AICAR (Acadesine) Research: What Published Studies Have Investigated

What is AICAR?

What is AICAR? It is 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, a nucleoside built from a purine-precursor base joined to a ribose sugar. It is also called acadesine, AICA riboside, and — in the anti-doping literature — AICAr. It is a small molecule of formula C₉H₁₄N₄O₅, and it is not a peptide. There is no amino-acid sequence, so the sequence row that appears on every peptide page in this library does not apply here and has been omitted rather than filled with something inapplicable.

One naming trap deserves flagging at the top, because it catches automated lookups. Searching public chemical databases for the bare string “AICAR” frequently returns AICA ribotide — the monophosphate, also called ZMP, formula C₉H₁₅N₄O₈P — rather than the riboside that laboratories actually order. The two are related by one phosphate group and by one enzymatic step, and confusing them produces wrong molecular weights. The reference table below uses the acadesine record deliberately.

That phosphate is also the whole of the pharmacology. AICAR is taken into cells by adenosine transporters and phosphorylated by adenosine kinase to ZMP. ZMP resembles AMP closely enough to occupy AMP-binding sites, and it is ZMP — not AICAR — that acts on AMP-activated protein kinase. AICAR is, in the strict sense, a prodrug of an AMP mimetic.

Discovery and origin in the literature

A question mark in the founding title

AICAR entered the AMPK field through Corton, Gillespie, Hawley and Hardie, European Journal of Biochemistry, 1995 (PMID 7744080). The title is worth quoting because of its punctuation: “5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells?” The authors introduced the compound as a way to activate AMPK inside intact cells without the metabolic poisons previously used for the job, and simultaneously asked in their own title whether it was really specific.

That question was never fully closed, and it is the single most important piece of context for reading anything else in this literature. ZMP is an AMP analogue, and AMP-binding sites are not unique to AMPK — fructose-1,6-bisphosphatase and glycogen phosphorylase, among others, also read AMP. Any result obtained with AICAR therefore carries an interpretive caveat that a genuinely selective activator would not, and careful papers in this field say so.

From tool compound to drug candidate

In parallel with its laboratory career, the same molecule was developed as a pharmaceutical under the name acadesine, framed as an “adenosine-regulating agent” for ischaemia–reperfusion injury in cardiac surgery. That programme ran through the 1990s and was revived in a large trial two decades later. Both halves of its history — reagent and drug candidate — are reported below, because the drug half is where the real human evidence lives.

Reference data

Values from the public chemical record (PubChem CID 17513, acadesine). Identity and physical form only.

No handling, dilution or reconstitution guidance is given anywhere on this page, and no route or quantity is stated or implied.

Mechanisms researchers have examined

The AICAR mechanism literature is built on one enzymatic step and one kinase. Each point below is what studies characterise in defined systems:

• Uptake and phosphorylation to ZMP — adenosine transporters carry AICAR into cells; adenosine kinase phosphorylates it. Cells lacking adenosine kinase activity do not accumulate ZMP, which is why AICAR responses vary sharply between cell types.
• Allosteric activation of AMPK by an AMP mimetic — ZMP binds the γ-subunit nucleotide sites that normally read AMP, producing allosteric activation and promoting phosphorylation of the α-subunit activation loop by upstream kinases. This is the mechanism Corton and colleagues described in 1995.
• Downstream metabolic branches — the AMPK literature examines acetyl-CoA carboxylase phosphorylation, fatty-acid oxidation, and glucose transport as canonical readouts. Merrill and colleagues (1997, PMID 9435525) reported increased AMPK activity, fatty-acid oxidation and glucose uptake in perfused rat muscle.
• AMPK-independent effects, documented in humans — Cuthbertson and colleagues (2007, Diabetes, PMID 17513706) reported increased muscle 2-deoxyglucose uptake in healthy men while AMPK α1 and α2 activity and AMPK phosphorylation were unchanged, with ERK1/2 phosphorylation increased instead. A readout can move without the kinase the compound is named for moving with it.
• Endogenous origin — AICAR is not foreign to human metabolism. Its monophosphate is an intermediate in de-novo purine biosynthesis, and AICAR itself is measurable in normal human urine. This is a mechanism fact with a direct analytical consequence, discussed below.

Research findings by area

Exercise physiology and the “exercise mimetic” papers

The most-cited single study is Narkar and colleagues, Cell, 2008 (PMID 18674809), titled “AMPK and PPARδ agonists are exercise mimetics”. Working in mice, the authors examined AICAR alongside the PPARδ agonist GW1516 and reported changes in endurance-related gene programmes and running performance in those animals. The paper is the origin of essentially all popular writing about this compound, and two things about it are routinely dropped in retelling: the work is in mice, and the “mimetic” framing is the authors’ description of a transcriptional resemblance, not a demonstration that anything substitutes for training in a person.

Human metabolic physiology

Two human studies from the Dundee group define what is actually known in people. Cuthbertson and colleagues (2007) reported acute stimulation of muscle 2-deoxyglucose uptake in 29 healthy men, with a modest 7% change in whole-body glucose disposal and, as noted above, no measurable change in AMPK activity or phosphorylation. Babraj and colleagues (2009, PMID 19190259) followed with a study reporting that blunting of the AICAR glucose-uptake response was dependent on age rather than diabetic status. These are small acute physiology experiments with mechanistic readouts, not outcome trials.

The acadesine clinical programme

This is where the largest human dataset sits, and it has a clean arc. Mangano (1997, JAMA, PMID 9002496) published a meta-analysis of five international randomised trials of perioperative acadesine in cardiac surgery, reporting reductions in early cardiac death, myocardial infarction and combined adverse cardiac outcomes in patients undergoing on-pump coronary artery bypass grafting.

That signal was tested properly. The RED-CABG trial (Newman and colleagues, 2012, JAMA, PMID 22782417; NCT00872001) was a randomised, double-blind, placebo-controlled study at 300 sites in seven countries in intermediate-to-high-risk patients undergoing non-emergency on-pump CABG. It was stopped after a prespecified futility analysis, with 3,080 of a projected 7,500 participants randomised. The primary composite outcome occurred in 5.0% of placebo participants and 5.1% of acadesine participants (odds ratio 1.01, 95% CI 0.73–1.41), with no differences in key secondary endpoints. The authors concluded that acadesine did not reduce the composite of all-cause mortality, non-fatal stroke or severe left ventricular dysfunction.

A negative confirmatory trial of that size is a strong result, and it is reported here in full because it is the best-powered human evidence that exists for this molecule in any indication.

Anti-doping status and analytical chemistry

AICAR appears on the World Anti-Doping Agency Prohibited List. Stated as a regulatory fact and nothing else: the compound is prohibited in sport, and Cellworks supplies research material for laboratory use only. This page does not describe, imply or contemplate any use in sport, competition or people.

What is genuinely interesting scientifically is why the compound is analytically difficult, and the answer is the endogeneity point above. Piper and colleagues (2014, PMID 24760559) developed a gas-chromatography/combustion/isotope-ratio mass-spectrometry method to determine carbon isotope ratios of urinary AICAR, precisely because inter-individual variation in natural urinary concentration is too large for a concentration threshold to prove exogenous origin on its own. Sobolevsky and colleagues (2022, PMID 36342242) examined the urinary ratio of AICAr to the related purine metabolite SAICAr across 5,517 athlete samples and proposed it as an additional diagnostic trigger for isotope-ratio follow-up. Both papers exist because AICAR is a normal human metabolite — which is a fact about biochemistry, reported here as one.

Research models and evidence status

AICAR has a large literature and a small set of established conclusions. Those are different things, and the gap between them is the point of this section.

What is well supported

That AICAR is converted intracellularly to ZMP; that ZMP activates AMPK allosterically in cell-free and cellular systems; that AICAR reproduces several canonical AMPK-dependent metabolic readouts in rodent muscle; and that acadesine did not improve the primary composite outcome in a well-powered cardiac-surgery phase 3. All four are supported by primary data from independent groups.

What is not established

That AICAR is a specific AMPK activator — its own founding paper asked the question and the human data of Cuthbertson and colleagues show a metabolic readout moving without a measurable AMPK change. That rodent endurance-gene findings translate to humans in any form; no human study has examined that. That any of the popular claims attached to this compound online have a human evidence base; they do not. And nothing in this literature says anything about supplied research material in a person: the acadesine trials used clinical-grade drug product under trial protocols, which is a different thing from a laboratory reagent. This page makes no efficacy, therapeutic, metabolic, performance, endurance or other use claim of any kind, and the material is supplied for laboratory research use only — not for human or veterinary use.

Why the page is written this way

AICAR is a genuinely valuable research tool with a thirty-year publication record, and it is also the compound most often described online in language its own literature contradicts. Reporting the founding paper’s question mark, the negative human AMPK result and the futility-stopped phase 3 side by side is simply what the record contains.

How to verify this compound yourself

AICAR is a small molecule, so verification differs materially from the peptide workflow described elsewhere in this library. The differences matter:

• There is no sequence to confirm — peptide certificates rest on matching an amino-acid sequence to an expected mass. For a nucleoside there is no sequence at all; identity rests on the molecular structure itself.
• Identity by NMR or reference-standard comparison, not just mass — a mass of ≈ 258.2 Da narrows the field but does not uniquely identify a small molecule the way it identifies a long peptide chain. Proton and carbon NMR, or chromatographic comparison against a certified reference standard, is what small-molecule identity confirmation normally looks like.
• HPLC purity with a UV method — the aminoimidazole-carboxamide chromophore gives a usable UV signature. The purity percentage on the certificate is a chromatographic area figure, and the wavelength and column used should be stated.
• Watch the riboside/ribotide distinction — the monophosphate ZMP is a plausible related substance and differs by 80 mass units. A certificate that names only “AICAR” without a formula or CAS number leaves that unresolved; 2627-69-2 is the riboside.
• Residual solvents and water content — for small molecules these are the routine specification lines, in place of the counter-ion and endotoxin lines that dominate peptide certificates. Endotoxin testing is not a standard small-molecule specification and its absence on a certificate is not a red flag here.

See how to read a COA for what each certificate line means, and how to verify peptide purity for the peptide workflow this compound deliberately departs from. The exact batch received can be checked on the self-serve verify tool.

Research-grade sourcing and verification

AICAR is not held in stock. It appears on our sourcing catalogue as available to order — our supplier lists it, we have not bought it, and material of this kind typically takes about two to three weeks to reach us. For laboratory research use only, it is supplied with a per-batch Certificate of Analysis reporting purity and identity confirmation, verifiable at the lot level. For adjacent metabolic small molecules with their own separate literatures, see 5-Amino-1MQ research and SLU-PP-332 research; for the mitochondrially encoded peptide studied against the same kinase, see MOTS-c research. This is sourcing and quality-assurance framing only.

Frequently asked questions

Literature cited

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?” European Journal of Biochemistry. 1995;229(2):558–565. PMID 7744080. pubmed.ncbi.nlm.nih.gov/7744080.
2. Merrill GF, Kurth EJ, Hardie DG, Winder WW. “AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle.” American Journal of Physiology. 1997;273(6):E1107–E1112. PMID 9435525. pubmed.ncbi.nlm.nih.gov/9435525.
3. Narkar VA, Downes M, Yu RT, et al. “AMPK and PPARdelta agonists are exercise mimetics.” Cell. 2008;134(3):405–415. PMID 18674809. pubmed.ncbi.nlm.nih.gov/18674809.
4. Cuthbertson DJ, Babraj JA, Mustard KJ, et al. “5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men.” Diabetes. 2007;56(8):2078–2084. PMID 17513706. pubmed.ncbi.nlm.nih.gov/17513706.
5. Babraj JA, Mustard K, Sutherland C, et al. “Blunting of AICAR-induced human skeletal muscle glucose uptake in type 2 diabetes is dependent on age rather than diabetic status.” American Journal of Physiology — Endocrinology and Metabolism. 2009;296(5):E1042–E1048. PMID 19190259. pubmed.ncbi.nlm.nih.gov/19190259.
6. Mangano DT. “Effects of acadesine on myocardial infarction, stroke, and death following surgery. A meta-analysis of the 5 international randomized trials.” JAMA. 1997;277(4):325–332. PMID 9002496. pubmed.ncbi.nlm.nih.gov/9002496.
7. 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. PMID 22782417. pubmed.ncbi.nlm.nih.gov/22782417.
8. Piper T, Thomas A, Baume N, Sobolevsky T, Saugy M, Rodchenkov G, Schänzer W, Thevis M. “Determination of ¹³C/¹²C ratios of endogenous urinary 5-amino-imidazole-4-carboxamide 1β-D-ribofuranoside (AICAR).” Rapid Communications in Mass Spectrometry. 2014;28(11):1194–1202. PMID 24760559. pubmed.ncbi.nlm.nih.gov/24760559.
9. Sobolevsky T, Piper T, Ahrens B, Thevis M. “AICAr to SAICAr ratio can serve as additional marker of AICAr use.” Drug Testing and Analysis. 2022;14(11–12):2017–2025. PMID 36342242. pubmed.ncbi.nlm.nih.gov/36342242.
10. World Anti-Doping Agency. “The Prohibited List.” wada-ama.org/en/prohibited-list (regulatory reference only).
11. National Center for Biotechnology Information. “PubChem Compound Summary for CID 17513, Acadesine.” pubchem.ncbi.nlm.nih.gov/compound/17513 (formula, mass, CAS 2627-69-2).