A systematic review of twelve studies (three RCTs, nine observational) examined medium‑chain triglyceride (MCT)–based interventions, with or without a ketogenic diet, for drug‑resistant epilepsy. The authors found low‑to‑very‑low certainty that MCT ketogenic diet may achieve seizure control comparable to the classical ketogenic diet, while evidence for MCT supplementation alone remains very uncertain.
Study and findings
The authors performed a systematic search of PubMed, Web of Science, Scopus and the Cochrane Library up to April 2025, selecting randomized controlled trials and cohort studies that evaluated medium‑chain triglyceride (MCT) interventions in patients with drug‑resistant epilepsy. Twelve studies met inclusion criteria: three RCTs and nine observational cohorts. In a pediatric RCT comparing the MCT ketogenic diet (MCT KD) with the classical ketogenic diet (CKD), seizure outcomes did not differ clearly, although ketone levels were higher with CKD; the trial did not establish equivalence. A small pediatric crossover trial suggested a possible benefit of a C10‑enriched ketogenic diet, and a small adult RCT reported a tentative therapeutic signal from MCT supplementation. Observational reports generally described seizure reduction from baseline, but methodological limitations precluded firm conclusions. Gastrointestinal adverse events were frequent across studies but were usually manageable. Using GRADE, the certainty of evidence was judged low to very low, and synthesis was performed without meta‑analysis due to heterogeneity.
Clinical interpretation
For clinicians considering dietary options in drug‑resistant epilepsy, the review indicates that an MCT‑based ketogenic diet may provide seizure control comparable to a classical high‑fat, low‑carbohydrate regimen, but the available data do not confirm statistical equivalence. The higher ketone production observed with CKD suggests a metabolic difference, yet this did not translate into a clear advantage in seizure frequency within the limited pediatric trial. Small crossover and adult RCTs hint at a possible benefit of adding MCTs, either as part of a modified ketogenic formula or as a supplement, but the signal is weak and derived from underpowered studies. Gastrointestinal tolerance remains a practical concern, although most adverse events were reported as manageable. Overall, the evidence does not support a definitive recommendation for MCT KD over CKD, nor does it substantiate the use of MCT supplementation without a structured ketogenic protocol.
Limitations and open questions
The primary limitation is the low certainty of the evidence, driven by small sample sizes, heterogeneous study designs, and methodological weaknesses in the observational reports. The pediatric RCT did not achieve statistical power to demonstrate equivalence, and the crossover and adult trials were exploratory. Heterogeneity in MCT formulations, dietary ratios, and outcome measures prevented quantitative synthesis. Consequently, it remains unclear whether any observed seizure benefit is mediated by ketosis, direct MCT effects, or other dietary factors. Future research should employ adequately powered, parallel‑group RCTs that directly compare MCT KD with CKD using standardized seizure endpoints, report detailed macronutrient composition, and assess long‑term safety and adherence.
Source
Pellizzari M, De Clauser L, Mir-Majidi S, Leone A, Veggiotti P, Previtali R, et al. Impact of medium-chain triglyceride with and without ketogenic diet in the management of drug-resistant epilepsy: a systematic review. Nutr Neurosci. 2026:1-22. doi: 10.1080/1028415x.2026.2720527. PMID: 42623429.