REVIEW OF: Aubin H et al, Addiction 2024;119:1211–1223
STUDY TYPE: Randomized double-blind placebo-controlled trial

Treating alcohol use disorder (AUD) is challenging, even with FDA-approved medications like naltrexone and acamprosate. Serotonin and norepinephrine, respectively, have been implicated in cravings and impulsivity associated with AUD. This study examines whether prazosin, an alpha-1b antagonist, and cyproheptadine, a 5-HT2A antagonist, can be taken together to reduce alcohol consumption. (Cyproheptadine has similar properties to mirtazapine and is sometimes used for anorexia, nightmares, sexual dysfunction, or serotonin syndrome, at a dose of 4–12 mg.)

This Phase 2 study was funded by Kinnov Therapeutics, maker of an investigational prazosin-cyproheptadine combo pill, although the study drugs here were separate. A total of 154 patients with severe AUD and high-risk drinking (defined as about 4 or more daily standard drinks for men or about 3 for women) were recruited from addiction treatment centers in France. Patients were randomly assigned to 3 groups for 12 weeks: high dose (prazosin ER 10 mg and cyproheptadine 12 mg daily), low dose (prazosin ER 5 mg and cyproheptadine 8 mg daily), or placebo. All received therapy focused on treatment adherence and alcohol use reduction. The primary outcome was a change in alcohol consumption at three months.

Compared to placebo, patients in both treatment groups decreased their alcohol consumption. The reduction was about three standard drinks per day for the high-dose group and two to three standard drinks for the low-dose group. Among patients with the heaviest drinking, the reduction was even greater, at about 3.8 drinks per day. There was a significant dose-response relationship, with a decrease in alcohol consumption by about 1.3 drinks per day between the low- and high-dose groups.

No serious adverse events were associated with the prazosin-cyproheptadine combination, and more than 90% of adverse events were considered mild or moderate. Sedation and orthostatic hypotension were similar in all three groups. Using ER prazosin likely resulted in an incidence of orthostatic hypotension that did not differ between the placebo and prazosin groups.

CARLAT TAKE
This study suggests that prazosin and cyproheptadine may reduce alcohol intake, particularly in patients with more severe drinking. The combination could be a useful off-label option when standard treatments like naltrexone and acamprosate are ineffective. Industry funding and short duration are caveats.