JAMA Psychiatry. 2025 Nov 5:e253261. doi: 10.1001/jamapsychiatry.2025.3261. Online ahead of print.

ABSTRACT

IMPORTANCE: Ketogenic diets (KDs) have been hypothesized to influence mental health through pathways involving mitochondrial function, inflammation, and neurotransmitters, but their therapeutic value in psychiatric populations remains uncertain.

OBJECTIVE: To assess the associations between KDs and mental health outcomes in adults, with a focus on depressive and anxiety symptoms.

DATA SOURCES: MEDLINE, Embase, and APA PsycINFO were searched on April 18, 2025. Additional studies were identified through manual searches and clinical trial registries.

STUDY SELECTION: Studies involving adults aged 18 years or older receiving a KD (<26% energy from carbohydrates or <50 g/day) and assessed with validated psychiatric scales were eligible. Designs included randomized clinical trials (RCTs), quasi-experimental (QSE) studies, cross-sectional studies, case series, and case reports.

DATA EXTRACTION AND SYNTHESIS: Data were extracted by 1 reviewer and verified by 2 others. Risk of bias was assessed using critical appraisal tools from the Joanna Briggs Institute. Random-effects meta-analyses were run separately for RCTs and QSEs.

MAIN OUTCOMES AND MEASURES: The primary outcome was changes in psychiatric symptom severity measured by standardized scales, reported as standardized mean differences (SMDs) or standardized mean change using change scores (SMCCs).

RESULTS: A total of 50 studies (41 718 participants) were included. Ten RCTs on KD for depressive symptoms vs control diets showed a significant association (SMD, -0.48; 95% CI, -0.87 to -0.10; I2 = 67.2%), with stronger associations in studies using ketone monitoring, nonobese participants, very low-carbohydrate interventions, and non-high-carbohydrate comparators. Nine RCTs on anxiety showed no significant association (SMD, -0.03; 95% CI, -0.18 to 0.12; I2 = 41%). In QSEs, 9 on depressive symptoms showed a consistent association (SMCC, -0.66; 95% CI, -0.83 to -0.50; I2 = 0%), and 6 on anxiety showed similar results (SMCC, -0.58; 95% CI, -0.81 to -0.36; I2 = 0%).

CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, KDs were associated with modest improvements in depressive symptoms, particularly with biochemical ketosis verification, while anxiety evidence was inconclusive. Given heterogeneity, comparators, and short follow-up, well-powered trials with standardized, verified protocols, structured support, and prespecified outcomes are needed to confirm efficacy and durability.

PMID:41191382 | PMC:PMC12590392 | DOI:10.1001/jamapsychiatry.2025.3261

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