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ENDURANCE

AICAR

AICAR (5-Aminoimidazole-4-Carboxamide Ribonucleoside)

AMPK Activator for Endurance and Metabolic Performance

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Based on the combined works of Dr. William A. Seeds and Dr. Ian W. Hamley
— authoritative voices whose published research informed this article

The information on this page is compiled from peer-reviewed research and is provided for educational and research purposes only. It is not medical advice, a diagnosis, or a treatment recommendation. Peptides discussed here may not be approved for human use in your jurisdiction. Always consult a qualified healthcare provider before starting, stopping, or modifying any health protocol.

Overview

What is AICAR?

AICAR (5-aminoimidazole-4-carboxamide ribonucleoside, also written as acadesine or AICA-riboside) is a nucleoside analogue that is taken up by cells and phosphorylated to form ZMP, a structural analogue of AMP. ZMP accumulation mimics the cell's perception of low energy status by activating AMP-activated protein kinase (AMPK), a central metabolic sensor that governs cellular energy homeostasis across virtually all tissues. AMPK is sometimes described as the cell's master energy switch: it is activated when the AMP-to-ATP ratio rises and it orchestrates a coordinated response to restore energy balance.

By activating AMPK pharmacologically without requiring actual energy stress, AICAR simulates many of the adaptive metabolic responses associated with endurance exercise. Key downstream effects include increased mitochondrial biogenesis, enhanced fatty acid oxidation, upregulation of glucose transporter expression (GLUT-4 and GLUT-1), increased oxidative fiber specification in skeletal muscle, and improved insulin sensitivity. Research published in Cell in 2008 by Evans and colleagues at the Salk Institute demonstrated that four weeks of AICAR administration in sedentary mice enhanced running endurance by 44% [1] and induced a gene expression profile in skeletal muscle resembling that of trained athletes, without any exercise training.

Subsequent research has provided important nuance. A systematic review published in Cells in 2021 documented that AICAR has numerous biological effects that are independent of AMPK activation [3], complicating the interpretation of earlier research. AICAR also inhibits AMP deaminase, affects adenosine signaling, and alters purine synthesis pathways. These off-target effects can influence inflammation, immune function, and cardiovascular biology in ways that are not fully characterized.

AICAR has been on the World Anti-Doping Agency (WADA) Prohibited List since 2011, classified under Hormone and Metabolic Modulators. It is prohibited at all times in competitive sport due to its potential to enhance endurance performance. AICAR has no FDA-approved therapeutic indication and is an investigational research compound available for laboratory and preclinical research use only.

Research Supply

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Protocol

Dosage Guide

Route: Subcutaneous or intramuscular injection (reconstituted from lyophilized powder)

Dosing Schedule

PeriodDose
Sedentary mice (Evans lab, Cell 2008)500 mg/kg/day IP for 4 weeks
Various rodent studies250-500 mg/kg/day
Estimated human equivalent (60 kg adult)~42 mg/kg (single dose pharmacokinetics studied)
Human tolerability studyUp to 210 mg/kg single dose

Reconstitution

VIAL SIZEVaries by supplier
WATER VOLUMEPer vial labeling with sterile saline or bacteriostatic water
CONCENTRATIONPer vial labeling
Varies by reconstitution volume

Injection Volumes

DoseVolumeSyringe Units

Administration Tips

  • AICAR is typically supplied as a lyophilized powder and is reconstituted with sterile saline or bacteriostatic water for injection
  • Reconstituted solutions should be stored at 2-8 degrees Celsius and used within 30 days
  • Rodent doses of 250-500 mg/kg do not translate reliably to human equivalent doses for performance purposes
  • No standard human dosing protocol exists with validated safety and efficacy data
  • Prohibited at all times under WADA rules; competitive athletes should not use AICAR
Safety

Risks & Side Effects

Commonly Reported

Hypoglycemia: AICAR increases glucose uptake and utilization via AMPK activation and GLUT-4 upregulation; risk is amplified in fasted individuals or those taking glucose-lowering medicationsFatigue and dizziness, potentially related to acute hypoglycemiaGastrointestinal discomfort including nausea, bloating, and loose stoolsInjection site reactions with subcutaneous or intramuscular administrationHyperuricemia (elevated uric acid) affecting purine metabolism, which may precipitate gout

Serious Risks

Severe hypoglycemia

The glucose-lowering effects of AICAR can be clinically significant, particularly at higher doses or in combination with insulin, metformin, or sulfonylureas. Symptomatic hypoglycemia requiring intervention has been reported in research contexts.

Cardiac arrhythmia

AICAR has complex effects on cardiac electrophysiology via AMPK and adenosine pathways. Arrhythmias have been observed in preclinical cardiac studies at high doses.

Unknown long-term consequences

AICAR's AMPK-independent effects (particularly on adenosine signaling, purine biosynthesis, and immune function) are not fully characterized over extended administration.

Immunosuppression

AMPK activation and adenosine pathway modulation can suppress immune responses, potentially increasing susceptibility to infection.

Related Research

Related Peptides

Expert Voices

Experts Covering AICAR

Dr. William A. Seeds

MD -- Regenerative Medicine Pioneer

Dr. Ian W. Hamley

Diamond Professor of Physical Chemistry -- University of Reading

LEGAL DISCLAIMER

The information provided on this page is for educational and informational purposes only and is not intended as medical advice. AICAR has not been approved by the FDA for any medical condition. AICAR is prohibited under the World Anti-Doping Agency (WADA) Prohibited List. Always consult with a qualified healthcare professional before starting any research compound. Individual results may vary. Peptides Institute is not responsible for any adverse effects resulting from the use of information provided on this site.

Frequently Asked Questions

What is AICAR and how does it mimic exercise?
AICAR is a nucleoside analog that activates AMP-activated protein kinase (AMPK), the cell's master energy sensor. By mimicking low energy status, it triggers metabolic adaptations normally produced by endurance exercise, including increased mitochondrial biogenesis, enhanced fatty acid oxidation, and improved insulin sensitivity.
Did AICAR really improve endurance without exercise?
Yes. A landmark 2008 study published in Cell demonstrated that four weeks of AICAR in sedentary mice enhanced running endurance by 44% [1] and induced a skeletal muscle gene expression profile resembling trained athletes, all without any exercise training. However, these results have not been replicated in human trials.
Is AICAR banned in sports?
Yes. AICAR has been on the World Anti-Doping Agency (WADA) Prohibited List since 2011, classified under Hormone and Metabolic Modulators. It is prohibited at all times in competitive sport due to its potential to enhance endurance performance. Competitive athletes should not use AICAR under any circumstances.
What are AICAR side effects?
The most significant risk is hypoglycemia from increased glucose uptake via AMPK activation and GLUT-4 upregulation [2]. Other effects include fatigue, dizziness, gastrointestinal discomfort, hyperuricemia that may trigger gout, and potential cardiac arrhythmia at high doses through adenosine pathway effects.
Is there a safe AICAR dosage for humans?
No standard human dosing protocol exists with validated safety and efficacy data. Rodent doses of 250 to 500 mg/kg do not translate reliably to human equivalents. Human tolerability studies have tested up to 210 mg/kg as a single dose, but chronic dosing protocols remain entirely unvalidated for performance use.
Is AICAR FDA approved?
AICAR has no FDA-approved therapeutic indication and remains an investigational research compound. It was studied as a potential cardioprotective agent during cardiac surgery but never completed the regulatory approval process. Its use outside of controlled research settings constitutes self-experimentation with uncharacterized risks.

References

  1. Narkar VA, Downes M, Yu RT, et al.. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008. PMID 18674809
  2. Merrill GF, Kurth EJ, Hardie DG, et al.. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol. 1997. PMID 9435525
  3. Visnjic D, Lalic H, Bhatt RR, et al.. AICAr, a Widely Used AMPK Activator with Important AMPK-Independent Effects: A Systematic Review. Cells. 2021. PMID 34064363

Regulatory & Official Sources