Its therapeutic use remains controversial due to its potential for craving and abuse, and further study on co-administration with other pharmacotherapies appears promising.Despite that the anti-convulsant medication topiramate has not been approved by the FDA or EMA for AUD treatment, the US Department of Veterans Affairs recommends topiramate as a treatment for AUD, and it has been suggested by the American Psychiatric Association for the pharmacological treatment of patients with AUD. Currently, the specific mechanisms of action of topiramate remain under investigation. However, the drug is thought to inhibit glutamate α-amino 3-hydroxy-5-methyl-4-isoxazoleproprionic acid and kainate receptors and L-type calcium channels, as well as enhance the inhibitory activity of GABA. These effects, taken together, work to attenuate dopaminergic activity mesolimbic reward circuits, thereby reducing both alcohol craving and withdrawal symptoms. Preclinically, topiramate was seen to decrease ethanol consumption in rodent models. Clinical studies have found that topiramate reduced craving and alcohol drinking in a sample of 150 participants over 12 weeks, and decreased drinking days, heavy-drinking days, and number of drinks per day in a sample of 85 participants in a 14-week trial. A large, multisite 14-week RCT that enrolled 371 participants with alcohol dependence found reductions in heavy-drinking days and improvements in various self-reported drinking-related outcomes. A meta-analysis including seven RCTs of topiramate for AUD with a total of 1125 participants found that topiramate significantly increased number of days abstinence and decreased heavy-drinking days compared to placebo. Of interest,grow solutions greenhouse this meta-analysis also directly compared effect sizes for topiramate and naltrexone, finding that topiramate was significantly more effective than naltrexone in reducing binge drinking, but not in improving abstinence.
Another recent month-long study of 94 patients that directly compared topiramate and baclofen demonstrated that baclofen was overall more effective and better tolerated than topiramate. The potential of reduced tolerability and significant side effects such as pruritis, paresthesia, anorexia, dysgeusia, dizziness, nervousness, and cognitive impairment, including difculty with concentration and attention, are concerns for the use of topiramate in the treatment of AUD. These cognitive impairments were found to be dose-associated and include impairments in working memory and verbal fuency, as well as mental slowing. Topiramate’s side effects, especially those affecting memory and cognition, present reasons for concern and warrant long-term trials to further investigate these effects. Slow dose titration and ongoing patient monitoring is also recommended. It is worth noting a potential strength of topiramate: the possibility of starting treatment while patients are still actively drinking, allowing topiramate to serve as a harmreduction or abstinence-initiation treatment, rather than only being used to prevent relapse in already detoxifed patients]. Topiramate has already been demonstrably effective in clinical applications across a number of drinking outcomes, but longer-term trials of topiramate are recommended to optimize dose and duration, as well as further exploring side effects.Another anti-convulsant medication, gabapentin, is also suggested by the APA for use in AUD treatment with the goal of reducing alcohol consumption or achieving abstinence. It is thought to modulate GABA activity by indirectly interacting with voltage-gated calcium channels. Preclinical studies of gabapentin’s effects on ethanol consumption have shown mixed results, with some studies finding that gabapentin reduced ethanol intake in alcohol dependent rodents and others finding that it increased self-administration and binge-like drinking. Gabapentin has shown promising results in human laboratory studies and clinical trials.
Gabapentin reduced percent heavy-drinking days and drinks per day, as well as increased percentage abstinent days in a 28-day trial with 60 participants. In another 10-day study with 21 participants, gabapentin significantly delayed return to heavy drinking. In a proof-of-concept one-week human laboratory trial , participants treated with gabapentin showed significant decreases in alcohol craving in comparison to placebo, and a follow-up 12-week RCT with 150 participants found that gabapentin significantly increased abstinence rates and percentage of no heavy-drinking days.For instance, a combination of gabapentin and fumazenil over 39 days in 60 participants increased percentage of abstinent days and delayed time to first heavy-drinking day compared to placebo. This trial also showed an interaction effect with pre-study alcohol withdrawal, such that those with more severe withdrawal symptoms at baseline benefitted more from the treatment during the trial. In combination with naltrexone, gabapentin was also shown to be more effective compared with naltrexone alone in a 6-week trial with 150 participants. A Cochrane review of 25 studies found anticonvulsants, including gabapentin, to significantly reduce both heavy-drinking days and drinks per drinking day in comparison to placebo. Anticonvulsants were also associated with longer time-to-relapse and fewer heavy-drinking days compared to naltrexone. A recent meta-analysis of 7 RCTs with a total of 751 participants found that gabapentin compared to placebo only significantly decreased percent heavy-drinking days, although trend-level effect estimates were shown for other alcohol-related outcomes. In a 16-week RCT with 96 participants, gabapentin improved the percentage of individuals with no heavy-drinking days and increased total abstinence rates over placebo, especially among participants with more severe pre-study withdrawal. However, another recent 6-month multisite RCT of extended-release gabapentin conducted in 346 participants with at least moderate AUD found no effects over placebo for any clinical outcomes including abstinence rate, percent heavy-drinking days, drinks per drinking day, or alcohol craving.
While these findings may be related to potential pharmacokinetic issues relating to the specific formulation of extended-release gabapentin used in the trial, it is also possible that gabapentin may simply be more effective in patients with more clinically relevant and severe symptoms of alcohol withdrawal. The most common adverse events associated with gabapentin treatment are somnolence, dizziness, peripheral edema, and ataxia or gait disorder. Notably, gabapentin does carry the potential for misuse and abuse, particularly in individuals with opioid use disorders; therefore, recommendation of gabapentin to individuals with comorbid substance use disorder should be carefully considered. In summary, gabapentin shows some clinical efficacy, especially in populations with more severe withdrawal symptomology, but more extensive investigation is recommended.Varenicline is a nicotinic acetylcholine receptor agonist that is used for the treatment of nicotine dependence. In rodent models, varenicline was shown to reduce ethanol seeking, intake, and binge-like consumption. Additionally, the combination of varenicline and naltrexone decreased alcohol drinking more effectively than either drug on its own. Clinically,marijuana drying rack varenicline was found to significantly reduce weekly percent heavy-drinking days, drinks per day, drinks per drinking day, and alcohol craving compared to placebo in a 13-week multisite RCT with 200 participants. However, a 12-week RCT found no effect of varenicline over placebo on heavy-drinking days, and a recent 6-week human laboratory study in 47 participants found that varenicline did not significantly attenuate cueinduced alcohol craving relative to placebo. Varenicline appears to be especially relevant to heavy drinking smokers. Approximately 20%–25% of current smokers are estimated to also be heavy drinkers.A human laboratory study with 20 heavy-drinking smokers on varenicline for 7 days found that varenicline significantly reduced the number of drinks consumed and increased the likelihood of complete abstinence in the human laboratory paradigm. Moderator analyses of data collected in the above multi-site trial indicated that varenicline was more efcacious in reducing drinking among smokers who also reduced their cigarette smoking and among individuals with lower severity of AUD, such that that varenicline significantly reduced percent heavy-drinking days and drinks per drinking day in low-severity individuals, while the most severe group showed no differences between varenicline and placebo on drinking outcomes. Findings also indicate that varenicline may be more effective as an AUD treatment in men, as a 16-week RCT with 131 participants found that varenicline combined with medication management decreased percent heavy-drinking days only in men, but improved smoking abstinence in both men and women. Varenicline is well tolerated, suggesting that it may serve as a promising option for AUD treatment, especially in the case of individuals co-using alcohol and nicotine.Aripiprazole is an antipsychotic drug that acts as a partial agonist at the dopamine D2 and 5-HT1A receptors and as an antagonist at the 5-HT2A receptor. Preclinically, aripiprazole has been shown to reduce ethanol-induced place preference and decrease drinking behaviors in mice, as well as reducing alcohol consumption in alcohol-preferring rats. A human laboratory study in 18 healthy participants indicated that aripiprazole affected outcomes related to alcohol consumption , including reducing the euphoric effects of alcohol and increasing sedative effects. In a sample of 30 participants with AUD, aripiprazole compared to placebo, was found to attenuate cue-induced neural activation in the ventral striatum, a region associated with reward. Another recent clinical laboratory study in which 99 participants with AUD took aripiprazole over eight days found that aripiprazole reduced the number of drinks consumed in a bar lab setting, especially among individuals with low self-control, and prolonged the latency to drink in individuals with high impulsivity.
Results from clinical trials of aripiprazole are mixed. A 16-week RCT directly comparing aripiprazole against naltrexone found that the two medications were overall comparable in reducing heavy-drinking days and increasing days of abstinence, although patients treated with naltrexone had reduced craving compared to aripiprazole. A 35-day open-label trial assessing the combination of aripiprazole and topiramate in 13 heavy drinking participants found significant reductions in alcohol use. Additionally, this trial provided no evidence that the side effects of the two medications are additive, indicating that the combination is generally safe and well tolerated. However, another recent five-week study assessing topiramate, aripiprazole, and their combination with 90 participants found that effects on drinking reduction were due to topiramate, while no significant findings were seen for aripiprazole for any outcomes. Another multi-center RCT enrolling 295 participants over 12 weeks found no significant difference between the aripiprazole and placebo groups in percentage of participants completely abstinent from alcohol throughout the study or time to first drinking day; however, the average number of drinks per drinking day was significantly lower for aripiprazole. The aripiprazole group yielded significantly higher discontinuation rates and earlier discontinuation, largely due to adverse events associated with side effects, especially when dosage exceeded 15 mg/day. The most common side effects cited in cases of discontinuation were fatigue, insomnia, restlessness, anxiety, and deficits in attention. Of note, long-term use of antipsychotics like aripiprazole may be associated with more severe adverse effects such as tardive dyskinesia, with risk factors including older age and female sex . In summary, these findings suggest that aripiprazole may be more effective at lower doses and in more impulsive individuals, although larger confirmatory studies are needed to pursue these personalized medicine approaches.Ondansetron is a 5-HT3 antagonist that is used to treat nausea and vomiting. Although the specific mechanism of action remains under investigation, ondansetron may address serotonergic dysfunction common in early-onset AUD, and may reduce alcohol craving via 5-HT3 projections to dopaminergic connections in the midbrain. Preclinically, 5-HT3 antagonism has been shown to block acquisition and maintenance of ethanol self-administration and reduce ethanol-associated dopamine concentration in the nucleus accumbens. Ondansetron was also found to block the development and expression of sensitization to the locomotor stimulant effects of ethanol and reduce voluntary ethanol intake, preference, and withdrawal seizures in rodent models. Clinically, ondansetron may be particularly effective in combination with naltrexone. In an 8-week RCT in 20 participants with early-onset AUD, ondansetron and naltrexone significantly reduced drinks per drinking day and trended towards an increase in percentage of days abstinent. Another combination study in 90 participants after 7 days on ondansetron and naltrexone found that the combination decreased craving for alcohol and ventral striatal activation to alcohol cues. Ondansetron may also be suitable for individuals with biological predisposition to early-onset AUD. In an 11-week RCT of 271 participants, ondansetron was shown to reduce self-reported drinking such that patients with early-onset AUD who received ondansetron reported fewer drinks per day and more days of abstinence compared to placebo. Ondansetron, combined with cognitive behavioral therapy in an 8-week open-label trial comparing effects in early-onset versus late-onset AUD, found that drinks per drinking day and alcohol-related problems were significantly decreased among those with early-onset AUD compared to those with late-onset AUD. Furthermore, in an 11-week study with 253 participants, ondansetron at 4 μg/kg reduced overall craving significantly in participants with early-onset AUD, while a lower dose reduced craving in participants with late-onset AUD. These reductions in craving were also associated with reduced drinking and an increased percentage of abstinent days. Ondansetron is well tolerated with relatively mild side effects including diarrhea, constipation, and headache. Overall, these studies suggest a potential role for ondansetron as an AUD treatment, especially in participants with early-onset AUD and possibly in combination with naltrexone.