Overview
AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), also known as acadesine, is an endogenous intermediate in purine biosynthesis and the gold standard pharmacological AMPK activator. It gained worldwide attention in 2008 when Salk Institute researchers showed mice treated with AICAR had 44% improved running endurance without exercise.
Clinically, acadesine was evaluated in Phase III trials for reducing peri-operative myocardial ischemia during CABG surgery, with mixed results. It is WADA-banned as a metabolic modulator.
AICAR sits at the intersection of sports science, metabolic medicine, and cardiovascular research. Despite its research significance, it is not FDA-approved for any indication.
This guide examines AICAR's molecular biology, metabolic effects, and ongoing research into exercise mimesis and cardioprotection.
Quick facts
- Mechanism
- Endogenous purine intermediate and direct AMPK activator
- Primary use
- AMPK Activation & Exercise Mimetic Research
- Evidence
- moderate
- FDA
- Not approved
- Route
- Intravenous infusion (clinical) or subcutaneous injection (research)
- Typical results
- Enhanced fatty acid oxidation and glucose uptake within hours in preclinical models
Chemical information
AICAR (C₉H₁₅N₄O₈P) is a metabolic compound with a molecular weight of 338.21 g/mol. Its structural characteristics underpin its biological activity in metabolic regulation and energy homeostasis.
How AICAR works
AICAR is phosphorylated intracellularly to ZMP, which mimics AMP and directly activates AMPK by binding to its γ regulatory subunit. This triggers comprehensive metabolic reprogramming: ACC inhibition → increased fatty acid β-oxidation, GLUT4 translocation → enhanced glucose uptake, and PGC-1α activation → mitochondrial biogenesis.
AMPK activation inhibits ACC, reduces malonyl-CoA, and relieves CPT1 inhibition for increased mitochondrial fatty acid oxidation. Simultaneously, GLUT4 translocation enhances insulin-independent glucose uptake.
In skeletal muscle, AMPK drives PGC-1α-mediated mitochondrial biogenesis, type I fiber switching, and autophagy via ULK1 phosphorylation—mimicking exercise adaptations.
Cardiovascular: enhanced eNOS activity, reduced myocardial O2 consumption, increased glycolytic ATP during ischemia, and anti-inflammatory NF-κB inhibition provide cardioprotection.
- Direct AMPK activation: ZMP allosterically activates AMPK via γ-subunit binding
- Fatty acid oxidation: Inhibits ACC → reduces malonyl-CoA → relieves CPT1 inhibition
- Glucose uptake: Promotes GLUT4 translocation for insulin-independent glucose transport
- Mitochondrial biogenesis: Upregulates PGC-1α for increased mitochondrial content
- Cardioprotection: Enhanced eNOS and reduced NF-κB in cardiac tissue
- Autophagy: ULK1 phosphorylation initiates cellular cleanup
Pharmacokinetics
| Parameter | Value | Significance |
|---|---|---|
| Bioavailability | Cellular uptake via nucleoside transporters; IV for clinical use | Clinical dose in CABG trials: 0.1 mg/kg/min IV over 7 hours |
| Onset of Action | AMPK activation within 30–60 minutes; peak 1–3 hours | Time to measurable clinical/biological response |
| Half-life | ~1.5 hours plasma; ZMP accumulation extends effective duration | Determines dosing frequency |
| Duration of Effect | Metabolic effects persist 4–8 hours; chronic treatment needed for exercise adaptations | Functional activity beyond plasma clearance |
| Metabolism | Phosphorylated to ZMP; purine salvage pathway; renal excretion | Primary elimination pathway |
Dosing & administration
AICAR dosing varies by indication and individual factors. No FDA-approved dosing exists for this compound; protocols in the literature derive from limited clinical or preclinical data and practitioner experience.
Any use should be conducted under qualified medical supervision with appropriate monitoring of safety markers.
Important: These dosing ranges are not FDA-approved. Any use should be under qualified medical supervision.
Side effects & safety
Safety data for AICAR is primarily derived from preclinical studies and limited human data. Long-term effects in humans remain incompletely characterized.
Common
- • Facial flushing during IV infusion
- • Transient bradycardia
- • Mild hypoglycemia
- • Nausea at high doses
- • Injection site reactions
- • Uric acid elevation
Serious / potential risks
- • Significant bradycardia/AV block at high doses
- • Theoretical lactic acidosis
- • Renal toxicity with chronic high-dose use
- • Context-dependent tumor effects
- • Limited chronic safety data
Drug interactions
| Medication | Interaction | Recommendation |
|---|---|---|
| Metformin | Both activate AMPK; potential additive hypoglycemia and lactic acidosis | Monitor closely; dose adjustment may be required |
| Insulin / Sulfonylureas | Enhanced glucose uptake may cause significant hypoglycemia | Avoid combination or use with extreme caution under medical supervision |
| Adenosine / Dipyridamole | Adenosine-like effects may cause severe bradycardia | Avoid combination or use with extreme caution under medical supervision |
| Allopurinol | Both affect purine metabolism; may alter AICAR catabolism | Generally safe; monitor if concerns arise |
Storage & handling
Lyophilized Powder (Research)
- • Store at -20°C long-term
- • Protect from light/moisture
- • Reconstitute in sterile water or PBS
- • Stable at 4°C for 2 weeks
Clinical Infusion Solution
- • Dilute in normal saline for IV
- • Use within 24 hours
- • Controlled infusion pump required
- • Monitor heart rate and glucose during infusion
Cost & availability
| Source | Cost | Notes |
|---|---|---|
| Research suppliers | Varies widely | Quality and purity vary significantly between sources |
| Compounding pharmacies | Prescription required | Higher quality assurance and purity testing |
The bottom line
AICAR is a metabolic compound with research interest in ampk activation, exercise mimetic, fat metabolism. While preclinical evidence is encouraging, it remains investigational and is not FDA-approved. Any use should be under qualified medical supervision.
Best for
- • Researchers studying metabolic regulation and energy homeostasis
- • Individuals interested in ampk activation under medical guidance
Not for
- • Self-administration without medical supervision
- • Pregnant or breastfeeding individuals
- • Individuals with contraindicated conditions
Related compounds
Frequently asked questions
References
- [1] Narkar VA, Downes M, Yu RT, et al.. AMPK and PPARδ agonists are exercise mimetics. Cell (2008). doi: 10.1016/j.cell.2008.06.051 PMID: 18674809
- [2] Corton JM, Gillespie JG, Hawley SA, Hardie DG.. 5-aminoimidazole-4-carboxamide ribonucleoside: a specific AMPK activator. Eur J Biochem (1995). doi: 10.1111/j.1432-1033.1995.tb20498.x PMID: 7649177
- [3] Mangano DT, Miao Y, Tudor IC, Dietzel C.. Acadesine and long-term survival after CABG. J Am Coll Cardiol (2006). doi: 10.1016/j.jacc.2006.04.044 PMID: 16814647
- [4] Merrill GF, Kurth EJ, Hardie DG, Winder WW.. AICA riboside increases AMPK, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol (1997). PMID: 9252541