An intriguing anti-inflammatory hypothesis, a clean trial, a null result
STUDY: Moloney BD et al, Front Pharmacol 2026;17:1767654
STUDY TYPE: Randomized, double-blind, placebo-controlled trial
FUNDING: Health Research Council of New Zealand
Background
Naltrexone has two mechanisms in psychiatry. It treats addictions by partially blocking the opioid receptor, and is FDA-approved for alcohol and opioid use disorders. In low doses, it lowers inflammation, which contributes to 30% of depressions and 50% of treatment-resistant depressions. But whether it treats depression is an open question. Only one randomized trial has tested it and was too small (12 patients) to detect any statistical signals.
The Study
Thirty-seven adults with moderate major depression, all already on antidepressants, were randomized to add low dose naltrexone (up to 4.5 mg/day) or placebo for 12 weeks. The primary outcome was change in the depression rating scale (MADRS). Patients with treatment resistant depression were excluded, as were those with inflammatory illness (naltrexone has known benefits there, and we know that depressive symptoms tend to improve when underlying medical disorders are treated).
Both groups improved about equally. Depression MADRS scores dropped by roughly 10.5 points with low dose naltrexone and 9.8 with placebo — no difference (p = 0.97). Low dose naltrexone also had no effect on C-reactive protein (CRP), self-reported mood, quality of life, or sickness symptoms. Side effects included vivid dreams, sleep disturbance, and headaches, leading to more dropouts in the low dose naltrexone arm (6 vs. 2).
Practice Implications
There are three sides to this negative finding:
- Optimistically: The study was too small to detect a difference
- Cynically: It simply doesn’t work
- Middle ground: Let’s hold off on using it, but look out for more trials. This study excluded severe and treatment-resistant depression, populations with higher rates of inflammation.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
What’s Your Take? Share in Comments
- Many patients take low-dose naltrexone from naturopathic practitioners. What have you seen with it?
