**Background:** The ketogenic diet (KD), a high-fat, low-carbohydrate dietary regimen historically used for drug-resistant epilepsy, has gained renewed interest for its potential neuroprotective properties. KD induces nutritional ketosis, producing ketone bodies (primarily beta-hydroxybutyrate, BHBA) that can cover approximately 80% of the brain's energy requirements while exerting anti-inflammatory and antioxidant effects. This scoping review systematically maps the literature from 2000-2023 on KD's effects against neurodegenerative and psychiatric diseases, covering basic research (in vitro and in vivo) and clinical evidence.
**Methods:** A comprehensive search of PubMed, Scopus, Web of Science, and Google Scholar was conducted using keywords including ketogenic diet, ketosis, ketone bodies, neurodegenerative diseases, psychiatric diseases, Alzheimer's disease (AD), Parkinson's disease (PD), cognitive impairment, dementia, Huntington's disease (HD), autism spectrum disorder (ASD), eating disorders, depression, schizophrenia, and anxiety. Inclusion criteria encompassed peer-reviewed papers published between 2000-2023 in English, involving in vitro studies, in vivo animal studies, and human participants. Only studies applying classical KD interventions inducing endogenous nutritional ketosis were included; MCT diet, MAD, LGIT, and exogenous ketone supplementations were excluded. Six reviewers worked in pairs to screen titles, abstracts, and full texts, with disagreements resolved by consensus.
**Key Results — Basic Research:** Multiple molecular mechanisms were identified through which KD exerts neuroprotective effects. In vitro, BHBA stimulated microglial polarization to an M2 anti-inflammatory phenotype, decreased proinflammatory cytokines (IL-17, iNOS, COX-2, TNF-α, IL-1β, IL-6), and increased anti-inflammatory IL-10. BHBA inhibited NF-κB signaling and NLRP3 inflammasome activation, reducing ROS production and cellular mortality. In vivo, BHBA suppressed IL-6 and TNF-α while inducing BDNF and TGF-β in LPS-treated mouse brains. In transgenic AD mouse models, BHBA administration improved cognitive function, diminished Aβ peptide accumulation, and reduced microglial overactivation. A 16-week KD in 5XFAD mice lowered hippocampal Aβ accumulation, enhanced spatial learning and working memory, and increased neuron and synapse numbers. In a rat PD model, KD protected dopaminergic neurons against 6-OHDA neurotoxicity by increasing glutathione levels. In a murine MS model, KD reduced disease development, enhanced motor disability, and inhibited inflammation-related cytokines and ROS. KD also attenuated Aβ 40 and 42 accumulations after 43 days in a mouse AD model and repaired motor deficits in transgenic ALS mice. Additional mechanisms included stimulating mitochondrial biogenesis, enhancing gut microbial diversity (increasing Bacteroidetes to Firmicutes ratio and Akkermansia muciniphila), restoring histone acetylation in Shank3-deficient autism models, and suppressing ferroptosis through the Sirt1/Nrf2 pathway.
**Key Results — Clinical Studies:** Clinical evidence remains limited and heterogeneous. For AD, a randomized crossover trial of a 3-month modified KD in 21 individuals significantly increased ADCS-ADL and QOL-AD scores, with borderline cognitive improvement (~2 points on ACE-III). A small study of 15 older adults with AD showed mean ADAS-cog improvement of ~4 points during KD. For PD, a pilot RCT in 47 patients showed both low-fat and KD improved motor and nonmotor symptoms, with KD showing greater nonmotor improvement. A 2-month RCT in 14 PD-MCI patients showed improved vocabulary access and recall with KD. For MS, a 6-month RCT in 60 relapsing-remitting MS patients showed KD significantly reduced ALOX5, COX1, and COX2 production and improved MSQOL-54 scores. An open-label trial in 20 MS patients showed reduced BMI, body fat mass, fatigue, and depressive symptoms. For ASD, a longitudinal study of 30 children (ages 4-10) showed 60% remained on KD with improvements in CARS scores. An open-label trial in 15 children found 8 of 15 improved by at least 4 points on ADOS-2. For HD, a case report of a 41-year-old man showed 52% improvement in motor symptoms and 28% improvement in daily living activities after 48 weeks of KD. For psychiatric conditions, a cross-sectional analysis of 31 inpatients with serious mental illness showed KD linked to improvements in depressive and psychotic symptomatology with high effect sizes. Two case reports documented mood stabilization in type II bipolar disorder maintained for 2-3 years. For migraine, a trial of 22 patients with refractory migraine showed KD substantially decreased attack frequency, headache intensity, and medication use, with median days with symptoms reduced from 30 to 7.5.
**Clinical Implications:** The review identifies a substantial gap between robust preclinical mechanistic evidence and the scarcity of high-quality clinical trials. Most clinical studies are small, short-term (typically ≤6 months), uncontrolled, and have high dropout rates with poor compliance assessment. KD shows promise for improving quality of life, daily functioning, and certain symptoms across multiple conditions, but definitive efficacy remains unestablished. The authors note that KD is highly restrictive, associated with gastrointestinal complications, "keto flu," electrolyte disturbances, and potential malnutrition risk in frail older adults. They emphasize that BHBA is a low-cost biomarker of KD compliance that should be incorporated in future trials. Large, long-term, randomized double-blind controlled trials with prospective design are strongly recommended to determine whether KD can attenuate or treat neurodegenerative and psychiatric disease development, progression, and symptomatology.