The only drug currently FDA-approved for AUD treatment with potential to target the neuroimmune system is the opioid receptor antagonist naltrexone. Naltrexone is available in both (−) and (+) stereoisomers, both of which have antagonist activity at TLR4 receptors (Hutchinson et al., 2008b). Shortly after identifying naltrexone as a therapeutic agent, its derivative, nalmefene, was tested in two double-blind placebo-controlled laboratory studies (Mason et al., 1994, 1999). Individuals who took nalmefene drank fewer drinks per day, had a greater number of abstinent days, and experienced fewer relapses; in addition, nalmefene does not show the same dose-dependent liver-toxicity as naltrexone (Mason et al., 1999). Phase III clinical trials for nalmefene were completed in 2013 (Gual et al., 2013), but it is currently only approved in Europe to reduce heavy drinking. It’s unclear whether these opioid antagonists help to reduce drinking through TLR4 blockade, but their effects are usually considered to be due to actions on opioid receptors (Quelch et al., 2017).
