Feasibility and Tolerability of Ketogenic Interventions in Amyotrophic Lateral Sclerosis—A Dose-Finding Case Series

Background/Objectives: Weight loss and hypermetabolism are negative prognostic factors in amyotrophic lateral sclerosis (ALS). Ketone bodies (β-hydroxybutyrate, βHB) as high-energy substrates may compensate for this energy deficit, since a ketogenic diet (KD) has been shown to increase survival and stabilize body weight in the SOD1 mouse model. In this case series, we tested exogenous ketone salts (KS), ketone esters (KE), and a KD, in patients with ALS and in healthy subjects to identify novel therapeutic interventions for subsequent clinical studies. Methods: KS (KetoForce® (KetoSports, Frisco, TX, USA)) were tested in healthy subjects (11.7 g and 15.6 g βHB) and patients (15.6 g βHB 3×/day over 3 days). KE (KE4® (KetoneAid, Falls Church, VA, USA)) containing 10.0 g βHB were applied in healthy subjects (once) and in patients (3×/day over 2 days). For the KD, KetoCal® 2.5:1 LQ MCT MF Vanilla (Nutricia, Frankfurt, Germany) was applied via percutaneous endoscopic gastrostomy over four weeks. Regular capillary βHB measurements were conducted, and adverse events were recorded. Results: Between January 2021 and March 2025, we treated nine patients with ALS and two healthy subjects at the Department of Neurology of Ulm University, Germany. KE and KS increased βHB temporarily. However, the elevation was more pronounced following KE (maximum 2.2–2.7 mmol/L vs. 0.8–1.2 mmol/L). The KD increased βHB levels continuously with nighttime fluctuations. No adverse events occurred under KE. KS caused diarrhea in 3/5 patients and 1/2 healthy subjects. The KD was well tolerated, with mild gastrointestinal symptoms occurring in all patients. Conclusions: All ketogenic approaches increased βHB blood levels. While the KD and KE provided good tolerability, KS caused significant gastrointestinal side effects. KD seems to be an interesting candidate for future clinical studies, as it prompted a long-term increase in βHB while providing satisfying tolerability. Since maintaining a KD long-term is difficult for oral-feeding patients, KE may constitute a feasible alternative.