Pyridostigmine and low-dose naltrexone for ME/CFS: study protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial
6 affiliations
- 1Open Medicine Foundation, 29302 Laro Dr, Agoura Hills, CA 91301 USA
- 2Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 USA
- 3Innovation Center for Computational Health, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA
- 4Department of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA
- 5Analytical Chemistry and Neurochemistry, Department of Chemistry—BMC, Uppsala University, 751 24, Uppsala, Sweden
- 6The ME/CFS Collaborative Research Centre at Uppsala University, 751 24, Uppsala, Sweden
Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic disease with no FDA-approved treatments. This report describes a protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial investigating the impact of low-dose naltrexone (LDN) and pyridostigmine (Mestinon) on physiological response, symptoms, and functionality of ME/CFS patients.
Methods: Participants (target n = 160) are recruited through clinics at Massachusetts General Hospital and Brigham and Women’s Hospital, and through Open Medicine Foundation’s StudyME registry. They are then randomized into one of four arms: LDN/pyridostigmine, LDN/placebo, placebo/pyridostigmine, placebo/placebo. Treatment is administered for 13 weeks after an initial screening period of up to 4 weeks. Primary outcomes are FUNCAP-55 score, peak oxygen utilization, heart rate recovery, and oxygen uptake efficiency slope. Secondary outcomes are scores from DSQ-PEM and PROMIS-29 surveys, DANA Brain Vital score, step count, heart rate, and heart rate variability.
Discussion: The results of this trial will provide novel insights into the efficacy of and predictors of response to LDN and pyridostigmine in ME/CFS. This may inform future treatment strategies for ME/CFS. The trial will also validate what primary and secondary outcomes to use in similar clinical trials.
Trial registration: This trial was registered on clinicaltrials.gov (NCT06366724) on April 16, 2024.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13063-026-09943-6.
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BibTeX
@article{meadows2026pyridostigmine,
title = {{Pyridostigmine and low-dose naltrexone for ME/CFS: study protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial}},
author = {Danielle Meadows and Johanna Squires and Joshua Dibble and Shreya Palwayi and Donna Felsenstein and Linda Tannenbaum and Peng Li and Wenzhong Xiao and Jonas Bergquist and David Systrom},
journal = {Trials},
year = {2026},
month = aug,
doi = {10.1186/s13063-026-09943-6},
url = {https://doi.org/10.1186/s13063-026-09943-6},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Pyridostigmine and low-dose naltrexone for ME/CFS: study protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial
AU - Danielle Meadows
AU - Johanna Squires
AU - Joshua Dibble
AU - Shreya Palwayi
AU - Donna Felsenstein
AU - Linda Tannenbaum
AU - Peng Li
AU - Wenzhong Xiao
AU - Jonas Bergquist
AU - David Systrom
PY - 2026
DA - 2026/08/12
JO - Trials
DO - 10.1186/s13063-026-09943-6
UR - https://doi.org/10.1186/s13063-026-09943-6
AB - Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic disease with no FDA-approved treatments. This report describes a protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial investigating the impact of low-dose naltrexone (LDN) and pyridostigmine (Mestinon) on physiological response, symptoms, and functionality of ME/CFS patients. Methods: Participants (target n = 160) are recruited through clinics at Massachusetts General Hospital and Brigham and Women’s Hospital, and through Open Medicine Foundation’s StudyME registry. They are then randomized into one of four arms: LDN/pyridostigmine, LDN/placebo, placebo/pyridostigmine, placebo/placebo. Treatment is administered for 13 weeks after an initial screening period of up to 4 weeks. Primary outcomes are FUNCAP-55 score, peak oxygen utilization, heart rate recovery, and oxygen uptake efficiency slope. Secondary outcomes are scores from DSQ-PEM and PROMIS-29 surveys, DANA Brain Vital score, step count, heart rate, and heart rate variability. Discussion: The results of this trial will provide novel insights into the efficacy of and predictors of response to LDN and pyridostigmine in ME/CFS. This may inform future treatment strategies for ME/CFS. The trial will also validate what primary and secondary outcomes to use in similar clinical trials. Trial registration: This trial was registered on clinicaltrials.gov (NCT06366724) on April 16, 2024. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13063-026-09943-6.
SN - 1745-6215
ER -