Nutraceuticals and phytoceuticals in the treatment of bipolar disorder: A systematic review and network meta-analysis

Nutraceuticals and phytoceuticals are increasingly investigated for bipolar disorder (BD). We conducted a systematic review and network meta-analysis of randomized controlled trials (RCTs). PubMed/MEDLINE, EMBASE, Scopus, PsycINFO, and ClinicalTrials.gov were searched from inception to July 1, 2025. Co-primary outcomes were changes in depressive or manic symptoms (standardized mean difference [SMD]), treatment response, and acceptability (risk ratio [RR]); tolerability and remission (RR) were secondary outcomes. Heterogeneity, transitivity, inconsistency, small-study effects, risk of bias, and confidence in evidence (CINeMA) were assessed. Twenty-eight RCTs (n=2,222) evaluated 22 treatments. No treatment outperformed placebo for depressive symptoms; placebo outperformed palmitoylethanolamide (SMD=2.69, 95% CI 1.43-3.95), based on one trial, amid substantial heterogeneity (I²=86%) but no global inconsistency. For manic symptoms, palmitoylethanolamide (SMD=-4.58, 95% CI -6.24 to -2.92) and folic acid (SMD=-2.42, 95% CI -4.06 to -0.79) outperformed placebo, with substantial heterogeneity (I²=91.3%) and no global inconsistency. Sensitivity analyses supported palmitoylethanolamide, although the finding relied on one RCT from a region producing larger-than-average SMDs. Meta-regression indicated that larger effects were associated with lower adapted AMSTAR-Plus scores. Free-and-easy-wanderer-plus™ combined with carbamazepine outperformed placebo for response and acceptability. CINeMA ratings varied and were predominantly low or very low, particularly for manic symptoms. Current evidence does not support firm recommendations for any nutraceutical or phytoceutical in acute bipolar depression or mania, and further high-quality research is needed.