The LIFT will be conducted at Brigham and Women's Hospital (BWH) of Harvard Medical School, focusing on the effect of Pyridostigmine (Mestinon) and Low-Dose Naltrexone (LDN) in subjects aged 18-70 meeting the Canadian consensus criteria (CCC) for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) as well as having specifically Orthostatic Intolerance (OI). Long COVID (LC) subjects will also be included if they meet CCC and have OI.

This double-blind, placebo-controlled study will involve 160 participants randomized into one of four possible groups: Pyridostigmine/LDN (40), Pyridostigmine/Placebo (40), LDN/Placebo (40), Placebo/Placebo (40). The dose of Pyridostigmine will be carefully titrated from 30mg to 60mg three times a day, and the dose of LDN will be titrated from 1.5 mg to 4.5 mg once daily.

The trial includes a scale-back plan, allowing participants to reduce their dosage if they experience intolerance symptoms, with adjustments made during weekly visits. This plan provides a personalized approach to medication tolerance, ensuring participant's safety and comfort throughout the trial.

The time commitment for the participant is approximately three (3) months, and during this time, there will be three (3) in-person visits to BWH and four (4) virtual visits. Study procedures will include two (2) submaximum cardiopulmonary exercise tests, questionnaires (virtually completed), and blood and urine collection. We will be recruiting from the BWH Dyspnea Clinic as well as the Open Medicine Foundation (OMF) StudyME Registry and anticipate the entire trial will take two (2) years to complete.

The LIFT represents a significant endeavor to improve treatment options for ME/CFS patients and contribute to the broader understanding of this debilitating condition.

Inclusion Criteria:

1. Meet National Academy of Medicine Criteria, Canadian Consensus Criteria (See appendix), and demonstrate orthostatic intolerance for diagnosis of ME/CFS

2. Participant is ≥ 18 and ≤ 70 years of age at screening, inclusive.

3. The onset of symptoms prior to December 2023.

4. Female participant is not pregnant and at least 1 of the following conditions apply:

   1. Not a woman of childbearing potential
   2. Woman of childbearing potential who agrees to follow the contraceptive guidance. from the time of informed consent.

5. Participant agrees and can adhere to the study requirements for the length of the study.

6. Participant has a body mass index (BMI) range of 17 to 40 kg/m2, inclusive.

7. Participant agrees not to participate in another interventional study while participating in the present study.

8. Participant has a functioning smart phone to download and run the DANA Brain Vital Mobile Application.

Exclusion Criteria:

1. Pregnant, planning to become pregnant, or breastfeeding.
2. Any use of opioid medications within 30 days of screening.
3. Positive urine test for opioids
4. History of alcohol, opioid or other substance misuse
5. Participation in another interventional clinical trial in the last 30 days or planned during the trial period.
6. Allergy to medication components
7. Participant has any condition which, in the investigator's opinion, makes the participant unsuitable for study participation.
8. Participant has diabetes mellitus (type 1 or 2).
9. Participant has undergone an inpatient hospitalization within the 30 days prior to the randomization or has a planned hospitalization or a surgical procedure during the study, which may affect the study assessments, in the opinion of the investigator.
10. Participant has clinically significant respiratory disease (such as chronic obstructive pulmonary disease, cystic fibrosis, severe asthma, lung infections including tuberculosis, sarcoidosis, thoracic endometriosis, pulmonary fibrosis, and lung cancers) and/or cardiac disease (medical history or current clinical findings)
11. Participant has an active malignancy or any other cancer.
12. Participant has initiated an exercise regimen within 4 weeks prior to randomization.

Individual participant data that underlie the results reported in this article, after de-identification(text, tables, figures, and appendices) will be available for researchers who provide a methodologically sound proposal to achieve aims in the approved proposal.

Beginning 9 months and ending 36 months following article publication.

Proposals should be directed to jsquires1@bwh.harvard.edu. To gain access, data requestors will need to sign a data access agreement.

The Mass General Brigham Investigational Drug Services (IDS) will be responsible for randomizing the four arms. The rest of the study staff and collaborators will be blinded as well as the participant.