NAC represents a promising potential treatment for AUD and merits further exploration. The orexin/hypocretin system is well known for its role in sleep-wake regulation but has more recently been implicated in AUD. Orexins are neuropeptides that are densely localized in the lateral hypothalamus. Orexins A and B bind to the G-protein coupled orexin-1 and orexin-2 receptors. Orexin A has equal affinity for both receptors, whereas orexin B has selectivity for orexin-2 receptors.

The dense orexin projections from the lateral hypothalamus to the ventral tegmental area provide neurobiological support that orexins may influence responses to rewarding stimuli, including alcohol. Animal models demonstrate that orexin-1 receptor antagonists reduce alcohol drinking in alcohol-dependent mice and alcohol-preferring rats. Orexin-2 antagonists also reduce alcohol drinking and reinstatement/relapse in mice and rats. Similarly, dual orexin antagonists reduce alcohol consumption in alcohol-preferring rats. Given the effectiveness of orexin antagonists in reducing alcohol drinking at the preclinical level of analysis, suvorexant has garnered interest as a drug that can be repurposed to treat AUD. While no animal or human laboratory study has directly examined the efficacy of suvorexant on alcohol-related behaviors, two ongoing Phase 2 RCTs will assess suvorexant’s potential as a treatment for AUD and comorbid AUD + insomnia . The sedative effects of suvorexant are of notable concern, particularly if individuals engage in alcohol drinking during treatment. Thus, the level of patient monitoring throughout the treatment phase and finding the optimal time of dosing to negate the additive sedative effects are important factors to consider to fully evaluate its therapeutic potential.The following sections discuss novel agents that have not yet been approved for any use. These medications are early in development and the majority do not yet have available clinical findings on their application toward the treatment of AUD.ABT‐436 is an orally active, highly selective vasopressin type 1B receptor antagonist. V1B antagonists attenuate basal hypothalamic-pituitary-adrenal axis activity and have shown favorable effects in rat models of alcohol dependence, including attenuating reinstatement of alcohol self-administration, and diminishing alcohol intake by alcohol-preferring and alcohol-dependent rats. ABT-436 has been shown to attenuate basal HPA axis activity in humans. A 12-week RCT enrolling 150 participants found ABT-436 to be associated with an increased percentage of days of abstinence compared to placebo, as well as significantly reduced cigarette use. However, no differences were found on heavy-drinking days or alcohol craving. A subgroup analysis also showed that ABT-436 appeared to have greater efficacy among participants with high baseline stress levels. This study was the first Phase 2 clinical trial that tested a V1B receptor antagonist for AUD. The finding that ABT-436 reduced both alcohol drinking and smoking indicate a potential use for V1B antagonists to treat co-use of alcohol and nicotine. ABT-436 is generally well tolerated in humans, with the most common side effect being diarrhea. Furthermore, results indicate that patients with high levels of stress may specifically benefit from medications targeting the vasopressin receptor.N-[ benzyl] 4-methoxybutyramide is a GHB analogue that has shown promising in vitro and in vivo preclinical results as a potential agent for the treatment of AUD. The addition of GET73 to cultures of rat hippocampal neurons rescued negative ethanolinduced effects, reductions in cell viability, and increases in reactive oxygen species production, providing evidence for a neuroprotective role of GET73 as an AUD treatment. In vivo, GET73 treatment at low, non-sedative doses reduced alcohol intake and suppressed relapse in alcohol-preferring rats, as well as exerting anxiolytic effects. These effects are similar to those seen with GHB administration; however, GET73 was shown not to bind to either high- or low-affinity GHB binding sites in rat cortical membranes. Recent studies indicate that GET73 may act as a negative allosteric modulator at the metabotropic glutamate sub-type 5 receptor; however, the complete mechanism of action of GET73 remains unclear. A translational study examining GET73-alcohol interactions found that neither 30 nor 100 mg/kg GET73 administered in rats potentiated alcohol-induced intoxication. Additionally, GET73 administered both in the presence and absence of alcohol was well tolerated in two samples of 14 and 11 participants, with no severe adverse events and no difference in adverse events. A Phase I clinical trial in two samples of 48 and 32 participants found that both single doses and repeated ascending doses of GET-73 were safe and well tolerated. Another inpatient human laboratory study conducted by the same group confirmed the safety and tolerability of GET73 such that no serious or severe adverse events occurred when GET73 was co-administered with alcohol. Co-administration also did not affect the pharmacokinetics of either GET73 or alcohol. However, GET73 also had no effect on alcohol cue-induced craving or self-administration, warranting additional research. A clinical trial of the effects of GET73 on magnetic resonance spectroscopy measures of glutamate and GABA levels in individuals with AUD was recently completed ; however, the results have not yet been posted, and another trial, which includes a free-drinking bar lab component, is ongoing .In comparison to the drawbacks presented by GABAB agonists like baclofen and SMO, positive allosteric modulators at this receptor present a potential alternative.