Magnesium supplementation for anxiety and depression: a systematic review of clinical evidence and mechanistic insights

Abstract

Magnesium is an essential cofactor in numerous enzymatic reactions regulating neuronal excitability, neurotransmission, and stress response. Deficiency has been linked to affective dysregulation through altered N-methyl-D-aspartate (NMDA) and γ-aminobutyric acid (GABA) signaling, impaired neuroplasticity, and activation of the hypothalamic–pituitary–adrenal (HPA) axis (Murck, 2002; Singewald et al., 2004; Poleszak et al., 2004; see Appendix C for detailed preclinical evidence). This systematic review aims to synthesize clinical and epidemiological evidence on magnesium and affective disorders, summarizing preclinical findings separately as mechanistic background. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, a systematic search of PubMed, Scopus, Embase, and PsycINFO (January 2000–June 2026) identified 21 eligible human studies (9 randomized controlled trials [RCTs], 8 observational, 4 systematic reviews or meta-analyses). Preclinical and mechanistic studies (n = 14) were reviewed separately in the Supplementary Material and were not part of the systematic synthesis. Because of substantial heterogeneity, no new meta-analysis was conducted; a structured narrative synthesis integrated quantitative estimates from existing trials and meta-analyses. Across clinical studies, magnesium supplementation was associated with reductions in depressive and anxiety symptoms, especially in individuals with low magnesium or partial antidepressant response. Combination regimens with vitamin B6 or D improved stress resilience and quality of life. Evidence quality ranged from moderate to high, though differences in dosage, formulation, and population limited comparability. Magnesium supplementation shows preliminary evidence of efficacy as an adjunctive treatment for mood and anxiety symptoms, with moderate certainty for depression and low-to-moderate certainty for anxiety. While preclinical data support biological plausibility, mechanistic validation in human trials remains limited. Large, biomarker-guided randomized trials are needed to confirm efficacy and define optimal dosing within precision psychiatry.