Vol.:(0123456789) EPMA Journal (2025) 16:541–553 https://doi.org/10.1007/s13167-025-00420-9 MINI REVIEW Creatine as a mitochondrial theranostic in predictive, preventive, and personalized medicine Sergej M. Ostojic1,2 · László Rátgéber1 Received: 6 August 2025 / Accepted: 15 August 2025 / Published online: 1 September 2025 © The Author(s) 2025 Abstract Creatine, traditionally recognized for its role in skeletal muscle energy metabolism, is increasingly emerging as a mitochondria- targeted theran

The short version: the creatine dose-ranging trial you asked about (6 g vs 18 g vs placebo) is not in the evidence I was given. What is here tests different doses and populations, and the results are mixed.

The evidence I have does not include the ERS 2025 trial you named. It tests creatine in preterm infants, healthy athletes, and mitochondrial disease patients — none of whom have PEM or post-exertional crashes. The closest match is a 2005 study of 8 patients with mitochondrial DNA deletions (CPEO and Kearns-Sayre syndrome) who took oral creatine and showed no improvement in skeletal muscle energy metabolism or clinical outcomes [4]. That is a small, negative trial in a population with a clear mitochondrial defect.

What the evidence does show about creatine in general: it increases muscle phosphocreatine stores and improves high-intensity, repeated-bout exercise performance in healthy people by about 4% [2, 3]. The benefit depends on individual uptake — people with lower baseline stores get more [2]. But these are healthy athletes doing maximal efforts, not people with PEM who need to avoid crashing. The mechanism that helps a sprinter repeat a 30-second burst may not help someone whose mitochondria are already struggling to meet baseline demand.

My call: the evidence does not support creatine for PEM or pacing. The one trial in people with mitochondrial disease was negative. The positive trials are in healthy athletes doing short, maximal efforts — a different physiology from PEM. Without a trial in ME/CFS or long COVID patients using PEM as an endpoint, there is no basis to recommend it.

Confidence: moderate — the negative trial in mitochondrial disease is directly relevant, but it is small (8 patients) and the dose and duration are not reported in the evidence I have.