Metabolic Research Comparison

AICAR vs MOTS-c: AMPK Activators Compared

Two research compounds that switch on the same energy sensor by different routes: how they work, what studies show, which has human data, and where regulators stand.

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Fact-checked · Reviewed by Remy Research Editorial Board
Update History ▾
October 27, 2026: Initial publication, built from primary AICAR and MOTS-c studies, the RED-CABG and acadesine leukaemia trials, FDA’s 2026 MOTS-c briefing, ClinicalTrials.gov and the WADA 2027 Prohibited List.
Research-use-only framing applied throughout in line with Remy editorial standards.
TL;DR — Research Summary

AICAR vs MOTS-c comes down to two different molecules that reach the same energy sensor. AICAR is a small-molecule nucleoside that cells turn into ZMP, an AMP mimic that switches on AMP-activated protein kinase (AMPK) directly. MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA that activates AMPK indirectly, through the folate cycle and purine synthesis.[1][2]

AICAR has more human evidence, including a 3,080-patient phase 3 heart-surgery trial that found no benefit, and documented side effects such as high uric acid and low blood pressure.[3][4] MOTS-c has no published human treatment trial.[5] Neither is an approved medicine, both are prohibited by WADA under S4.4.1, and Remy Research supplies both for in-vitro laboratory research only.[6]

Compliance note: this page is a research review, not a treatment guide. It does not provide human-use dosing, therapeutic recommendations, or any clinical-use instructions, and should be read in the same non-therapeutic frame required across Remy's research content.

AICAR vs MOTS-c: Side-by-Side Comparison

AICAR vs MOTS-c — Key Differences
Feature AICAR (acadesine) MOTS-c
Molecule type Nucleoside (not a peptide) 16-amino-acid peptide
Origin Synthetic research and drug compound Encoded in mitochondrial DNA
AMPK route Direct: ZMP mimics AMP Indirect: folate cycle and purine synthesis
Key animal result 44% more running endurance in sedentary mice Less diet-induced obesity and insulin resistance
Human trials Phase 1 to 3; phase 3 stopped for futility None published; analogue CB4211 in phase 1
Known side effects Uric acid rise, hypotension (trial data) Unknown in humans
FDA status Not approved Not approved
WADA status S4.4.1, prohibited S4.4.1, prohibited

What Is AICAR? An AMPK Activator Nucleoside

AICAR is 5-aminoimidazole-4-carboxamide ribonucleoside, also called acadesine or AICA riboside. Cells take it up and phosphorylate it to ZMP, an analogue of AMP. ZMP mimics both activating effects of AMP on AMPK, which made AICAR the standard tool for activating AMPK in intact cells.[1] AICAR is not a peptide, even though it is often sold as the “AICAR peptide”.

AMP-activated protein kinase is a key regulator of cellular energy: a nutrient and energy sensor that maintains energy homeostasis and energy balance across many cellular processes.[7] AICAR acts on this energy sensor AMPK in skeletal muscle as well as liver. In a 1997 study in the American Journal of Physiology, perfusing rat hindlimb muscle with AICAR activated AMPK, raised fat oxidation (fatty acid oxidation) 2.8-fold and increased glucose uptake.[8] AMPK switches these pathways on when cellular energy production falls behind demand.[7] In hepatocytes, AICAR almost stopped fatty acid and sterol synthesis.[1] These effects on lipid metabolism and glucose uptake are why AICAR is used as an AMPK activator in metabolic research.

How MOTS-c Acts: AMPK Activation From the Mitochondria

MOTS-c, the mitochondrial open reading frame of the 12S rRNA-c, is a peptide the body makes from mitochondrial DNA. Its main target organ appears to be skeletal muscle. In cells it inhibits the folate cycle and the de novo purine biosynthesis tied to it, which leads to AMPK activation.[2] Under metabolic stress, MOTS-c also moves into the nucleus and changes nuclear gene expression.[9]

In muscle, a 2026 study reported that MOTS-c improved intrinsic mitochondrial function and efficiency in a PGC-1α- and AMPK-dependent way.[10] So both compounds converge on AMPK, but by different routes: AICAR supplies an AMP mimic directly, while MOTS-c works upstream through metabolic pathways. For the full MOTS-c evidence review, including human MOTS-c level studies, see MOTS-c benefits and side effects.

AICAR Research: Exercise, High Fat Diet and Body Weight

The most cited AICAR research is a 2008 mouse study. In sedentary mice, AICAR alone induced metabolic genes in muscle and enhanced running endurance by 44% without physical activity, which led the authors to call AMPK and PPARδ agonists exercise mimetics with potential in metabolic disorders. In the same study, a PPARδ agonist combined with training increased oxidative muscle fibres; AICAR was the compound that worked without training.[11] Other animal models point the same way. In a 2022 study in the International Journal of Molecular Sciences, male mice fed a high fat diet developed weight gain, high blood glucose and insulin, and abdominal fat; AICAR lowered body weight and abdominal fat and improved the appearance of internal organs in this model of metabolic syndrome and type 2 diabetes.[12]

In humans, a small study in 10 men with type 2 diabetes found that intravenous AICAR reduced hepatic glucose output, lowered blood glucose levels and reduced plasma fatty acids compared with a saline control test. The authors concluded that AICAR stimulated hepatic fatty acid oxidation and/or inhibited whole-body lipolysis. In skeletal muscle, AMPK phosphorylation itself did not rise, although its target acetyl-CoA carboxylase was phosphorylated.[13] That study measured short-term metabolic pathways; it did not test exercise, insulin sensitivity over time or body mass.

AICAR in Cardiovascular Research and Cancer Cells

Acadesine was also developed as a heart drug. As an adenosine-regulating agent it was given around bypass surgery to limit ischaemia-reperfusion injury, and a meta-analysis of earlier randomized trials had linked it to fewer early cardiac deaths and heart attacks. The larger RED-CABG trial then found no benefit (see below).[3]

In haematology, acadesine selectively induced apoptosis in B cells from patients with chronic lymphocytic leukaemia in laboratory studies, which led to a phase 1/2 trial. Trends such as fewer circulating leukaemia cells were seen, but results varied in the small group; the authors described the therapeutic potential as worth further study in CLL.[4] An older phase 2 pilot also tested AICAR in Lesch-Nyhan disease, a disorder of purine metabolism.[14] AICAR appears in research far beyond exercise: wherever cellular energy and AMPK matter.[7]

MOTS-c Research: Insulin Resistance and Physical Capacity

In mice, MOTS-c treatment prevented age-dependent and high-fat-diet-induced insulin resistance and prevented diet-induced obesity.[2] A 2021 study found the body’s own MOTS-c rose in human muscle and blood with exercise, and in mice MOTS-c treatment improved physical performance, including in old age.[15] In the original study the peptide regulated insulin sensitivity and metabolic homeostasis mainly through skeletal muscle.[2] These findings overlap with AICAR’s animal data on endurance and body weight. One difference: the body makes MOTS-c itself, and its levels in muscle and blood change with exercise, while AICAR as a research compound is an outside agent. MOTS-c has not been tested as a treatment in people.[5]

Potential Benefits: What the Animal Models Share

The potential benefits claimed for both compounds overlap: better glucose handling, less fat gain on a high fat diet and more endurance without extra physical activity. For AICAR these come from rat and mouse studies; for MOTS-c from mouse studies.[8][11][12][2][15] Neither has shown that it can improve metabolic health, energy levels or physical capacity in people, so claims that either compound will enhance insulin sensitivity in humans are unsupported.[13][5]

Which Has More Human Evidence?

AICAR, clearly. As acadesine it reached phase 3: the RED-CABG trial randomized 3,080 intermediate- to high-risk patients having bypass surgery, and was stopped early for futility after the composite of death, stroke or severe heart dysfunction occurred in 5.1% on acadesine and 5.0% on placebo.[3] It was also tested in a phase 1/2 study in 24 patients with relapsed chronic lymphocytic leukaemia.[4] ClinicalTrials.gov lists five AICAR or acadesine clinical trials.[14]

MOTS-c has no published human trial. FDA’s 2026 review found a lack of any safety and effectiveness information in humans.[5] The only industry human study in this area tested CB4211, an analogue of MOTS-c, in a phase 1 study of 88 people.[16] Human MOTS-c research otherwise measures natural levels, not effects of MOTS-c given as a treatment.

AICAR Side Effects vs MOTS-c Side Effects

The AICAR data come from patients given the drug in hospital trials. Neither record supports any use outside a laboratory.

Regulatory Status and Anti-Doping Rules

Where AICAR and MOTS-c stand as of October 27, 2026.
  • AICAR and FDA. Not approved: Drugs@FDA has no application for acadesine.[17]
  • MOTS-c and FDA. Not approved. In July 2026 FDA’s advisory committee voted 7 to 5, with two abstentions, to recommend allowing it in compounding pharmacy use, against FDA reviewers’ advice; the vote is non-binding.[18][5]
  • Sport. WADA’s 2027 Prohibited List names both AICAR and MOTS-c under S4.4.1, activators of AMPK, among the metabolic modulators prohibited at all times.[6]
  • UAE. Neither is a registered medicine. Remy Research supplies both for research purposes only, in vitro, not for human or veterinary use. This is not medical advice; health questions belong with a qualified healthcare professional.

What Future Research Needs to Show

Related mitochondrial research: SS-31 benefits and side effects and MOTS-c vs SS-31.

AICAR and MOTS-c for Laboratory Research

Remy Research supplies AICAR for in-vitro research as the Genovare AICAR 250mg AQ pen, and MOTS-c as the MOTS-c 10mg research vial and other formats on the MOTS-c page. Each product page carries its batch testing details. For AICAR’s full mechanism, see the AICAR research review.

Our Research Standards

This comparison prioritizes primary literature, trial registries and regulator records, and keeps cell, animal and human evidence apart. Where the human record is empty, we say so directly. No therapeutic, dosing or administration guidance is given. Read our editorial policy →

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Editorial Review

Editorial Board, Remy Research

The Remy Research Editorial Board reviews Remy's peptide research library, with a focus on analytical verification, clinical-trial interpretation, and compliance-safe scientific communication.

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AICAR vs MOTS-c FAQ

What is the difference between AICAR and MOTS-c?

AICAR is a small-molecule nucleoside that activates AMPK directly through its metabolite ZMP. MOTS-c is a mitochondrial-DNA-encoded peptide that activates AMPK indirectly through the folate cycle.[1][2]

Is AICAR a peptide?

No. AICAR (acadesine) is a ribonucleoside. Cells convert it to ZMP, an analogue of AMP.[1]

What are the side effects of AICAR?

In a phase 1/2 trial, common effects were raised uric acid and transient low blood pressure during infusion, with temporary anaemia, low platelets and renal impairment also reported.[4]

What are the side effects of MOTS-c?

They are unknown. FDA found no safety information on MOTS-c in humans.[5]

What are AICAR benefits in research?

In mice it raised running endurance by 44% without exercise; in men with type 2 diabetes it lowered hepatic glucose output in a small study. A large heart-surgery trial found no benefit.[11][13][3]

Is AICAR or MOTS-c FDA approved?

Neither. Drugs@FDA lists no acadesine application, and MOTS-c is not an approved drug.[17][5]

Are AICAR and MOTS-c banned in sport?

Yes. WADA’s 2027 Prohibited List names both under S4.4.1, activators of AMPK.[6]

Which has more human evidence, AICAR or MOTS-c?

AICAR. It has phase 1 to phase 3 trial data, while MOTS-c has no published human treatment trial.[3][5]

Sources

  1. Corton JM, Gillespie JG, Hawley SA, Hardie DG. 5-Aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem. 1995;229(2):558-565. doi: 10.1111/j.1432-1033.1995.tb20498.x · PMID: 7744080 ↩
  2. 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. doi: 10.1016/j.cmet.2015.02.009 · PMID: 25738459 ↩
  3. Newman MF, Ferguson TB, White JA, et al. Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial. JAMA. 2012;308(2):157-164. doi: 10.1001/jama.2012.7633 · PMID: 22782417 ↩
  4. Van Den Neste E, Cazin B, Janssens A, et al. Acadesine for patients with relapsed/refractory chronic lymphocytic leukemia (CLL): a multicenter phase I/II study. Cancer Chemother Pharmacol. 2013;71(3):581-591. doi: 10.1007/s00280-012-2033-5 · PMID: 23228986 ↩
  5. U.S. Food and Drug Administration. FDA Briefing Document: MOTS-c-Related Bulk Drug Substances (MOTS-c (free base) and MOTS-c acetate). Pharmacy Compounding Advisory Committee meeting, July 23-24, 2026. fda.gov/media/193347 ↩
  6. World Anti-Doping Agency. The 2027 Prohibited List (in force January 1, 2027), S4.4.1 metabolic modulators: activators of AMPK, e.g. BAM15, AICAR, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c). wada-ama.org ↩
  7. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13(4):251-262. doi: 10.1038/nrm3311 · PMID: 22436748 ↩
  8. Merrill GF, Kurth EJ, Hardie DG, Winder WW. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol. 1997;273(6):E1107-E1112. doi: 10.1152/ajpendo.1997.273.6.E1107 · PMID: 9435525 ↩
  9. Kim KH, Son JM, Benayoun BA, Lee C. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab. 2018;28(3):516-524.e7. doi: 10.1016/j.cmet.2018.06.008 · PMID: 29983246 ↩
  10. Gudiksen A, Hansen CC, van der Stede T, et al. MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner. Free Radic Biol Med. 2026;246:682-696. doi: 10.1016/j.freeradbiomed.2026.01.002 ↩
  11. Narkar VA, Downes M, Yu RT, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008;134(3):405-415. doi: 10.1016/j.cell.2008.06.051 · PMID: 18674809 ↩
  12. Tukhovskaya EA, Shaykhutdinova ER, Pakhomova IA, et al. AICAR improves outcomes of metabolic syndrome and type 2 diabetes induced by high-fat diet in C57Bl/6 male mice. Int J Mol Sci. 2022;23(24):15719. doi: 10.3390/ijms232415719 · PMID: 36555360 ↩
  13. Boon H, Bosselaar M, Praet SF, et al. Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients. Diabetologia. 2008;51(10):1893-1900. doi: 10.1007/s00125-008-1108-7 · PMID: 18709353 ↩
  14. ClinicalTrials.gov API search for intervention AICAR or acadesine, run October 27, 2026 (5 studies: RED-CABG phase 3 terminated, two CLL phase 1/2 studies, a Lesch-Nyhan phase 2 pilot and a type 2 diabetes physiology study). clinicaltrials.gov ↩
  15. Reynolds JC, Lai RW, Woodhead JST, 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. doi: 10.1038/s41467-020-20790-0 · PMID: 33473109 ↩
  16. ClinicalTrials.gov. NCT03998514, Phase 1a/1b study of CB4211 in healthy non-obese subjects and subjects with NAFLD (completed; 88 enrolled; record checked October 27, 2026). clinicaltrials.gov/study/NCT03998514 ↩
  17. openFDA Drugs@FDA query for acadesine, run October 27, 2026 (no matches). api.fda.gov ↩
  18. Jacobus N. FDA panel votes to loosen restrictions for four peptides (MOTS-c recommended 7-5 with two abstentions). Pharmaceutical Executive, July 24, 2026. pharmexec.com ↩

For catalog details, see the Genovare AICAR 250mg AQ pen and the MOTS-c 10mg research vial. For editorial standards, continue to the editorial policy.

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