Athletic performance / endurance
Work capacity and recovery via AMPK/mito and GH/IGF pathways.
Decision support, not prescription. You decide.
Candidate agents
7 agents · tap to expand▶MOTS-cLeadPreclinicalMOTS-c is a mitochondrial-derived peptide being explored as an endurance and work-capacity enhancer; for athletic performance the human evidence is essentially zero, so treat it as a promising animal story only.expand
MOTS-c is a mitochondrial-derived peptide being explored as an endurance and work-capacity enhancer; for athletic performance the human evidence is essentially zero, so treat it as a promising animal story only.
▸Full clinical story
MOTS-c is encoded in mitochondrial DNA and translocates to the nucleus under metabolic stress, activating AMPK and regulating nuclear genes tied to glucose handling, fatty-acid metabolism and proteostasis in skeletal muscle. Exercise itself raises endogenous MOTS-c in human muscle and plasma, which is the basis for giving it exogenously as an exercise mimetic.
Preclinical. Intermittent injection improved treadmill/running performance in young, middle-aged and old mice, including late-life initiation (Nat Commun 2021), and improved myocardial mechanical efficiency during aerobic training in rats (Sci Rep 2021); a review confirms exercise induces MOTS-c in humans but no human performance trials exist (Biochim Biophys Acta Gen Subj 2021). Grade preclinical is correct — all efficacy data are in rodents.
Anecdotal community signal only: sold by research-chemical vendors and used off-label by biohackers and some athletes as subcutaneous injections, often 'exercise-mimetic' microdosing on training days, with self-reported gains in endurance and recovery. These reports are uncontrolled, unblinded, and confounded by concurrent training and stacks; they are not evidence of efficacy.
No validated human dose. Rodent studies used roughly 0.5-15 mg/kg intermittently (e.g. 3x/week); community protocols circulate around 5-10 mg subcutaneous doses several times weekly. This is context, not a protocol.
Purity and identity of research-grade peptide are unverified; injectable use carries infection and contamination risk. As an AMPK activator it could theoretically stack additively with metformin, AICAR or NAD+ precursors and with insulin-sensitizing effects. Note WADA/anti-doping exposure for competitive athletes — peptide 'exercise mimetics' are a prohibited-substance category concern.
Mechanistically appealing and exercise-linked, but MOTS-c has no human efficacy or safety data for performance. It sits firmly in preclinical/experimental territory; any clinical use is off-label and unproven.
▶NAD+EmergingNAD+ precursors (chiefly nicotinamide riboside) are marketed for energy and endurance; the human performance data are genuinely mixed and mostly null, so keep expectations low and age-dependent.expand
NAD+ precursors (chiefly nicotinamide riboside) are marketed for energy and endurance; the human performance data are genuinely mixed and mostly null, so keep expectations low and age-dependent.
▸Full clinical story
NAD+ is the central redox cofactor for oxidative metabolism and the substrate for sirtuins and PARPs; the theory is that raising NAD+ boosts mitochondrial biogenesis, sirtuin signalling and redox capacity to support work output. In practice, whether oral precursors meaningfully raise skeletal-muscle NAD+ in healthy people is the crux — and often they do not.
Emerging, leaning negative in the young. In a double-blind crossover, acute NR improved isometric strength and fatigue index and reduced oxidative stress in older men but had no effect in young men (Eur J Nutr 2019). A separate controlled trial found 7-day NR did not raise muscle NAD+ or alter whole-body/skeletal-muscle metabolic and mitochondrial-biogenic responses to endurance exercise in young men (J Physiol 2021). Grade emerging is appropriate: real human RCTs exist, but they are small and largely show benefit only where a deficit exists.
Anecdotal community signal only: NR and NMN are among the most widely used OTC 'longevity/energy' supplements, taken orally daily, with some users adding IV NAD+ infusions for recovery. Self-reported energy gains are common but subjective and prone to placebo; controlled data do not support an endurance benefit in healthy young athletes.
Context, not a protocol: oral NR trials used ~250-1000 mg/day (the endurance study used 1000 mg/day for 7 days); NMN products cluster around 250-900 mg/day. IV NAD+ dosing is unstandardized.
Generally well tolerated; flushing is more a niacin than an NR issue. The key clinical caution is efficacy, not toxicity — benefit appears confined to deficient/older individuals, so avoid overselling to young trained athletes. Long-term high-dose safety and any interaction with NAD-consuming disease states remain under study.
A biologically reasonable, safe supplement with honest but underwhelming human performance data: possible small benefit in older or deficient people, no convincing ergogenic effect in healthy young athletes.
▶AICARPreclinicalAICAR is a direct AMPK agonist studied as a pharmacologic 'exercise in a pill' for endurance; the headline result is real but rodent-only, so take it as proof of concept, not a human therapy.expand
AICAR is a direct AMPK agonist studied as a pharmacologic 'exercise in a pill' for endurance; the headline result is real but rodent-only, so take it as proof of concept, not a human therapy.
▸Full clinical story
AICAR is converted intracellularly to ZMP, an AMP mimetic that allosterically activates AMPK, driving PGC-1alpha and a PPAR-delta oxidative program that increases mitochondrial biogenesis and a shift toward oxidative (fatigue-resistant) myofibers. The rationale for performance is that this reproduces part of the endurance-training transcriptional signature without exercise.
Preclinical. In sedentary mice, 4 weeks of AICAR alone increased treadmill running endurance by ~44% and induced oxidative-metabolic genes, demonstrating drug-induced endurance without training (Cell 2008). No controlled human endurance efficacy data exist. Grade preclinical is correct.
Anecdotal community signal only: known in doping circles as an 'exercise mimetic' and occasionally used by endurance athletes; practical uptake is limited by poor oral bioavailability, very high effective doses, and cost. Reported experiences are sparse and unreliable.
No validated human performance dose. The endurance mouse study used 500 mg/kg/day subcutaneously — a dose that does not translate practically to humans. Treat any circulating protocol as unsupported context, not guidance.
AICAR is explicitly prohibited by WADA (metabolic modulator, class S4) — a hard stop for any competitive athlete. AMPK activation can lower blood glucose and would stack additively with metformin, insulin or other AMPK/mito agents; oncologic safety of chronic AMPK activation is unresolved. Human safety at effective doses is unknown.
A landmark proof-of-concept that AMPK activation can raise endurance pharmacologically, but AICAR remains rodent-only for efficacy, is doping-banned, and has no established human performance use.
▶BPC-157PreclinicalBPC-157 is a synthetic gastric peptide used off-label for tendon, ligament and muscle injury recovery in athletes; the healing data are consistent but entirely animal-based, so it is unproven in humans.expand
BPC-157 is a synthetic gastric peptide used off-label for tendon, ligament and muscle injury recovery in athletes; the healing data are consistent but entirely animal-based, so it is unproven in humans.
▸Full clinical story
BPC-157 appears to promote angiogenesis and fibroblast/tenocyte activity (up-regulating growth factors and egr-1) and modulates the nitric-oxide system, which in injury models accelerates soft-tissue repair. The performance relevance is recovery and return-to-play from musculoskeletal injury rather than direct work-capacity enhancement.
Preclinical. Rodent studies show accelerated, biomechanically and functionally superior healing of transected medial collateral ligament (J Orthop Res 2010) and, per a review, consistent healing of tendon, ligament and skeletal-muscle injuries across models — but efficacy is unconfirmed in humans, with no completed controlled human trials (Cell Tissue Res 2019). Grade preclinical is correct.
Anecdotal community signal only, and it is large: BPC-157 is one of the most widely used recovery peptides among athletes and lifters, taken as subcutaneous injections (often near the injury) or orally, with abundant self-reports of faster tendon/joint recovery. These reports are uncontrolled and confounded by natural healing, rest and rehab; they are not proof.
No validated human dose. Community protocols commonly cite ~200-500 mcg/day (sometimes split, sometimes injected locally) for a few weeks; rodent efficacy spanned an extremely wide ng-to-mcg/kg range. Context only, not a protocol.
Not an approved drug; sourced from research-chemical suppliers with unverified purity/sterility and injection-related risks. Prohibited under WADA (non-approved substance, class S0) — disqualifying for tested athletes. Human long-term safety, angiogenesis-related oncologic risk, and interactions are essentially unstudied.
Heavily used and mechanistically plausible for injury recovery, but BPC-157 rests entirely on animal data plus community anecdote, is banned in sport, and carries real sourcing/safety unknowns — promising but unproven in humans.
▶ElamipretidePreclinicalElamipretide (SS-31) is a mitochondria-targeting peptide studied for restoring exercise tolerance in aged/dysfunctional muscle; for healthy athletic performance the direct evidence is preclinical, and its human data live mostly in mitochondrial disease.expand
Elamipretide (SS-31) is a mitochondria-targeting peptide studied for restoring exercise tolerance in aged/dysfunctional muscle; for healthy athletic performance the direct evidence is preclinical, and its human data live mostly in mitochondrial disease.
▸Full clinical story
Elamipretide concentrates in the inner mitochondrial membrane and binds cardiolipin, stabilizing cristae and improving electron-transport efficiency, which raises ATP production and lowers mitochondrial ROS. The performance rationale is correcting an age- or disease-related energetic and redox deficit rather than augmenting already-healthy muscle.
Preclinical for performance. In aged mice, 8 weeks of SS-31 reversed the age-related decline in maximal mitochondrial ATP production, restored muscle redox homeostasis, increased fatigue resistance and significantly improved treadmill endurance (Free Radic Biol Med 2018). Human trials exist but are in mitochondrial myopathy and heart failure, not athletic populations, so grade preclinical is correct for this condition.
Anecdotal community signal only: used off-label by longevity and biohacker communities and some masters athletes as subcutaneous injections for 'mitochondrial recovery,' with self-reported reductions in fatigue. These are uncontrolled anecdotes; note that a healthy trained athlete may have little energetic deficit to correct, so a benefit seen in aged muscle may not transfer.
No validated performance dose. The aged-mouse study used 3 mg/kg/day; human disease trials have used roughly 40 mg/day subcutaneously. Context only, not a protocol.
Injectable peptide with contamination/purity risk from non-pharmaceutical sources; injection-site reactions are the most common trial adverse event. Benefit appears deficit-dependent, so expectation-setting matters. Anti-doping status should be checked before use in sanctioned sport.
Strong mitochondrial mechanism and genuine human development, but for athletic performance in healthy people the evidence is preclinical and the strongest signal is in restoring impaired muscle, not enhancing normal muscle.
▶SLU-PP-332PreclinicalBoosted endurance in mice by mimicking the muscle-adaptation signals of aerobic exercise.expand
Boosted endurance in mice by mimicking the muscle-adaptation signals of aerobic exercise.
▸Full clinical story
ERRα-dependent induction of the acute aerobic-exercise gene program increases mitochondrial respiration and oxidative (type IIa) muscle fibers.
Treated mice ran ~70% longer and ~45% further than controls; C2C12 myocytes showed enhanced mitochondrial respiration.
No verifiable community reports.
No human dose; rodent IP dosing only. Prohibited/detectable in anti-doping testing.
No human data; use in sport is banned and detectable.
Striking endurance gains in mice, but unproven and unsafe to assume in humans.
Not recommended for this condition
Shown to close the loop — the evidence points the wrong way here.
▶MetforminStrongFor athletic performance metformin carries a human-RCT signal of harm: in older adults it blunted the muscle-building and adaptive response to resistance training, so it is best avoided or carefully timed as a performance adjunct.expand
For athletic performance metformin carries a human-RCT signal of harm: in older adults it blunted the muscle-building and adaptive response to resistance training, so it is best avoided or carefully timed as a performance adjunct.
▸Full clinical story
Metformin activates AMPK and inhibits complex I, which suppresses mTORC1-driven protein synthesis and dampens the anabolic and extracellular-matrix remodeling programs that resistance training normally switches on. The same AMPK activation touted as beneficial elsewhere works against hypertrophy here.
Emerging (single human RCT) for a negative effect. In a randomized, double-blind, placebo-controlled trial in older adults (~47 participants), adding metformin to 14 weeks of progressive resistance training blunted muscle hypertrophy and attenuated the training-induced ECM-remodeling transcriptomic response versus placebo (Aging 2020). The adverse direction is well-supported and biologically coherent, but it rests on one modest-sized trial in older adults, so grade emerging is more honest than strong.
Anecdotal community signal: metformin is popular in longevity circles taken daily for healthspan, and some users combine it with training unaware of the interaction. The trial-level signal that it can offset training gains is often under-appreciated in that community; note the same study suggested possible benefits on aging-associated pathways, so the tradeoff is nuanced.
Context only: the trial used standard clinical dosing (titrated toward ~1700 mg/day). There is no performance-enhancing dose — the relevant point is that typical therapeutic doses are enough to blunt adaptation.
Condition-specific flag: metformin plus resistance training in older or hypertrophy-seeking individuals may reduce muscle gains — counsel patients pursuing strength/mass. Its AMPK effect can compound with other AMPK/mito agents (AICAR, MOTS-c). Standard GI intolerance and B12 depletion apply but are secondary to the adaptation-blunting concern here.
Supported by a single human RCT as counterproductive for training adaptation in older adults; the adverse direction is credible but rests on one modest trial, so treat as a drug to avoid or time carefully when muscle hypertrophy and strength are the goal, weighing it against its metabolic/longevity indications.
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