AICAR

AICAR (5-aminoimidazole-4-carboxamide ribonucleoside, pharmaceutical name acadesine) is a synthetic adenosine analogue. It occurs endogenously as an intermediate in de novo purine biosynthesis; the exogenous compound mimics that intermediate and activates AMP-activated protein kinase (AMPK), the energy-sensing enzyme that exercise and fasting activate.

The compound's profile was established by the 2008 Salk Institute study in which sedentary mice dosed for four weeks ran 44% further on a treadmill endurance test without training, with induction of the same oxidative metabolic genes exercise turns on. The French Anti-Doping Agency suspected use during the 2009 Tour de France; WADA banned it in 2011; in 2012 Spanish police arrested ten people in Operacion Skype for trafficking AICAR and TB-500 to professional athletes.

As acadesine, AICAR was studied in the 1990s in five large randomised trials involving over 4,000 coronary artery bypass patients for perioperative cardioprotection. These remain the largest human datasets for the compound.

AICAR is not FDA approved, is a WADA prohibited substance, and is available only as a research chemical.

AICAR enters cells via adenosine transporters and is phosphorylated by adenosine kinase to ZMP, an AMP mimetic. ZMP binds the gamma regulatory subunit of AMPK, inducing a conformational change that exposes threonine-172 on the alpha subunit for phosphorylation by LKB1, and protects the enzyme from phosphatase-mediated deactivation. The cell responds as if the AMP:ATP ratio had risen, without any actual ATP depletion.

Downstream, AMPK drives insulin-independent GLUT4 translocation in skeletal muscle via TBC1D1 rather than the PI3-kinase pathway; phosphorylates and inactivates acetyl-CoA carboxylase, lowering malonyl-CoA and relieving CPT-1 inhibition so long-chain fatty acids enter mitochondria for oxidation; and activates PGC-1alpha, which in turn drives NRF1 and TFAM to promote mitochondrial biogenesis. PGC-1alpha also mediates the SIRT3 and MnSOD antioxidant pathway, and Brandauer et al. (2015) showed these increases required functional AMPK. Skeletal muscle gene expression shifts toward an oxidative phenotype, with upregulation of UCP3, CPT1 and PDK4.

AICAR also inhibits NF-kB DNA binding in human macrophages and dose-dependently reduces IL-6 and IL-8 in human adipose tissue and skeletal muscle cells. Kirchner et al. (2018) found the macrophage effect was AMPK-independent.

Visnjic et al. (2021) demonstrated in a systematic review that many effects attributed to AICAR are AMPK-independent: it alters purine and pyrimidine synthesis, inhibits adenosine kinase and adenosine deaminase (raising adenosine), and affects ERK1/2 phosphorylation. Effects observed with AICAR therefore cannot be assumed to reflect AMPK activation alone.

In sedentary mice, Narkar et al. (2008) reported 23% longer running time and 44% greater distance after four weeks at 500 mg/kg/day, with induction of 32 oxidative metabolism genes, reduced epididymal fat mass and increased oxygen consumption via the AMPK-PPARdelta axis. Wilcox et al. (2025) found one month of treatment in 23-month-old mice prevented the 24.5% loss of running performance seen in untreated controls, increased tetanic force 26.4%, quadriceps mass approximately 8%, cytochrome C 33% and citrate synthase 22%, reduced MAFbx and MuRF1 expression, raised serum IGF-1, and reversed 84 genes toward youthful expression.

Human IV data: Cuthbertson et al. (2007) showed a 2.1-fold increase in skeletal muscle glucose uptake in 29 healthy men. Babraj et al. (2009) found responses of 2.9-fold in young men (average age 23), 1.8-fold in older men (average age 59) and 1.6-fold in men with type 2 diabetes (average age 62), attributing the blunting to age rather than diabetic status. Boon et al. (2008) showed reduced hepatic glucose output and inhibited whole-body lipolysis in 10 men with type 2 diabetes.

Mangano et al. (1997), a meta-analysis of five randomised placebo-controlled trials in 4,043 bypass patients, found acadesine reduced perioperative MI by 27%, cardiac death by 50% through postoperative day 4, and the combined outcome of MI, stroke or cardiac death by 26%; cardiac mortality after MI fell from 13.3% to 1.4%.

Chandrasekaran et al. (2024) reported prevention and reversal of diabetic peripheral neuropathy in type 1 and type 2 diabetic mouse models via AMPK-dependent mitophagy, with a 3-fold rise in AMPK phosphorylation in dorsal root ganglion neurons. No published study has examined subcutaneous AICAR at practical doses.

No human timeline data exist for subcutaneous AICAR. Human studies used IV infusions at far higher doses. Animal research used 500 mg/kg/day, translating to roughly 45 grams per day for a 200-pound person, while practical protocols use 10 to 50 mg daily. Whether these doses activate AMPK meaningfully in humans is an open question; reported benefits could be real, placebo, or driven by non-AMPK mechanisms responsive to lower concentrations.

In Narkar et al. (2008), four weeks of daily treatment produced measurable endurance and gene expression changes. In Wilcox et al. (2025), one month reversed age-related muscle and performance decline, with cytochrome C and citrate synthase changes measurable within that window.

Users report improved exercise endurance and recovery within 1 to 2 weeks, with some describing blood pressure improvements at 2 to 3 weeks. One user documented a drop from 115/80 to 110/70-75 during a 3-week run. Common subjective reports are faster inter-set recovery, longer sustained cardio and a sense of improved metabolic efficiency. CGM users report blood sugar improvements within 1 to 2 weeks. Those running 2.5 mg daily alongside MOTS-c report fasted readings in the low 70s, improved diastolic pressure and improved vasculature, emerging over several weeks.

Effects are not acute. Some users describe solo low-dose AICAR as underwhelming; the GW-501516 combination receives better reports but introduces a compound with its own risk profile. Several users note benefits disappear after discontinuation, consistent with ongoing pharmacological effect rather than durable adaptation. Objective metrics (glucose, resting heart rate, blood pressure, performance) are the appropriate signal.

Studied doses and practical doses are separated by orders of magnitude. Animal studies used 500 mg/kg/day for 4 to 5 weeks; allometric scaling gives a human equivalent of approximately 3 to 4 grams per day for a 200-pound person. Cardiac surgery trials infused 0.1 mg/kg/min IV over 7 hours plus cardioplegia delivery; glucose metabolism studies used 10 mg/kg/hour IV; the CLL trial established a maximum tolerated single IV dose of 210 mg/kg (roughly 19 grams for a 200-pound person). No published study has tested subcutaneous AICAR at practical doses. The protocols below reflect practice, not dose-finding data.

Standard: 25 to 50 mg daily subcutaneous, 2 weeks maximum.

Conservative: 10 to 25 mg daily or every other day, 2 to 4 weeks.

Alternative: 50 mg every other day for 2 weeks (7 doses total); same total exposure as daily dosing over a shorter period.

Low-dose metabolic: 2.5 to 5 mg daily for 4 to 8 weeks, used by some alongside other AMPK-targeting compounds such as MOTS-c (5 to 10 mg 3x per week). No published data support this range.

Cycling: maximum 14 days at 25 to 50 mg daily; 4 to 8 weeks at 2.5 to 10 mg; 1 to 2 months washout; no more than 3 cycles per year at standard doses. Chronic AMPK activation carries theoretical downsides including mTOR suppression and off-target nucleotide synthesis effects. Monitor renal function, uric acid and glucose throughout. Reduce or discontinue if fasted glucose is consistently below 65 mg/dL with symptoms. Caution with metformin, insulin and other glucose-lowering agents due to additive hypoglycaemia risk.

Reconstitution: 50 mg vial with 2 mL bacteriostatic water gives 25 mg per mL, 250 mcg per unit on an insulin syringe.

Site: AICAR is systemic; subcutaneous injection at abdomen, thigh or upper arm is equivalent. No fasting requirement, unlike GH secretagogues; morning dosing is common and consistency matters more than timing.

Cardiac surgery trials. Mangano et al. (1997), a JAMA meta-analysis of five randomised, placebo-controlled trials of acadesine in 4,043 coronary artery bypass patients across 81 centres, is the strongest human dataset. Dosing was 0.1 mg/kg/min IV for 7 hours plus delivery in cardioplegia solution. Perioperative MI fell 27%, cardiac death fell 50% through postoperative day 4, and the combined endpoint of MI, stroke, or cardiac death fell 26%. Cardiac mortality following MI dropped from 13.3% (placebo) to 1.4% (acadesine).

Human glucose metabolism. Cuthbertson et al. (2007) showed IV AICAR increased skeletal muscle 2-deoxyglucose uptake 2.1-fold in 29 healthy men. Babraj et al. (2009) found the response was 2.9-fold in young men (mean age 23), 1.8-fold in older men (mean age 59), and 1.6-fold in type 2 diabetics (mean age 62), attributing the blunting to age rather than diabetic status. Boon et al. (2008) demonstrated reduced hepatic glucose output and inhibited whole-body lipolysis in 10 men with type 2 diabetes. IV infusions ran at 10 mg/kg/hour.

Oncology. Van Den Neste et al. (2013), a Phase I/II trial in 24 patients with relapsed or refractory CLL, established a maximum tolerated single IV dose of 210 mg/kg, with variable trends toward reduced peripheral CLL cells and lymphadenopathy.

Animal endurance and ageing. Narkar et al. (2008), Cell: 500 mg/kg/day for four weeks in sedentary mice increased running time 23% and distance 44%, induced 32 oxidative metabolism genes, and reduced epididymal fat, mediated via the AMPK-PPARdelta axis. Wilcox et al. (2025), FASEB BioAdvances: one month of treatment in 23-month-old mice prevented a 24.5% decline in running performance seen in controls, raised tetanic force 26.4%, quadriceps mass approximately 8%, cytochrome C 33%, and citrate synthase 22%, reduced MAFbx and MuRF1 expression, elevated serum IGF-1, and reversed 84 genes toward youthful expression.

Mechanistic studies. Brandauer et al. (2015) showed four weeks of AICAR raised SIRT3 and MnSOD in wild-type but not AMPK-knockout mice, with PGC-1alpha also required. Chandrasekaran et al. (2024) reversed diabetic polyneuropathy in type 1 and type 2 mouse models via AMPK-dependent mitophagy, with 3-fold AMPK phosphorylation in dorsal root ganglion neurons. Kirchner et al. (2018) showed NF-kB DNA binding inhibition in human macrophages independent of AMPK; Lihn et al. (2008) showed dose-dependent IL-6 and IL-8 reduction in human adipose and skeletal muscle cells.

Systematic review. Visnjic et al. (2021), Cells, concluded many effects attributed to AMPK are AMPK-independent, involving purine and pyrimidine synthesis, adenosine kinase and deaminase inhibition, and ERK1/2 phosphorylation.

No published study has tested subcutaneous AICAR at the 10 to 50 mg daily doses used in practice; the animal dose scales allometrically to approximately 3 to 4 grams daily for a 200-pound person.