AICAR (Acadesine)
AICAR (Acadesine) — the original exercise-mimetic AMPK activator: the science, the Tour de France scandal, the caveats

Class: small_molecule
Synonyms: AICAR
AICAr
Acadesine (its drug name)
AICA-riboside
5-aminoimidazole-4-carboxamide ribonucleoside
(intracellular active form: ZMP). INCI: none
Function tags: metabolic
endurance / performance (exercise mimetic)
fat oxidation
insulin sensitivity
(cardioprotection, as Acadesine)
Overall evidence grade: B
WADA prohibited: yes
WADA note: Sport — WADA-prohibited since 2009 (S4 metabolic modulators), banned at all times, in and out of competition; detectable in blood/urine; serious sanctions. This is one of the register's most enforcement-relevant compounds in a sporting context.
Last updated: 2026-07-13

In brief: AICAR (Acadesine) is a small-molecule AMPK activator — not a peptide — and the original "exercise in a pill." By entering cells and mimicking AMP (as ZMP), it switches on AMPK, the master energy sensor, triggering a metabolic shift toward fat oxidation, insulin-independent glucose uptake, mitochondrial biogenesis (PGC-1α) and autophagy. Its fame comes from Narkar et al. (Cell, 2008): sedentary mice given AICAR for 4 weeks ran ~44% longer with no training — the study that coined "exercise mimetic." That headline launched a genuine doping saga: WADA banned it in 2009, French authorities suspected it at the Tour de France, and a supply-network bust followed in 2012 — with the striking irony that the discoverer of its performance effect (Ronald Evans) also created the anti-doping test for it. Meanwhile it lived a double life as a legitimate cardiac-surgery drug candidate and the lab's #1 AMPK research tool — until a 2021 review showed many of its effects are AMPK-independent, complicating decades of interpretation. The honest bottom line: elegant, historically important biology; zero human endurance data; a banned, detectable substance in sport; and a mechanism messier than its "clean AMPK activator" reputation.

## Identity a **cell-permeable small molecule** — a purine nucleoside — that acts as a **pharmacological activator of AMPK (AMP-activated protein kinase)**, the cell's "master metabolic energy sensor." It is itself biologically inert until it enters cells (via adenosine transporters) and is phosphorylated to **ZMP**, an **AMP-mimic** that allosterically switches AMPK on. It has been the **most widely used AMPK activator in laboratory research** for decades — and, separately, a clinical drug candidate (**Acadesine**). ## Mechanism (as proposed) AICAR is a **nucleoside** that enters cells through **adenosine transporters (ENT1/2, CNT2/3)**, where it's phosphorylated to **ZMP** — a molecule that **mimics AMP**. Rising "AMP-like" signal **allosterically activates AMPK**, the master sensor that cells use to detect low energy. Activated AMPK flips the metabolic switch from **anabolic (storing) to catabolic (burning)**: it **phosphorylates/inactivates ACC** (↑fatty-acid oxidation), **translocates GLUT4** (↑glucose uptake, insulin-independent), **activates PGC-1α** (↑mitochondrial biogenesis), and **inhibits mTORC1** (↓protein synthesis, ↑autophagy) — collectively reproducing much of the muscle's response to endurance exercise. Elegant and foundational — but note the **2021 caveat** that some AICAR actions bypass AMPK entirely.

Evidence grades by outcome:
outcome: Endurance / exercise performance (the marketed use)
grade: F
base: Narkar 2008 (Cell): sedentary mice +~44% running endurance, type-I fiber shift
caveat: Landmark — but mouse-only; no human endurance trials; WADA-banned precisely for this
outcome: Fat oxidation / metabolic / insulin sensitivity
grade: F
base: Well-characterised: AMPK → ACC inactivation, GLUT4, PGC-1α (cells + animals)
caveat: Strong mechanistic/animal data; not established as a human therapeutic
outcome: Cardioprotection (Acadesine, cardiac surgery)
grade: C
base: Legitimate clinical trials in cardiac-surgery ischemia
caveat: Real clinical study history — but did not achieve general approval; not a consumer indication
outcome: AMPK-activation (as a research tool)
grade: B
base: Decades of use as the standard AMPK probe
caveat: BUT 2021 review: many effects AMPK-independent → interpret AICAR-only studies cautiously
outcome: Human safety (self-use)
base: Trial data at therapeutic doses
caveat: Trials: transient uric-acid rise, mild lactic acidosis, possible hypoglycemia (insulin-independent glucose uptake); no organ-toxicity signal noted — but gray-market self-injection is unstudied, and it's banned/detectable in sport

Legal status:
region: EU
status: Not FDA-approved (gray-market)
note: not an approved consumer drug; Acadesine did not reach general approval. Investigational / research chemical. Not a cosmetic.

Cosmetic claims:

Note: The original "exercise in a pill" — and the register's best doping-scandal story. This entry closes the exercise-mimetic triad and carries genuine intrigue. Three threads: (1) it's the compound behind the famous "44% more endurance in sedentary mice" headline that coined "exercise mimetic"; (2) that finding triggered a real Tour de France doping saga — arrests, a supply network, and the twist that the scientist who discovered its performance effect also built the test to catch it; (3) it lived a double life — a legitimate cardiac-surgery drug candidate (Acadesine) and the lab's #1 AMPK tool — until a 2021 review revealed many of its effects aren't even AMPK-dependent. Zero human endurance data; it's a small molecule, not a peptide.
Status note: status: foundational animal data, no human endurance trials, WADA-banned; watch AMPK-activator drug development — e.g. next-gen activators like O304 — rather than AICAR itself

Sources:
Narkar VA, et al. AMPK and PPARδ Agonists Are Exercise Mimetics. Cell. 2008;134:405-415 (the ~44% endurance / "exercise mimetic" paper; Evans lab, Salk).
Visnjic D, et al. AICAr, a widely used AMPK activator with important AMPK-independent effects: a systematic review. Cells. 2021 (the AMPK-independence caveat).
WADA Prohibited List (AICAR added 2009; S4 metabolic modulators); doping-control detection methodology for AICAR/GW501516 (Evans-derived methods).
Acadesine cardiac-surgery clinical literature (myocardial protection/ischemia); Corton JM, et al. Eur J Biochem. 1995 (AICAR as AMPK activator).
(No human endurance-efficacy trials; partner compound GW501516 dropped for carcinogenicity.)