AICAR — Research, Dosing & Price Guide

AICAR (5-aminoimidazole-4-carboxamide ribonucleoside, also known as Acadesine) is a potent AMP-activated protein kinase (AMPK) activator that mimics the metabolic effects of endurance exercise at the cellular level. Originally developed as a cardioprotective agent for coronary bypass surgery, it gained widespread attention after a landmark 2008 study showed it improved running endurance by 44% in sedentary mice. Banned by WADA in 2011, it remains one of the most studied exercise-mimetic compounds in metabolic research.

Once inside cells, AICAR is rapidly phosphorylated by adenosine kinase to ZMP (AICA ribotide, also known as 5-aminoimidazole-4-carboxamide ribotide). ZMP structurally mimics AMP and directly activates AMPK by binding to its γ-subunit, inducing a conformational change that promotes AMPK phosphorylation at Thr172 by upstream kinases (LKB1 and CaMKKβ). AMPK is the master metabolic energy sensor — when activated, it orchestrates a comprehensive shift from anabolic to catabolic metabolism. Key downstream effects include: stimulation of glucose uptake in skeletal muscle via GLUT4 translocation to the plasma membrane (insulin-independent); increased fatty acid oxidation through phosphorylation and inhibition of acetyl-CoA carboxylase (ACC), reducing malonyl-CoA and relieving CPT1 inhibition; enhanced mitochondrial biogenesis through PGC-1α activation; inhibition of mTORC1 signaling (reducing protein and lipid synthesis to conserve energy); and upregulation of genes associated with slow-twitch oxidative muscle fiber types. The net effect is that cells behave as though they are energy-depleted and undergoing sustained aerobic exercise — burning fat, taking up glucose, and building more mitochondria — without actual physical exertion. However, AICAR also has direct effects on purine metabolism (it is an intermediate in the de novo purine synthesis pathway) and adenosine receptor modulation, contributing to its cardioprotective effects.

• The landmark 2008 study in Cell by Narkar et al. showed AICAR treatment improved treadmill running endurance by 44% in completely sedentary mice over 4 weeks, without any exercise training.
• The same study demonstrated AICAR increased the expression of 32 genes involved in oxidative metabolism and slow-twitch muscle fiber specification, effectively reprogramming muscle toward an endurance phenotype.
• Clinical trials demonstrated significant cardioprotective effects during coronary artery bypass grafting, reducing perioperative myocardial infarction and death.
• AICAR-treated animals showed increased mitochondrial density and enhanced fatty acid oxidation capacity in skeletal muscle, confirmed by electron microscopy and metabolic flux analysis.
• WADA (World Anti-Doping Agency) banned AICAR in 2011, classifying it as a metabolic modulator — the first exercise-mimetic compound to receive this designation.
• Research in diabetic models shows AICAR improves insulin sensitivity and glucose homeostasis through insulin-independent GLUT4 translocation, suggesting therapeutic potential for type 2 diabetes.
• A 2012 study demonstrated AICAR reduced hepatic lipid accumulation by 40% in high-fat-diet-fed mice, indicating liver-specific metabolic benefits.

• Research subcutaneous dose: 150–500 mg daily, typically divided into morning and pre-workout administrations. The injectable form provides the most consistent bioavailability.
• Clinical cardiac studies used intravenous infusion at 0.1 mg/kg/min for up to 7 hours during coronary artery bypass surgery.
• Standard research cycle: 4–6 weeks on, 4 weeks off. Extended cycles increase the risk of metabolic disturbances.
• Often stacked with GW501516 (Cardarine) in research settings for synergistic endurance effects — AICAR activates AMPK directly while GW501516 activates PPARδ, and the combination produced greater endurance gains than either alone.
• Dose titration is critical: start at the lower end (150 mg) and increase gradually. Excessive AMPK activation can cause hypoglycemia, particularly in fasted individuals.
• Take on training days 30–60 minutes before exercise for maximum synergistic effect with physical activity.
• Blood glucose monitoring is recommended, especially during the first week and when combining with fasting or low-carbohydrate diets.

Known Side Effects

• Hypoglycemia — the most significant acute risk, particularly in fasted states or combined with insulin-sensitizing agents. AMPK activation drives glucose uptake independently of insulin.
• Lactic acidosis — excessive AMPK activation can shift metabolism in ways that promote lactate accumulation, particularly at high doses.
• Gastrointestinal distress — nausea, cramping, and diarrhea reported at higher doses, likely related to AMPK activation in intestinal epithelium.
• Potential muscle catabolism — AMPK activation inhibits mTORC1, which is essential for muscle protein synthesis. Prolonged high-dose use could theoretically impair muscle building.
• Cardiac effects — while low-dose AICAR is cardioprotective, excessive adenosine receptor activation could theoretically cause bradycardia.
• Unknown long-term effects on purine metabolism and uric acid levels, as AICAR is an intermediate in the purine synthesis pathway.

Safety Profile

AICAR has a reasonably well-characterized safety profile from clinical cardiac studies, where it was administered intravenously in controlled settings with good tolerability. However, the subcutaneous dosing protocols used in research settings are less well-studied in humans. The primary acute risk is hypoglycemia, which can be managed through glucose monitoring and appropriate carbohydrate intake. The risk increases significantly when combined with fasting, ketogenic diets, or other glucose-lowering agents. Contraindications include hypoglycemia-prone conditions (insulinoma, adrenal insufficiency), severe hepatic or renal impairment, and concurrent use of metformin or other AMPK-activating drugs (risk of excessive AMPK activation). The mTORC1 inhibition caused by AMPK activation means AICAR should be used cautiously by those seeking muscle hypertrophy — timing doses away from resistance training may mitigate this. Not recommended during pregnancy or in individuals under 18. WADA-tested athletes should be aware of its banned status.

Days 1–3: Increased warmth and subtle energy shift as AMPK activation begins modifying cellular metabolism. Blood glucose may dip lower than usual — have carbohydrates available. Some users notice enhanced aerobic capacity even in the first few sessions. Weeks 1–2: Endurance improvements become noticeable. Activities that previously caused fatigue feel easier. Fat oxidation increases, and some users notice reduced body fat, particularly with concurrent exercise. Appetite may decrease slightly. Weeks 3–4: Peak endurance effects. The 44% improvement in sedentary mice occurred over this timeframe. Active users report significantly improved cardiovascular performance, longer time to exhaustion, and improved recovery between sets/intervals. Weeks 5–6: Continued benefits with potential plateau. This is typically the endpoint of a cycle. Fat loss and endurance gains achieved during the cycle tend to partially persist after cessation, especially if exercise habits are maintained.

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