{
  "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.\n\nMethods: 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.\n\nDiscussion: 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.\n\nTrial registration: This trial was registered on clinicaltrials.gov (NCT06366724) on April 16, 2024.\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13063-026-09943-6.",
  "abstract_shown": true,
  "affiliations": [
    "Open Medicine Foundation, 29302 Laro Dr, Agoura Hills, CA 91301 USA",
    "Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 USA",
    "Innovation Center for Computational Health, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA",
    "Department of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA",
    "Analytical Chemistry and Neurochemistry, Department of Chemistry—BMC, Uppsala University, 751 24, Uppsala, Sweden",
    "The ME/CFS Collaborative Research Centre at Uppsala University, 751 24, Uppsala, Sweden"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Danielle Meadows"
    },
    {
      "affs": [
        1
      ],
      "name": "Johanna Squires",
      "orcid": "0000-0003-3294-5992"
    },
    {
      "affs": [
        2
      ],
      "name": "Joshua Dibble"
    },
    {
      "affs": [
        1
      ],
      "name": "Shreya Palwayi"
    },
    {
      "affs": [
        3
      ],
      "name": "Donna Felsenstein"
    },
    {
      "affs": [
        0
      ],
      "name": "Linda Tannenbaum"
    },
    {
      "affs": [
        2
      ],
      "name": "Peng Li"
    },
    {
      "affs": [
        2
      ],
      "name": "Wenzhong Xiao"
    },
    {
      "affs": [
        0,
        4,
        5
      ],
      "name": "Jonas Bergquist"
    },
    {
      "affs": [
        1
      ],
      "name": "David Systrom"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9sfm67knha3vb.bib",
  "cited_by": 2,
  "doi": "10.1186/s13063-026-09943-6",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13746464/",
  "id": "9sfm67knha3vb",
  "issns": [
    "1745-6215"
  ],
  "landing_url": "https://doi.org/10.1186/s13063-026-09943-6",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Study Protocol"
    ],
    [
      "openalex",
      "2738|Fibromyalgia and Chronic Fatigue Syndrome Research"
    ]
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  "openalex": "W4408134060",
  "pdf_url": null,
  "pmcid": "PMC13746464",
  "pmid": "43000413",
  "published": "2026-08-12",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/9sfm67knha3vb.ris",
  "sources": [
    {
      "first_seen": "2026-11-11T12:23:48Z",
      "native_id": "PMC13746464",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s13063-026-09943-6"
    }
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2738|Fibromyalgia and Chronic Fatigue Syndrome Research",
      "subfield": "psychiatry"
    }
  ],
  "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",
  "title_text": "Pyridostigmine and low-dose naltrexone for ME/CFS: study protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial",
  "type": "peer-reviewed",
  "updated_at": "2026-11-12T12:22:45Z",
  "url": "https://research.draconitic.com/paper/9sfm67knha3vb",
  "venue": "Trials",
  "versions": []
}