Naltrexone + Pyridostigmine for Chronic Fatigue Syndrome

(LIFT Trial)

Overseen By Research Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Brigham and Women's Hospital

Must not be taking: Opioids

Disqualifiers: Pregnancy, Diabetes, Respiratory disease, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 13 weeks

160 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how two drugs, Pyridostigmine and Low-Dose Naltrexone, can assist people with Chronic Fatigue Syndrome, particularly those experiencing dizziness or faintness when standing (orthostatic intolerance). Researchers aim to determine if these drugs improve symptoms by testing various combinations. It suits individuals with persistent fatigue and dizziness when standing, who have experienced these issues since before December 2023. Participants will visit the hospital several times and complete tests and questionnaires over approximately three months. The trial seeks to find better ways to manage Chronic Fatigue Syndrome and understand its effects. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to potential new therapies.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use opioid medications within 30 days of screening. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that Pyridostigmine and Low-Dose Naltrexone (LDN) have been studied for safety in various contexts. Pyridostigmine, already used to treat myasthenia gravis, has been shown in studies to improve muscle strength in other conditions as well. However, its safety for conditions like ME/CFS and Long COVID remains less established due to fewer large studies.

Conversely, LDN has been found to be safe and well-tolerated. Research indicates that LDN can reduce symptoms like pain and inflammation without causing serious side effects, making it a promising treatment option for several conditions, including Long COVID.

While specific data on using Pyridostigmine and LDN together is lacking, studies suggest that LDN alone is safe. Participants in similar studies have not reported serious side effects, indicating it is generally well-tolerated.

As this trial is in an early phase, research continues to confirm the safety and effectiveness of these treatments when used together. The trial includes careful monitoring and allows for dose adjustments to ensure participant safety and comfort. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of low-dose naltrexone (LDN) and pyridostigmine for chronic fatigue syndrome because it offers a novel approach compared to standard treatments like cognitive behavioral therapy and graded exercise therapy. Unlike most current treatments that focus on behavioral strategies, LDN targets the immune system and inflammation, potentially reducing symptoms by modulating immune responses. Pyridostigmine, on the other hand, enhances communication between nerves and muscles, potentially improving physical stamina and reducing fatigue. This dual-action approach could provide a more comprehensive management of symptoms, addressing both immune and muscle function aspects of chronic fatigue syndrome.

What evidence suggests that this trial's treatments could be effective for ME/CFS?

Studies have shown that pyridostigmine can improve muscle strength and symptoms in people with chronic fatigue syndrome (CFS). Many patients report significant improvement, with 91% finding it helpful. Research also suggests that low-dose naltrexone (LDN) might reduce pain and swelling, benefiting those with chronic fatigue. Some patients with similar conditions have reported feeling better after using LDN. This trial will evaluate the effects of pyridostigmine and LDN, both separately and in combination, for CFS. Although no direct clinical trial data exists on using pyridostigmine and LDN together for CFS, both treatments show promise individually. ^{2 3 6 7 8}

Who Is on the Research Team?

David Systrom, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

The LIFT trial is for adults aged 18-65 with ME/CFS who meet specific criteria, including orthostatic intolerance. Participants must not be women of childbearing potential or agree to contraception, have a BMI between 17 and 40, and commit to the study without joining another trial. They need a smartphone for an app used in the study.

Inclusion Criteria

I cannot become pregnant.

I agree to follow the contraceptive advice given.

I agree not to join another clinical trial while in this study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Pyridostigmine and/or Low-Dose Naltrexone or placebo, with dosage titration and weekly adjustments based on tolerance

13 weeks

3 visits (in-person), 4 visits (virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of functional capacity and physiological responses

2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Low-Dose Naltrexone
• Pyridostigmine

Trial Overview This study at Brigham and Women's Hospital tests Pyridostigmine (30mg-60mg) and Low-Dose Naltrexone (1.5mg-4.5mg) on ME/CFS patients with Orthostatic Intolerance. It's double-blind with four groups: both drugs, each drug alone with placebo, or double placebo.

How Is the Trial Designed?

Group I: Pyridostigmine/Placebo Active Control 2 Interventions

Pyridostigmine will be taken as liquid suspension three times a day, scaling up from 20mg (1.67mL) to 60mg (5mL) (180mg/day). Placebo will be taken as liquid suspension once a day, scaling up from 1.5mL to 4.5mL.

Group II: Placebo/LDN Active Control 2 Interventions

Placebo will be taken as liquid suspension three times a day, scaling up from 1.67mL to 5mL. Low dose naltrexone will be taken as liquid suspension once a day, scaling up from 1.5mL to 4.5mL (4.5mg/day).

Group III: Pyridostigmine/LDN Active Control 2 Interventions

Pyridostigmine will be taken as liquid suspension three times a day, scaling up from 20mg (1.67mL) to 60mg (5mL) (180mg/day). Low dose naltrexone will be taken as liquid suspension once a day, scaling up from 1.5mL to 4.5mL (4.5mg/day).

Group IV: Placebo/Placebo Placebo Group 1 Intervention

Placebo will be taken as liquid suspension three times a day, scaling up from 1.67mL to 5mL. Placebo will be taken as liquid suspension once a day, scaling up from 1.5mL to 4.5mL .

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Open Medicine Foundation

Collaborator

Trials

1

Recruited

160+

Published Research Related to This Trial

In a retrospective review of 3 patients with chronic fatigue syndrome (CFS) who had not benefited from standard treatments, the addition of modafinil to cognitive-behavioral therapy (CBT) resulted in significant improvements in energy and pain/concentration for 2 out of 3 patients.

All 3 patients achieved social recovery, suggesting that modafinil may enhance the effectiveness of CBT in treating treatment-resistant CFS over a medium-term period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recovery from refractory chronic fatigue syndrome with CBT and modafinil. Garg, H., Douglas, M., Turkington, GD., et al.[2023]

In a study of 31 patients with chronic fatigue syndrome (CFS), those treated with oral NADH showed a significant reduction in fatigue symptoms during the first trimester of treatment compared to those receiving conventional therapies.

While NADH demonstrated initial effectiveness, the symptom improvements were not sustained in later trimesters, suggesting that further research with a larger sample size is needed to fully evaluate its long-term efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of oral nicotinamide adenine dinucleotide (NADH) versus conventional therapy for chronic fatigue syndrome. Santaella, ML., Font, I., Disdier, OM.[2015]

Low-dose naltrexone (LDN) has shown potential efficacy in treating chronic immune-modulated disorders, with case reports indicating varied responses in patients with chronic fatigue syndrome, ranging from significant improvement to partial symptom relief.

Despite promising anecdotal evidence and small-scale trials for other conditions, there is a lack of clinical trials specifically investigating LDN for chronic fatigue syndrome, suggesting a need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose naltrexone as a treatment for chronic fatigue syndrome. Bolton, MJ., Chapman, BP., Van Marwijk, H.[2020]

In three cases of Chronic Fatigue Syndrome (CFS), patients exhibited defects in neuromuscular transmission and dysautonomia, which were linked to their fatigue symptoms.

All three patients showed significant improvement in their symptoms after treatment with the acetylcholinesterase inhibitor pyridostigmine, suggesting that cholinergic dysautonomia may play a role in the fatigue experienced by some CFS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports. Kawamura, Y., Kihara, M., Nishimoto, K., et al.[2020]

In a study of 49 patients with chronic fatigue syndrome, moclobemide showed small but significant reductions in fatigue, depression, and anxiety over 6 weeks, with the most notable improvements seen in patients who also had major depressive illness.

Moclobemide may be beneficial for chronic fatigue syndrome patients with co-existing major depressive disorder, but it is not supported as an effective treatment for chronic fatigue syndrome alone, indicating the need for further randomized, placebo-controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open study of the efficacy and adverse effects of moclobemide in patients with the chronic fatigue syndrome. White, PD., Cleary, KJ.[2019]

In a 6-week study involving 20 patients with chronic fatigue syndrome, dexamphetamine significantly improved fatigue severity in 9 out of 10 patients compared to only 4 out of 10 in the placebo group.

While there were notable improvements in quality of life measures like vitality and physical functioning, these changes were not statistically significant, suggesting that further research with a larger sample size is needed to confirm dexamphetamine's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot randomized controlled trial of dexamphetamine in patients with chronic fatigue syndrome. Olson, LG., Ambrogetti, A., Sutherland, DC.[2013]

Pilot studies, like the one reporting positive results for granisetron in chronic fatigue syndrome, can show promising outcomes but may not always predict success in larger trials due to issues like selection bias and nonvalidated measurement methods.

A larger, more rigorous clinical trial of granisetron is currently underway to better assess its efficacy in treating chronic fatigue syndrome, following the initial favorable results observed in a small group of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot studies: one swallow does not make a summer... van Gelder, T., Smits, P.[2004]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12017383/

Therapeutic Uses and Efficacy of Low-Dose Naltrexone [20] observed LDN treatment against several conditions and reported that 65% of patients perceived benefit in terms of their pain symptoms in ...

2. tandfonline.com tandfonline.com/doi/full/10.1080/21641846.2019.1692770

Low-dose naltrexone in the treatment of myalgic ... Results: Outcome data were available in 92.2% of patients with an average follow-up time of 1.7 years. A positive treatment response to LDN was ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2666354624000115

Low-dose naltrexone and NAD+ for the treatment of ... Our data suggest treatment with LDN and NAD+ is safe and may be beneficial in a subset of patients with persistent fatigue after COVID-19.

4. casereports.bmj.com casereports.bmj.com/content/13/1/e232502

Low-dose naltrexone as a treatment for chronic fatigue ... We know of no clinical trials of naltrexone in patients with chronic fatigue syndrome or myalgic encephalomyelitis, although some patients report benefits.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05430152

Low-dose Naltrexone for Post-COVID Fatigue Syndrome Overall, studies have found that LDN is safe and well-tolerated. It may help to reduce pain and inflammation and improve well-being and immune function.The ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10039621/

The Safety and Efficacy of Low-Dose Naltrexone in Patients ... Overall, LDN was found to be effective in the symptomatic management of FM, and of the 78% of included studies that evaluated for safety, no severe adverse ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2666354622000758

Safety and efficacy of low dose naltrexone in a long covid ... Low dose naltrexone (LDN) is safe to use in patients with long covid (LC). In patients with LC for a median 11 months, LDN reduced symptoms at 2 months.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11097836/

Low-dose naltrexone for post-COVID fatigue syndrome Additionally, we have formed a Data Safety and Monitoring Board ... Low-dose Naltrexone as a treatment for chronic fatigue syndrome.