A Randomized Safety and Feasibility Crossover Trial of two Mediterranean-Ketogenic Interventions in Individuals with Parkinson's Disease

BACKGROUNDBoth Mediterranean and ketogenic diets have been proposed as nutritional interventions in Parkinsons disease (PD). Combined approaches may offer maximal benefits. OBJECTIVEAssess the feasibility, safety and exploratory efficacy of two Mediterranean-ketogenic dietary interventions in individuals with PD (PwP). METHODSIn this Phase II, random-order crossover study, PwP followed two 8-week dietary interventions, separated by an 8-week washout: 1) a high-fat, low-carbohydrate Mediterranean diet (MeDi-KD) and 2) a standard Mediterranean diet supplemented with medium chain triglycerides (MeDi-MCT). RESULTSOf 52 participants randomized, 48 started the trial. Forty-one (79%) participants completed at least one and 33 (63%) completed both intervention phases. There were no intervention-related serious adverse events, nor any significant changes in plasma lipid profiles. Seventy-three percent and 92% of participants reported deviating from the MeDi-KD and MeDi-MCT no more than a few times per month, respectively. Moderate Mediterranean Diet Adherence Scores of 6.7 (SD: 1.6) and 7.2 (SD: 2.3) were achieved during the MeDi-KD and MeDi-MCT, respectively, out of a maximum of 14. Fifty percent of participants were in nutritional ketosis (BHB >0.5 mM) at follow-up for the MeDi-KD, as compared with only 1 (3%) participant following the MeDi-MCT. MDS-UPDRS Part II and IV scores decreased by a mean of -1.4 (SD: 4.2; p=0.039) and -1.0 (SD: 3.0; p=0.044) points, respectively, following the MeDi-MCT. CONCLUSIONSMediterranean-ketogenic interventions appear safe and potentially beneficial in PwP. Behavioral strategies to optimize adherence should be employed in future phase III trials. TRIAL REGISTRATIONThe trial was registered on ClinicalTrials.gov: NCT05469997. PLAIN LANGUAGE SUMMARYMany patients want to know what the best diet is to follow for their Parkinsons disease. Previous studies have suggested benefits of both ketogenic diets, which are high in fats and low in carbohydrates, and Mediterranean-style diets. Combining these two approaches could offer maximal advantages, while reducing the challenges of following a strict ketogenic diet. The aim of this study was to test whether so-called "Mediterranean-ketogenic" diets would be safe and practical for patients with Parkinsons disease to follow. Early indicators of potential clinical benefit were also assessed. Fifty-two participants were randomly assigned to follow two types of Mediterranean-ketogenic diets for eight weeks each, with an eight-week break in between. The two interventions were: 1) A high-fat, low carbohydrate version of a Mediterranean diet (MeDi-KD) and 2) A Mediterranean diet administered with a ketogenic supplement, medium-chain triglyceride oil (MeDi-MCT). Forty-eight people started the study, 41 completed at least one diet intervention phase and 33 completed both intervention phases. No serious side effects were reported. Although most participants felt they followed the diets closely, objective measures of adherence suggested room for improvement. The MeDi-MCT diet led to small but significant improvements in patient-reported motor activities of daily living and motor complications. Longer-term studies are needed to validate these findings. Future trials should incorporate behavioral coaching techniques to better help participants follow the diets.