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MOTS-c Side Effects: Incidence Rates Across Trials

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12 linked public sourcesEditorial, sourcing, and corrections policy

At a glance

  • Human trials of injected MOTS-c / None found by FDA; no human exposure data by any route [1]
  • Injection concern named by FDA / immunogenicity from aggregation and peptide impurities [2]
  • Approved dose / none; the nominated products were 5 mg and 10 mg subcutaneous injections [1]
  • Adverse-event reports / none retrieved; searches through March 9, 2025 [1]
  • Regulatory and sport status / not FDA-approved; in none of the categories on FDA's compounding lists [1][3][4][12]; prohibited at all times by WADA [5]

Trial incidence versus adverse-event reports

With no published human dosing study, there is no trial population from which to calculate a side-effect rate [1]. FDA's July 2026 evaluation searched PubMed, Embase, the Cochrane library and other sources and found no clinical study of MOTS-c given to humans [1]. Its adverse-event database searches through March 9, 2025 retrieved no MOTS-c reports [1]. The safety of MOTS-c in humans is therefore unknown.

The injection concern FDA named

For injectable peptides, FDA's stated concern is immunogenicity, an immune reaction driven by aggregation and peptide-related impurities [2]. MOTS-c has 16 amino acids, and no immunogenicity data exist for it [1].

What has been studied: mice, cells and people's own MOTS-c

In mice on a high-fat diet, injected MOTS-c at 0.5 mg/kg/day intraperitoneally for 8 weeks was associated with about 20% lower body weight [1]. In one mouse study, a late-life schedule (15 mg/kg three times weekly from 23.5 months of age) lengthened median lifespan from 912 to 970 days [1]. Human studies measured the body's own MOTS-c, not injections: exercise raised endogenous MOTS-c expression in muscle and circulation in Reynolds 2021 [6], while a randomized study of 30 healthy adults found circulating MOTS-c showed only a trend to increase after endurance exercise [7]. In an in-vitro study, MOTS-c was quickly broken down in human blood [1]. FDA says no dose-response relationships were assessed and no pharmacokinetic data exist in humans or live animals [1].

Regulatory and sport status

MOTS-c is not an FDA-approved drug and is not a component of one; FDA found no USP or National Formulary monograph, no European or Japanese pharmacopeia entry, and no EMA-authorized product [1]. It appears in none of the three categories on FDA's list for state-licensed pharmacies and physicians or on FDA's list for outsourcing facilities [3][4][12]. FDA lists it in the "nominated but withdrawn" table of its page on bulk substances that may raise significant safety risks; removal from that category was not a finding that it is safe [2]. FDA staff recommended against adding MOTS-c to the pharmacy bulks list, but the Pharmacy Compounding Advisory Committee voted on July 23, 2026 in favor of adding it. That advice is not binding, and MOTS-c is not on the list [1][8][9]. HHS's October 2026 draft enforcement-discretion policy names MOTS-c acetate for subcutaneous or intramuscular injection but states it is not binding and creates no rights [9][10]. WADA lists MOTS-c in S4.4.1 and prohibits it at all times [5][11].

Frequently asked questions

What are the most common side effects of MOTS-c?
No measured side-effect rate exists. The one injection-related concern FDA names is immunogenicity from aggregation and peptide-related impurities [2].
Is there an incidence rate for injection-site reactions?
No published rate exists. FDA found no human exposure data on MOTS-c products by any route of administration, so no injection-site reaction rate has been collected [1][2].
What did the animal studies show?
Mice on a high-fat diet had about 20% lower body weight after 8 weeks at 0.5 mg/kg/day intraperitoneal [1]. In one mouse study, median lifespan increased from 912 to 970 days with late-life MOTS-c treatment [1]. Mouse results are not human safety data.
Is MOTS-c FDA approved?
No. It is not an FDA-approved drug and is not a component of one, and it is in none of the categories on FDA's compounding lists [1][3][4][12]. The July 2026 advisory committee vote in favor of adding it to the pharmacy bulks list was non-binding, and the October 2026 HHS enforcement-discretion policy is a draft that creates no rights [8][9][10].

References

  1. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  2. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks | FDA. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks | FDA
  3. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  4. Bulk Drug Substances Used in Compounding | FDA. Bulk Drug Substances Used in Compounding | FDA
  5. World Anti-Doping Agency. World Anti-Doping Agency
  6. Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12(1):470. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
  7. von Walden F, Fernandez-Gonzalo R, Norrbom J, Emanuelsson EB, Figueiredo VC, Gidlund EK, et al. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans. J Appl Physiol (1985). 2021;131(3):1035-1042. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans
  8. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  9. Official web page. Official web page
  10. Official web page. Official web page
  11. World Anti-Doping Agency. World Anti-Doping Agency
  12. U.S. Food and Drug Administration. U.S. Food and Drug Administration
Evidence overview for MOTS-c Side Effects: Incidence Rates Across Trials