AICAR (5-aminoimidazole-4-carboxamide ribonucleoside), also called acadesine or AICA riboside, is a small nucleoside molecule. Inside cells it is converted to ZMP, a compound that mimics AMP and switches on AMP-activated protein kinase (AMPK), the enzyme that senses low cellular energy. It is not a peptide or a hormone.
Acadesine was developed as an intravenous drug to protect the heart during bypass surgery and was later tested in leukemia. It was never approved as a medicine: its large heart-surgery trial was stopped for futility in 2010, and no approved product exists in the US. Its reputation as an “exercise pill” comes from a 2008 mouse study, and no controlled human trial has tested it for athletic performance.
This page summarizes what the clinical trials, mouse studies and anti-doping authorities report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Class | Purine nucleoside analog; AMPK activator (via ZMP) |
| Other names | Acadesine, AICA riboside, AICAr, ARA 100, GP 1 110 |
| Developer | Gensia (cardiac use); later Schering-Plough and PeriCor; Advancell (leukemia) |
| Route in trials | Intravenous infusion; oral bioavailability under 5% |
| Doses studied in humans | 0.1 mg/kg/min for 7 h (heart surgery); 50–315 mg/kg single 4 h infusions (leukemia) |
| Half-life | ≈1.4 h (terminal plasma half-life after IV dosing in healthy men) |
| Main metabolite | Uric acid |
| US status | Not FDA-approved; no approved product |
| WADA status | Prohibited at all times (S4.4.1, metabolic modulators); non-specified |
What it is
AICAR has the formula C₉H₁₄N₄O₅ and a molecular weight of 258.23 g/mol (PubChem). It is a ribose sugar attached to an imidazole ring, the same building block cells use to make purines such as adenine and guanine.
The naming is confusing. Strictly, “AICAR” refers to the phosphorylated form (AICA ribotide, also called ZMP), which is a normal intermediate in the body’s own purine synthesis. The drug itself is the unphosphorylated riboside, which researchers sometimes write as “AICAr” (Višnjić et al., Cells 2021). In sport and in this library, “AICAR” means the drug.
How it activates AMPK
The steps are as follows (Višnjić et al., Cells 2021; Corton et al., Eur J Biochem 1995):
- AICAR enters cells through adenosine transporters.
- The enzyme adenosine kinase adds a phosphate, converting it to ZMP.
- In rat liver cells, ZMP mimicked AMP. It activates AMPK directly and makes AMPK easier for its upstream kinase to switch on, without changing the cell’s actual ATP, ADP or AMP levels.
- In those cells, activated AMPK shut down fat and cholesterol synthesis in liver cells and blocked fat breakdown signals in fat cells.
ZMP is 40- to 50-fold less potent than AMP at activating AMPK, so it has to build up to high levels to work. A 2021 systematic review found that many effects once credited to AMPK are in fact AMPK-independent, including effects on metabolism, nucleotide synthesis, exercise and cancer cells (Višnjić et al., Cells 2021).
Pharmacokinetics
The core human data come from two small studies by the original developer, Gensia, in healthy men.
In a placebo-controlled study, men received 10, 25, 50 or 100 mg/kg by IV infusion and by mouth (Dixon et al., J Clin Pharmacol 1991):
| Parameter | Value |
|---|---|
| Terminal half-life (IV) | 1.4 h (harmonic mean) |
| Mean residence time | 0.7 h |
| Total plasma clearance | 2.5 L/h/kg |
| Volume of distribution | 1.6 L/kg |
| Plasma protein binding | None detected |
| Excreted unchanged in urine | 8% of IV dose |
| Oral bioavailability | Under 5% |
Red blood cells took up the drug rapidly and converted it to ZMP. A follow-up study used radiolabeled acadesine (25 mg/kg IV over 15 minutes) in 4 men (Dixon et al., J Clin Pharmacol 1993):
- Intact acadesine was measurable for only 2 hours after the infusion.
- Uric acid was the main metabolite. By 6 hours it accounted for all of the radioactivity in plasma.
- ZMP stayed inside red blood cells and made up 30% of the radioactivity in blood at the end of the infusion.
- Only 5% of the dose appeared in urine as unchanged acadesine.
The very low oral bioavailability matters. AICAR was given intravenously in every clinical trial, and a review notes that this makes it poorly suited to long-term treatment (Višnjić et al., Cells 2021).
Regulatory status
Acadesine passed through several companies (Drugs R D 2008):
- Gensia ran the original trials in heart surgery in the US, Canada and Europe; the profile describes those results as inconclusive.
- Rights then moved to Metabasis (1997), to Dr. Mangano (2000) and to PeriCor Therapeutics (2005), with Schering-Plough developing it for heart protection.
- Advancell and Protherics developed it for B-cell chronic lymphocytic leukemia (CLL).
In the EU, acadesine received an orphan designation for B-cell CLL in May 2005 (EU/3/05/280). EMA notes that an orphan designation is not a marketing authorization (EMA). No acadesine product appears in the FDA’s drug approval database (openFDA Drugs@FDA).
What the research shows
Heart surgery: an early signal, then a failed confirmatory trial
A 1997 individual-patient meta-analysis pooled 5 randomized, placebo-controlled trials with 4,043 patients undergoing coronary artery bypass graft (CABG) surgery. Acadesine was given IV at 0.1 mg/kg/min for 7 hours and added to the cardioplegia solution used to stop the heart (Mangano, JAMA 1997):
| Outcome | Odds ratio, acadesine vs placebo (95% CI) |
|---|---|
| Perioperative heart attack | 0.69 (0.51–0.95) |
| Cardiac death through day 4 | 0.52 (0.27–0.98) |
| Heart attack, stroke or cardiac death | 0.73 (0.57–0.93) |
| Stroke | 0.69 (0.44–1.08), not significant |
The definitive test was RED-CABG, a randomized, double-blind trial at 300 sites in 7 countries using the same dose (Newman et al., JAMA 2012). It was stopped early for futility after 3,080 of a planned 7,500 patients:
| Outcome through day 28 | Placebo | Acadesine |
|---|---|---|
| Death, nonfatal stroke or severe heart failure needing mechanical support | 75 of 1,493 (5.0%) | 76 of 1,493 (5.1%) |
| Odds ratio (95% CI) | — | 1.01 (0.73–1.41) |
There were no differences in key secondary outcomes. A small crossover trial in 12 people with stable angina also found no consistent effect of 6–48 mg/kg on exercise-induced ischemia (Holdright et al., Cardiovasc Drugs Ther 1994).
Blood sugar and metabolism in humans
Short infusion studies tested whether AICAR could lower blood sugar the way AMPK activation does in rodents. Results were mixed:
| Study | People | AICAR given | Main finding |
|---|---|---|---|
| Cuthbertson et al., Diabetes 2007 | 29 healthy men | IV infusion | Muscle glucose uptake rose 2.1-fold (vs 4.7-fold with cycling); whole-body glucose disposal rose only 7%. Muscle AMPK activity did not change. |
| Babraj et al., Am J Physiol 2009 | 6 young, 8 older and 8 men with type 2 diabetes | 10 or 20 mg/kg/h for 3 h | Muscle glucose uptake rose 1.6- to 2.9-fold, less in older men; AMPK activity again unchanged |
| Boon et al., Diabetologia 2008 | 10 men with type 2 diabetes | 0.75 mg/kg/min | Lower liver glucose output and a greater fall in blood glucose; lower blood free fatty acids |
| Bosselaar et al., J Clin Pharmacol 2011 | 10 healthy people | 67 mg/kg over 60 min during an insulin clamp | No change in glucose uptake; heart rate rose and blood pressure fell |
These were single-session infusion studies. None tested repeated dosing, body composition or exercise performance.
Endurance: mouse data only
The “exercise in a pill” idea comes from a study in sedentary mice given AICAR at 500 mg/kg/day by injection into the abdomen for 4 weeks (Narkar et al., Cell 2008). Compared with untreated mice, the treated mice:
- ran about 23% longer and about 44% farther on a treadmill;
- had higher activity of genes linked to oxidative (fat-burning) metabolism in muscle;
- had a lower epididymal fat mass (an abdominal fat pad) relative to body weight, with no change in body weight.
This was an animal study at a dose given by injection. A review notes that its publication just before the 2008 Olympics prompted WADA to prohibit AMPK activators (Niederberger et al., Sports Med 2015). We found no controlled human trial of AICAR for endurance, fat loss or muscle.
About “oral AICAR.” The 2008 mouse paper called AICAR “orally active,” but the mice received it by injection. In healthy men, under 5% of an oral dose reached the bloodstream (Dixon et al., J Clin Pharmacol 1991).
Leukemia
In a phase I/II study, 24 people with relapsed or refractory CLL received acadesine as a 4-hour IV infusion (Van Den Neste et al., Cancer Chemother Pharmacol 2013):
- Single doses ranged from 50 to 315 mg/kg; 210 mg/kg was the maximum tolerated dose.
- At 315 mg/kg, 2 of 3 patients had dose-limiting toxicity, including one case of tumor lysis syndrome.
- Reductions in leukemia cells and lymph node size were seen in some patients but were variable.
A later phase I/II trial in 12 patients with myelodysplastic syndrome or acute myeloid leukemia was stopped because the highest dose caused serious kidney side effects in patients with severe comorbidities (Višnjić et al., Cells 2021).
Side effects and risks
Raised uric acid
Because AICAR is broken down to uric acid, hyperuricemia (high blood uric acid) is the most consistent finding:
- In the heart-surgery trials, adverse events were similar to placebo except for a transient rise in serum uric acid (Mangano, JAMA 1997).
- In the CLL study, one patient at 50 mg/kg had grade 4 hyperuricemia, and preventive allopurinol was then given to all later cohorts (Van Den Neste et al., 2013).
Blood pressure, heart rate and blood sugar
- In healthy volunteers, AICAR raised heart rate (from 58 to 70 beats per minute vs 60 to 63 on placebo) and lowered blood pressure, most likely through blood vessel dilation (Bosselaar et al., 2011).
- In the CLL study, two patients had transient low blood pressure after infusion; one needed IV fluids.
- In people with type 2 diabetes, AICAR lowered blood glucose more than saline (Boon et al., 2008).
Kidney and blood effects
In the CLL study, reported drug-related events included anemia, low platelets, kidney impairment, nausea and diarrhea. Kidney toxicity also ended the leukemia trial in MDS/AML, as noted above.
Unknowns
Every human safety finding comes from short courses of IV infusion in hospital settings. There are no data on repeated self-administration, on products of unknown purity, or on long-term use.
Anti-doping testing
WADA lists AICAR by name as an AMPK activator under S4.4.1 (metabolic modulators). It is prohibited in and out of competition and is a non-specified substance (WADA 2026 Prohibited List). The same class includes MOTS-c and PPARδ agonists such as Cardarine (GW-501516).
Testing is complicated because the body makes AICAR naturally and excretes it in urine:
| Study | Athletes tested | Urinary AICAR |
|---|---|---|
| Thomas et al., Anal Bioanal Chem 2010 | 499 | Mean 2,186 ng/mL (SD 1,655) |
| Sobolevsky and Ahrens, Drug Test Anal 2019 | 12,377 samples (US) | Mean 647 ng/mL; 99th percentile 1,786 ng/mL |
To tell natural from administered AICAR, laboratories use carbon isotope ratio testing. In a validation study, this method detected a single oral dose of AICAR for more than 40 hours (Piper et al., Rapid Commun Mass Spectrom 2014).
Key takeaways
- A nucleoside, not a peptide. AICAR is converted in cells to ZMP, which mimics AMP and activates AMPK, though many of its effects are AMPK-independent.
- A failed drug candidate. Early heart-surgery trials looked promising, but the 3,080-patient RED-CABG trial found no benefit (5.1% vs 5.0%), and acadesine was never approved.
- Short-lived and poorly absorbed by mouth. The half-life is ≈1.4 hours after IV dosing, and under 5% of an oral dose is absorbed.
- The endurance claim is from mice. Injected AICAR made sedentary mice run ≈44% farther; no controlled human trial has tested performance.
- Uric acid is the main safety signal. Hyperuricemia, low blood pressure, faster heart rate and kidney effects were seen in IV trials.
- Banned in sport and detectable. WADA prohibits it at all times, and isotope testing can separate it from the body’s own AICAR.
Sources
- National Center for Biotechnology Information. Acadesine, PubChem CID 17513. PubChem.
- Višnjić D, Lalić H, Dembitz V, Tomić B, Smoljo T. AICAr, a widely used AMPK activator with important AMPK-independent effects: a systematic review. Cells. 2021;10(5):1095. PubMed.
- 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. PubMed.
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- Acadesine: AICA riboside, ARA 100, arasine, GP 1 110. Drugs R D. 2008;9(3):169–175. PubMed.
- European Medicines Agency. EU/3/05/280: orphan designation for treatment of B-cell chronic lymphocytic leukaemia (acadesine). EMA.
- US Food and Drug Administration. Drugs@FDA data (openFDA). openFDA.
- Mangano DT. Effects of acadesine on myocardial infarction, stroke, and death following surgery. A meta-analysis of the 5 international randomized trials. The Multicenter Study of Perioperative Ischemia (McSPI) Research Group. JAMA. 1997;277(4):325–332. PubMed.
- 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. PubMed.
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- 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. PubMed.
- 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. Am J Physiol Endocrinol Metab. 2009;296(5):E1042–E1048. PubMed.
- 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. PubMed.
- Bosselaar M, Smits P, van Loon LJ, Tack CJ. Intravenous AICAR during hyperinsulinemia induces systemic hemodynamic changes but has no local metabolic effect. J Clin Pharmacol. 2011;51(10):1449–1458. PubMed.
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- World Anti-Doping Agency. 2026 Prohibited List. WADA 2026 Prohibited List.
- Thomas A, Beuck S, Eickhoff JC, et al. Quantification of urinary AICAR concentrations as a matter of doping controls. Anal Bioanal Chem. 2010;396(8):2899–2908. PubMed.
- Sobolevsky T, Ahrens B. Urinary concentrations of AICAR and mannitol in athlete population. Drug Test Anal. 2019;11(3):530–535. PubMed.
- Piper T, Thomas A, Baume N, et al. Determination of ¹³C/¹²C ratios of endogenous urinary 5-amino-imidazole-4-carboxamide 1β-D-ribofuranoside (AICAR). Rapid Commun Mass Spectrom. 2014;28(11):1194–1202. PubMed.