Low-Dose Naltrexone in Major Depressive Disorder: Trial Findings

Key Takeaways

• In patients with moderate major depressive disorder, adjunctive low-dose naltrexone was not associated with greater improvement than placebo.
• No effect was seen on hsCRP or on BDI-II, BADS, SF-36, POMS, and SicknessQ measures, and baseline hsCRP did not appear to modify the treatment effect on depressive symptoms.
• No serious adverse events occurred.

Adjunctive low-dose naltrexone did not separate from placebo for depressive symptoms during a 12-week randomized, double-blind, placebo-controlled trial in adults with moderate major depressive disorder who were already taking antidepressants. The study used a hybrid parallel-arm design to compare add-on low-dose naltrexone with placebo under blinded conditions.

Investigators enrolled adults with MDD who had moderate depressive symptoms, were receiving antidepressant treatment, had a MADRS score of at least 18, and had no more than Stage II resistance. Participants were recruited in greater Auckland between September 2022 and July 2025, then stratified by hsCRP before randomization. Low-dose naltrexone was titrated to 4.5 mg daily and compared with placebo during a 12-week blinded phase, followed by 12 weeks of open-label treatment. Of 38 randomized participants, 37 initiated dosing.

The primary endpoint was change in MADRS score at 12 weeks, analyzed with a baseline-adjusted linear mixed-effects model. Mean MADRS reductions were 10.5 ± 5.6 with low-dose naltrexone and 9.8 ± 5.9 with placebo. The adjusted mean difference was -0.096, with a 95% confidence interval from -4.420 to 4.228 and a p value of 0.965. This comparison did not favor either treatment arm.

Baseline hsCRP did not appear to modify the treatment effect on MADRS change during the blinded phase. Researchers also found no effect on hsCRP itself or on BDI-II, BADS, SF-36, POMS, and SicknessQ scores. Per-protocol analyses were similar overall, although a week-8 difference favored placebo.

No serious adverse events occurred during the blinded phase. Treatment was discontinued by 6 participants assigned low-dose naltrexone and 2 assigned placebo. The most frequent related events in the low-dose naltrexone group were nightmares or abnormal dreams in 8 participants (42.1%), sleep problems in 7 (36.8%), and headaches in 5 (26.3%). Slower up-titration and switching dosing from night to morning were used to ease symptoms, and the regimen was generally tolerated during the blinded phase.

The trial stopped before the planned sample size of 48 because recruitment into the high-inflammatory stratum was slow. The authors also noted attrition and missing data, leaving a smaller dataset with limited ability to detect small differences.