Purpose The ketogenic diet is a low-carbohydrate, moderate protein, high-fat diet that has emerged as a potential treatment for autism spectrum disorder. Autism spectrum disorder is a neurodevelopmental disorder of social communication, and restricted, repetitive behaviors and interests in need of novel therapies. An open-label clinical trial was done in Honolulu, Hawaii to test a modified ketogenic diet for improvement of core clinical impairments in children with ASD. Intervention A modified ketogenic gluten-free diet regimen with supplemental MCT was completed in 15 children ages 2 to 17 years for 3 months. Clinical (ADOS-2, CARS-2) and biochemical measures were performed at baseline and 3-months on the ketogenic diet. Main outcome Children administered a modified ketogenic gluten-free diet with supplemental MCT significantly improved core autism features assessed from the ADOS-2 after 3 months on diet (P = 0.006). No significant difference was observed in restricted and repetitive behavior score (P = 0.125) after 3 months on the diet protocol. Substantial improvement (> 30% decrease ADOS-2 total score) was observed in six participants, moderate improvement (> 3 units) in two participants, and minor/no improvement in seven participants. Ten participants assessed at a six-month time point sustained improvement in total ADOS-2 and social affect subdomain scores comparing baseline and 6 months (P = 0.019; P = 0.023), but no significant improvement in restricted and repetitive behavior scores were noted (P = 0.197). Significant improvements in CARS-2 items after 3 months of the modified ketogenic protocol were observed in imitation, body use, and fear or nervousness (P = 0.031, P = 0.008, P = 0.039). The percent change on ADOS-2 score from baseline to 3 months was associated with baseline high-density lipoprotein levels (ρ = −0.67, P = 0.007) and albumin levels (ρ = −0.60, P = 0.019). Moreover, the percent change from baseline to 3 months in ADOS-2 scores was significantly associated with percent change in high-density lipoprotein levels (ρ = 0.54, P = 0.049) and albumin levels (ρ = 0.67, P = 0.010). Conclusions A modified gluten-free ketogenic diet with supplemental MCT is a potentially beneficial treatment option to improve the core features of autism spectrum disorder and warrants further investigation. Trial registration Trial Registry: Clinicaltrials.gov Registration Number: NCT02477904URL: https://www.clinicaltrials.gov/ct2/show/NCT02477904?term=ketogenic+diet&cond=Autism&rank=1

The ketogenic diet (KD) can improve the core features of autism spectrum disorders (ASD) in some children, but the effects on the overall metabolism remain unclear. This pilot study investigated the behavioral parameters in relation to blood metabolites and trace elements in a cohort of 10 typically developed controls (TC) and 17 children with ASD at baseline and following 3 months of treatment with a modified KD regimen. A nontargeted, multiplatform metabolomic approach was employed, including gas chromatography–mass spectrometry, 1H nuclear magnetic resonance spectroscopy, and inductively coupled plasma–mass spectrometry. The associations among plasma metabolites, trace elements, and behavior scores were investigated. Employing a combination of metabolomic platforms, 118 named metabolites and 73 trace elements were assessed. Relative to TC, a combination of glutamate, galactonate, and glycerol discriminated ASD with 88% accuracy. ASD had higher concentrations of galactose intermediates, gut microbe-derived trimethylamine N-oxide and N-acetylserotonin, and lower concentrations of 3-hydroxybutyrate and selenium at baseline. Following 3 months of KD intervention, the levels of circulating ketones and acetylcarnitine were increased. KD restored lower selenium levels in ASD to that of controls, and correlation analysis identified a novel negative correlation between the changes in selenium and behavior scores. Based on the different behavior responses to KD, we found that high responders had greater concentrations of 3-hydroxybutyrate and ornithine, with lower galactose. These findings enhance our current understanding of the metabolic derangements present in ASD and may be of utility in predicting favorable responses to KD intervention.

Social affinity and collective behavior are nearly ubiquitous in the animal kingdom, but many lineages feature evolutionarily asocial species. These solitary species may have evolved to conserve energy in food-sparse environments. However, the mechanism by which metabolic changes regulate social affinity is not well investigated. In this study, we used the Mexican tetra (Astyanax mexicanus), which features riverine sighted surface (surface fish) and cave-dwelling populations (cavefish), to address the impact of metabolic shifts on asociality and other cave-associated behaviors in cavefish, including repetitive turning, sleeplessness, swimming longer distances, and enhanced foraging behavior. After 1 month of ketosis-inducing ketogenic diet feeding, asocial cavefish exhibited significantly higher social affinity, whereas social affinity regressed in cavefish fed the standard diet. The ketogenic diet also reduced repetitive turning and swimming in cavefish. No detectable behavioral shifts were found regarding sleeplessness and foraging behavior, suggesting that other evolved behaviors are not regulated by ketosis. We further examined the effects of the ketogenic diet via supplementation with extragenic ketone bodies, revealing that ketone bodies are pivotal molecules associated with social affinity. Our study indicated that fish that evolved to be asocial remain capable of exhibiting social affinity under ketosis.