Chronic fatigue / burnout
Bioenergetic failure with immune & HPA overlap; restore mitochondrial output.
Decision support, not prescription. You decide.
Warning — BPC-157 crash risk in post-viral/ME-CFS
Post-viral/ME-CFS patients report crashing at standard dose; microdose 10–25%.
Candidate agents
6 agents · tap to expand▶NAD+LeadEmergingAn NAD+ precursor strategy for chronic fatigue/ME-CFS that has the most actual human trial data of anything on this list, but the positive signal is for the NADH+CoQ10 combination, not NAD+ given alone. Take it as a reasonable, low-risk adjunct rather than a proven therapy.expand
An NAD+ precursor strategy for chronic fatigue/ME-CFS that has the most actual human trial data of anything on this list, but the positive signal is for the NADH+CoQ10 combination, not NAD+ given alone. Take it as a reasonable, low-risk adjunct rather than a proven therapy.
▸Full clinical story
The rationale here is bioenergetic: ME/CFS patients show reduced intracellular NAD+/NADH ratios and impaired ATP production, and NADH is a direct electron donor to complex I of the mitochondrial electron transport chain. Pairing it with CoQ10 (an electron carrier further down the chain) is meant to restore oxidative phosphorylation output in fatigued muscle and immune cells rather than act as a stimulant.
Emerging. Two small 8-week randomized, double-blind, placebo-controlled trials in diagnosed CFS tested oral CoQ10 (200 mg/day) plus NADH (20 mg/day): the first (n=73) reported reduced perceived fatigue and improved biochemical parameters including higher NAD+/NADH and ATP (Antioxid Redox Signal, epub 2014/print 2015), and the second (n=80) showed a significant reduction in maximum heart rate on exercise testing plus reduced fatigue perception, though not pain or sleep (Clin Nutr 2016). Both are small, single-combination, and short; the evidence supports the NADH+CoQ10 pairing, not NAD+ or NAD+-precursor monotherapy, so 'emerging' is the honest ceiling.
Anecdotal community signal only: patients in ME/CFS and long-COVID communities widely use oral NAD+ precursors (NR, NMN) and NADH, plus subcutaneous or IV NAD+ 'infusions,' often stacked with CoQ10, and report variable energy and post-exertional malaise improvement. This is self-report from forums and clinic marketing, not controlled data, and the injectable/IV routes have no trial support in this condition.
Context, not a protocol: the trials used NADH 20 mg/day with CoQ10 200 mg/day. Community use of NAD+ precursors runs far higher (NMN/NR 250-1000 mg/day; IV NAD+ 250-1000 mg per session), which is well outside anything tested for fatigue.
Generally well tolerated, but CoQ10 can modestly lower blood pressure and may reduce warfarin effect, so co-medication matters. NADH is best taken fasting; NAD+ precursors are theoretically worth caution in active malignancy given NAD+'s role in cell proliferation, and IV NAD+ carries infusion-related flushing/chest tightness with dose escalation.
The best-studied option in this bucket, but 'best-studied' still means two small trials of a specific NADH+CoQ10 combination. Reasonable to trial as a low-risk adjunct with realistic expectations; do not equate it with NAD+ IV therapy, which is unproven here.
- Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? ↗
- Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome - A randomized, controlled, double-blind trial. ↗
▶ElamipretideStrongA cardiolipin-targeting mitochondrial peptide that, despite an excellent mechanistic story for bioenergetic fatigue, has high-quality human evidence showing it did NOT improve fatigue in the most relevant trial. This is a strong-but-negative signal, not a recommendation.expand
A cardiolipin-targeting mitochondrial peptide that, despite an excellent mechanistic story for bioenergetic fatigue, has high-quality human evidence showing it did NOT improve fatigue in the most relevant trial. This is a strong-but-negative signal, not a recommendation.
▸Full clinical story
Elamipretide (SS-31) concentrates in the inner mitochondrial membrane and binds cardiolipin, stabilizing cristae structure and improving electron transport efficiency while reducing electron leak and reactive oxygen species. On paper that directly targets the 'restore mitochondrial output' lever, which is exactly why it keeps appearing in fatigue discussions.
Strong, and strongly negative. In the phase 3 MMPOWER-3 randomized, double-blind, placebo-controlled trial (N=218) in primary mitochondrial myopathy, 24 weeks of subcutaneous elamipretide did not improve the co-primary endpoints of total fatigue score (PMMSA) or 6-minute walk distance versus placebo, though it was well tolerated (Neurology 2023, Class I evidence). This is the highest-quality fatigue-outcome data in the whole list, and it argues against benefit in a genetically bioenergetic-failure population; there is no positive RCT in idiopathic chronic fatigue or burnout.
Anecdotal community signal is limited and mostly aspirational: it appears in biohacker and mito-medicine discussion as a 'holy grail' mitochondrial peptide, but it is not a compounding-pharmacy staple and real-world off-label use in fatigue is uncommon compared with NAD+ or LDN. Reports that do exist are scarce and uncontrolled.
Context, not a protocol: the trial used elamipretide 40 mg subcutaneously once daily. There is no established oral or fatigue-specific regimen.
Condition-specific caveat is really an expectation-setting one: the definitive trial was negative, so prescribing it for fatigue means paying (injectable, investigational) for an intervention that failed its fatigue endpoint. Injection-site reactions are the main tolerability issue; availability is restricted given its investigational status.
The cleanest evidence here, and it says no. A clinician should treat elamipretide as a cautionary example of a beautiful mechanism that did not translate to fatigue benefit, and not offer it for chronic fatigue/burnout outside a trial.
▶MOTS-cPreclinicalA mitochondrial-derived peptide with an appealing 'exercise mimetic' story for bioenergetic fatigue, but the evidence is entirely animal/cell-based. Treat any fatigue claim as hypothesis, not therapy.expand
A mitochondrial-derived peptide with an appealing 'exercise mimetic' story for bioenergetic fatigue, but the evidence is entirely animal/cell-based. Treat any fatigue claim as hypothesis, not therapy.
▸Full clinical story
MOTS-c is a 16-amino-acid peptide encoded in the mitochondrial 12S rRNA that activates AMPK, promoting glucose uptake, fatty-acid oxidation, and metabolic stress adaptation in skeletal muscle. Because it translocates to the nucleus under metabolic stress and mimics some effects of exercise, it is proposed as a way to raise cellular energy handling in fatigue states.
Preclinical only. The foundational work showed MOTS-c promotes metabolic homeostasis, improves insulin sensitivity, and reduces diet-induced obesity in mice (Cell Metab 2015). There are no human trials, and specifically no study evaluating MOTS-c in chronic fatigue, ME/CFS, or burnout, so 'preclinical' is accurate and should not be inflated by the strength of the mechanism.
Anecdotal community signal: MOTS-c is sold and self-administered subcutaneously in peptide/biohacker communities as an energy, endurance, and metabolic-health peptide, often cycled like other research peptides. Reported 'more energy/better workouts' effects are uncontrolled self-report, and product quality from research-chemical suppliers is unverified.
Context, not a protocol: community subcutaneous regimens commonly cited are roughly 5-10 mg per week, split across doses or cycled for several weeks. No dose has any efficacy or safety validation in humans for fatigue.
Because it drives AMPK and glucose uptake, the theoretical flags are additive glucose-lowering with insulin/other hypoglycemics and unknown effects in metabolic disease; there is no human safety database. Sourcing is a real risk since these are research-grade, non-pharmaceutical products with possible endotoxin/purity issues.
Mechanistically interesting and worth watching, but for chronic fatigue/burnout it is a lab hypothesis with zero human data. A clinician should frame it as experimental and not endorse community injectable use.
▶HumaninNoneA mitochondrial-derived cytoprotective peptide included as a mechanistic placeholder for bioenergetic decline, with no direct fatigue evidence at all. Treat it as a research gap, not an option.expand
A mitochondrial-derived cytoprotective peptide included as a mechanistic placeholder for bioenergetic decline, with no direct fatigue evidence at all. Treat it as a research gap, not an option.
▸Full clinical story
Humanin is a small mitochondrial-derived peptide with cytoprotective, anti-apoptotic, and metabolic-signaling roles, and circulating levels decline with age and mitochondrial stress. That biology makes it a plausible candidate for conditions of bioenergetic failure, which is the only reason it is mapped here.
None. A targeted PubMed search returns no human or animal study evaluating humanin in chronic fatigue, ME/CFS, or burnout as a clinical outcome; existing literature concerns aging, neuroprotection, and metabolic disease, not fatigue. This entry is an honest mechanistic gap, and no citation can support a fatigue claim.
Essentially none as a fatigue therapy: unlike MOTS-c, humanin is not a common compounded or biohacker peptide, and there is no meaningful off-label community protocol for energy or fatigue to report. Any use is fringe and undocumented.
No established or community dosing exists for this indication; nothing can be responsibly quoted as context.
Because there is no human therapeutic use in fatigue, the main caution is simply that any product marketed as 'humanin peptide' for energy is unvalidated and unregulated; safety and interactions are unknown.
Interesting mitochondrial biology, but for chronic fatigue/burnout it is a blank slate. A clinician should log it as a mechanism to watch and offer nothing on the strength of it today.
▶Low-Dose NaltrexoneAnecdotalAn off-label immunomodulator used for ME/CFS and post-viral fatigue where direct controlled efficacy data are still missing. Treat it as a plausible, low-cost, generally-safe trial-and-see option, not an evidence-backed standard.expand
An off-label immunomodulator used for ME/CFS and post-viral fatigue where direct controlled efficacy data are still missing. Treat it as a plausible, low-cost, generally-safe trial-and-see option, not an evidence-backed standard.
▸Full clinical story
At ~4.5 mg the rationale is not opioid blockade for its own sake but transient receptor antagonism that upregulates endogenous endorphins, plus antagonism of glial Toll-like receptor 4 (TLR4). Because chronic fatigue/ME-CFS has a neuroinflammatory and immune-dysregulation component, damping microglial activation is the proposed lever rather than a direct mitochondrial effect.
Anecdotal for this condition. The direct ME/CFS literature is a three-case report/small case-level experience (BMJ Case Rep 2020), and a double-blind RCT for post-COVID fatigue exists only as a published protocol (BMJ Open 2024), so confirmatory efficacy is not yet in. The nearest controlled data are a 2025 meta-analysis of seven RCTs in chronic pain syndromes, which found no significant pain benefit for LDN over placebo overall (a small benefit appeared only in the fibromyalgia subgroup) and more adverse events than placebo (Curr Pain Headache Rep 2025); that is adjacent, pain-focused, and not fatigue-outcome data. Grade stays 'anecdotal' for chronic fatigue/burnout specifically.
Anecdotal community signal, but large: LDN is one of the most widely self-adopted off-label agents in ME/CFS and long-COVID circles, obtained via compounding pharmacies and prescriber networks, with many patients reporting reduced post-exertional malaise, better sleep, and lower pain. A meaningful subset reports no benefit or vivid-dream/sleep disruption; none of this is controlled evidence.
Context, not a protocol: typically started very low (0.5-1.5 mg/day) and titrated over weeks toward 4.5 mg/day, dosed at bedtime or in the morning if dreams are disruptive; some clinicians use ultra-low microdoses. Compounded formulation is standard because commercial naltrexone is 50 mg.
Condition-specific flags: it will precipitate withdrawal in anyone on opioids or using opioid analgesics for the pain that often accompanies ME/CFS, so screen for that first. Use caution in acute hepatitis/hepatic impairment, and note it can blunt effectiveness of opioid-containing cough or antidiarrheal agents; interactions with the immunosuppressants some overlap patients take are theoretical but worth tracking.
Cheap, reversible, and mechanistically reasonable for a neuroinflammatory fatigue phenotype, but for chronic fatigue/burnout the efficacy case is still case-series plus an unfinished RCT. Defensible as a monitored individual trial; not something to present as proven.
- Low-dose naltrexone as a treatment for chronic fatigue syndrome. ↗
- Low-dose naltrexone for post-COVID fatigue syndrome: a study protocol for a double-blind, randomised trial in British Columbia. ↗
- Low Dose Naltrexone In The Management Of Chronic Pain Syndrome: A Meta-Analysis Of Randomized Controlled Clinical Trials. ↗
▶SLU-PP-332PreclinicalImproved muscle mitochondrial energy output and endurance in mice, suggesting fatigue-resistance potential.expand
Improved muscle mitochondrial energy output and endurance in mice, suggesting fatigue-resistance potential.
▸Full clinical story
Enhanced mitochondrial respiration and oxidative fiber content increase muscle energetic capacity.
Endurance and mitochondrial-respiration gains in rodent and myocyte models; no human fatigue endpoints.
No verifiable community reports.
No human dose established.
No human data; fatigue benefit is inferred, not demonstrated.
Biologically plausible for fatigue but untested in people.
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