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AOD-9604 vs MOTS-C — Trial Data

AOD-9604 and MOTS-C both appear in fat-loss and metabolic research, but they are structurally and mechanistically distinct compounds. This page reports what each is, the trial evidence behind each, and their current regulatory and anti-doping status — each figure attributed to the source that reported it.

AOD-9604MOTS-C
What it isSynthetic fragment of human growth hormone — the hGH 176-191 C-terminal regionMitochondrial-derived peptide (MDP) encoded in mitochondrial DNA (12S rRNA region); 16 amino acids
OriginLab-synthesized; modeled on the fat-metabolism (lipolytic) domain of hGHNaturally occurring, produced endogenously by mitochondria
Reported mechanismReported to stimulate lipolysis / fat oxidation, modeled on hGH's fat-metabolism action (Ng et al. 2000, PMID 11146367)Activates AMPK and is reported to improve metabolic homeostasis / insulin sensitivity (Lee et al. 2015, PMID 25738459)
Human trial evidencePhase 2b oral trial (company-reported as 536 adults, 24 weeks; the one peer-reviewed safety paper for this program, Stier et al. 2013, lists N=502 for the matching trial, METAOD006): no statistically significant weight loss vs placebo at any dose, per company/press disclosure — efficacy results were never peer-reviewed; development discontinued 2007No completed human efficacy trial identified; evidence base is preclinical (mouse) and in vitro
FDA statusNot FDA-approved; FDA proposed against adding AOD-9604 acetate to the 503A Bulks List (Dec 4, 2024 PCAC meeting)Not FDA-approved; no compounding-list nomination identified
WADA Prohibited ListProhibited (growth hormone fragments/releasing factors, S2)Prohibited — named by name under S4.4.1 (Metabolic Modulators) since the 2025 List; remains named in the current 2026 List
Route studied in human trialsOral (Phase 2b trial); research-market product is typically sold for subcutaneous useNo completed human trial identified; research-market product is typically sold for subcutaneous use
On this page
  1. 1.Mechanism
  2. 2.Trial Evidence
  3. 3.Adverse Events
  4. 4.Regulatory Status
  5. 5.Dosing
  6. 6.Evidence Level
  7. 7.Reading These Figures
  8. 8.FAQ
  9. 9.References

Mechanism

AOD-9604 is a lab-synthesized fragment of human growth hormone, engineered to isolate the hormone's fat-metabolism (lipolytic) action. Preclinical work (Ng et al. 2000, PMID 11146367; Heffernan et al. 2001, PMID 11673763) reported increased fat oxidation in mice without the growth (IGF-1) or blood-glucose effects associated with intact growth hormone.

MOTS-C is a peptide encoded in mitochondrial DNA and produced endogenously. Lee et al. 2015 (Cell Metabolism, PMID 25738459) reported that it activates AMPK and reduces obesity and insulin resistance in mice, positioning it as a metabolic-homeostasis and “exercise mimetic” research compound rather than a direct fat-burning agent.

Trial Evidence

AOD-9604: Metabolic Pharmaceuticals is reported to have conducted a Phase 2b trial, company-described as 536 adults with obesity, randomized to oral AOD-9604 (0.25, 0.5, or 1 mg/day) or placebo for 24 weeks. Stier et al. 2013 (PMID/DOI 10.4021/jem157w) — the one peer-reviewed safety paper for this program — confirms six real randomized, double-blind, placebo-controlled trials (METAOD001–006) and names the matching 24-week efficacy trial METAOD006 at N=502, not 536; that paper is safety-focused and does not report weight-loss efficacy results. None of the active-treatment arms are reported to have shown a statistically significant weight-loss difference versus placebo on the primary endpoint. Development as an anti-obesity drug was discontinued in 2007. No peer-reviewed publication of the efficacy results was found; this account is based on the trial's publicly reported topline outcome via company and press disclosures only.

MOTS-C: the primary published evidence is preclinical. Lee et al. 2015 (PMID 25738459) is a mouse and cell-culture study. No completed human efficacy trial for MOTS-C has been identified; the compound is at an earlier evidence stage than AOD-9604, which at least reached a Phase 2b human trial before being discontinued.

Adverse Events

  • AOD-9604 Phase 2b trial: reported tolerability indistinguishable from placebo, with no serious adverse events attributed to the peptide and no reported effect on IGF-1 or glucose metabolism.
  • MOTS-C: no human safety trial has been identified, so no human adverse-event data exists to report.

Regulatory Status

Neither compound is FDA-approved. The FDA's Pharmacy Compounding Advisory Committee reviewed AOD-9604 acetate for the 503A Bulks List on December 4, 2024 and the FDA proposed that it not be added to the list. No equivalent 503A nomination for MOTS-C has been identified.

Both are prohibited under WADA rules: AOD-9604 falls under the S2 category for growth hormone fragments and related substances. MOTS-C is prohibited under S4.4.1 (Metabolic Modulators), listed as an example within the “Activators of the AMP-activated protein kinase (AMPK)” class. The 2024 List covered that class generally (naming only AICAR as an example) without naming MOTS-C specifically; WADA began naming MOTS-C explicitly with the 2025 List (effective January 1, 2025), and it remains named in the current 2026 List (effective January 1, 2026): “Activators of the AMP-activated protein kinase (AMPK), e.g. … AICAR, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c).” It is banned at all times.

Dosing

AOD-9604's only completed human efficacy trial used an oral dose of 0.25–1 mg/day and did not show significant weight loss; there is no established effective dosing protocol for this compound in humans. No completed human dosing trial exists for MOTS-C. A dosing guide covering research protocols in circulation is available for MOTS-C; no dosing guide is published for AOD-9604.

Evidence Level

AOD-9604: Human RCT (negative primary endpoint) for weight loss, plus Animal Model evidence for the underlying lipolytic mechanism (PMID 11146367, PMID 11673763). MOTS-C: Animal Model / In Vitro (Lee et al. 2015, PMID 25738459); no Human RCT identified.

AOD-9604 and MOTS-C have not been tested against each other in any identified trial, and their respective evidence bases are at different stages (a discontinued Phase 2b human trial for AOD-9604 versus preclinical mouse/cell data for MOTS-C). The table above reports each compound's own evidence record; it is not a head-to-head comparison.

FAQ

Are AOD-9604 and MOTS-C the same?

No — they are different compounds. AOD-9604 is a synthetic fragment of human growth hormone (the hGH 176-191 region), while MOTS-C is a peptide encoded in mitochondrial DNA. Different origins, different structures, different mechanisms. They overlap only in that both are studied in a metabolic context.

Did AOD-9604 succeed in human trials?

No, by company/press account — but that account was never peer-reviewed. Its Phase 2b trial, company-reported as 536 adults with obesity randomized to oral AOD-9604 (0.25, 0.5, or 1 mg/day) or placebo for 24 weeks, is reported to have shown no statistically significant weight loss at any dose versus placebo. The one peer-reviewed safety paper for this program, Stier et al. 2013, lists N=502 (not 536) for the matching trial, METAOD006, and does not report its efficacy results. Metabolic Pharmaceuticals discontinued development of AOD-9604 as an anti-obesity drug in 2007. Earlier preclinical work (Ng et al. 2000, PMID 11146367; Heffernan et al. 2001, PMID 11673763) reported fat-oxidation and weight-loss effects in mice, but those results were never confirmed in a peer-reviewed human efficacy report.

Has MOTS-C been tested in humans?

No completed human efficacy trial for MOTS-C has been identified. Its evidence base is preclinical: Lee et al. 2015 (Cell Metabolism, PMID 25738459) reported that MOTS-C reduced obesity and insulin resistance in mice via AMPK activation. It is described as an “exercise mimetic” based on this mouse and cell-culture work, not human trial data.

Are either AOD-9604 or MOTS-C on the WADA Prohibited List?

Both are. AOD-9604 is prohibited as a growth hormone fragment under WADA's S2 category (peptide hormones, growth factors, related substances). MOTS-C is prohibited under S4.4.1 (Metabolic Modulators, within the “Activators of the AMP-activated protein kinase (AMPK)” class) — the current 2026 Prohibited List names it explicitly: “e.g. … AICAR, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c).” The 2024 List covered the AMPK-activator class generally but did not name MOTS-C; WADA added the explicit name starting with the 2025 List (effective January 1, 2025), and it remains named in the 2026 List (effective January 1, 2026). Both compounds are banned at all times for athletes subject to anti-doping testing.

Can they be studied together?

They act through different pathways (lipolysis vs AMPK/metabolic homeostasis), so a researcher might study them for complementary metabolic questions — and they are sold together as a combined AOD-9604 + MOTS-c blend. There is no published trial of the combination, and human efficacy evidence for either compound individually is limited or absent.

References

  1. Ng FM, Sun J, Sharma L, et al. Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone. Horm Res. 2000;53(6):274-278. https://pubmed.ncbi.nlm.nih.gov/11146367/
  2. Heffernan MA, Thorburn AW, Fam B, et al. Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment. Int J Obes Relat Metab Disord. 2001;25(10):1442-1449. https://pubmed.ncbi.nlm.nih.gov/11673763/
  3. Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443-454. https://pubmed.ncbi.nlm.nih.gov/25738459/
  4. Zheng Y, Wei Z, Wang T. MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Front Endocrinol (Lausanne). 2023. https://pmc.ncbi.nlm.nih.gov/articles/PMC9905433/
  5. Stier CT. Safety and Tolerability of the Hexadecapeptide AOD9604 in Humans. J Endocrinol Metab. 2013. DOI 10.4021/jem157w. Confirms six randomized, double-blind, placebo-controlled trials (METAOD001–006, ~900 subjects); the matching 24-week efficacy trial, METAOD006, is listed at N=502, not the commonly cited 536; the paper is safety-focused and does not report efficacy results. https://doi.org/10.4021/jem157w
  6. FDA Pharmacy Compounding Advisory Committee. December 4, 2024 meeting briefing document (503A Bulks List, AOD-9604). https://www.fda.gov/media/185642/download
  7. World Anti-Doping Agency. The Prohibited List 2026, effective January 1, 2026, category S4.4.1 (Metabolic Modulators). MOTS-c is named explicitly as of the 2025 List (effective January 1, 2025); the 2024 List covered the AMPK-activator class without naming it. https://www.wada-ama.org/en/prohibited-list
AOD-9604 ProfileMOTS-C ProfileMOTS-C Dosing GuideAOD-9604 + MOTS-c Blend

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