DIET & NUTRITION 
PATIENT EDUCATION 
OBESITY/WEIGHT MANAGEMENT 
EXERCISE/TRAINING 
LEGAL MATTERS 
GUIDELINES/RECOMMENDATIONS ⚠️ Small Study / Early Comparative Evidence
A New Zealand 12-week randomized, double-blind, placebo-controlled trial evaluated adjunctive low-dose naltrexone 4.5 mg daily versus placebo in 38 adults with moderate MDD already receiving antidepressants. The trial stopped before reaching its planned sample of 48 due to slow recruitment in the high-inflammatory stratum.
Clinical Considerations
- MADRS reductions were nearly identical between arms (10.5 with naltrexone vs 9.8 with placebo; adjusted mean difference -0.096, 95% CI -4.42 to 4.23).
- Baseline hsCRP did not modify the treatment effect, and no effect was seen on hsCRP itself or on secondary measures including BDI-II, BADS, SF-36, POMS, or SicknessQ.
- The naltrexone arm reported nightmares or abnormal dreams in 42%, sleep problems in 37%, and headaches in 26%, prompting protocol adjustments to morning dosing and slower titration.
- Early termination, attrition, and missing data limit the trial’s ability to detect small effects, and the null result should not be interpreted as definitive evidence of no benefit.
Practice Applications
- Interpret the null result as inconclusive rather than confirmatory given the underpowered sample.
- Recognize sleep-related adverse effects as a tolerability consideration if low-dose naltrexone is used off-label.
- Avoid extrapolating these findings to inflammatory-subtype MDD given incomplete enrollment in that stratum.
- Monitor ongoing investigation of low-dose naltrexone for depression before reaching practice conclusions.
