IngredientesGW501516 (cardarine) has the systematic IUPAC name 2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]phenoxy]acetic acid and belongs to the peroxisome-proliferator-activated receptor delta (PPAR-δ) agonists group. It is also known as GW-501,516, GW1516, GSK-516, cardarine, and, within performance-enhancing drug communities, as "endurobol."
The molecular formula of GW501516 is C₂₁H₁₈F₃NO₃S₂, with a molecular weight of 453.5 g/mol. Structurally, GW501516 is a small-molecule, nonsteroidal PPAR-δ ligand built around a 1,3-thiazole core flanked by a 4-(trifluoromethyl)phenyl group and a phenoxyacetic acid tail linked via a methylenethio bridge. The trifluoromethyl group and the two sulfur centers (one in the thiazole ring, one in the sulfide linker) are key structural features contributing to receptor affinity and subtype selectivity.
Cardarine has no botanical or natural origin. GW501516 is a synthetic peroxisome-proliferator-activated receptor delta (PPAR-δ) agonist agent developed for applications in the treatment of metabolic disorders and cardiovascular diseases. It is not derived from any plant, animal, or microbial source and has no traditional or herbal equivalent.
GW501516 is not approved by the U.S. Food and Drug Administration (FDA) for any human or veterinary use and is legally available only as a research chemical. In the marketplace it is encountered primarily in two physical forms. Cardarine can be bought in powder or liquid forms. It is slightly soluble in water, which influences the formulations used in research settings; it is typically dissolved in solvents such as DMSO or ethanol for laboratory use, or suspended in carrier oils for oral administration. Pharmaceutical-grade crystalline material achieves purities of 99% or higher, and multiple polymorphic forms of the pure compound have been characterised by X-ray diffraction.
GW501516 was invented in a collaboration between Ligand Pharmaceuticals and GlaxoSmithKline (GSK) in the 1990s. The compound was initially discovered during a research collaboration between GSK and Ligand Pharmaceuticals that began in 1992. It was first developed by GlaxoSmithKline in 1992 as a potential treatment for obesity, type 2 diabetes, and hypercholesterolemia.
It entered clinical development as a drug candidate for metabolic and cardiovascular diseases, but was abandoned in 2007 because animal testing showed that the drug caused cancer to develop rapidly in several organs. By 2007, GW501516 had completed two Phase II clinical studies and other studies relating to obesity, diabetes, dyslipidemia, and cardiovascular disease, but GSK abandoned further development in 2007 for reasons which were not disclosed at the time.
In 2007, research was published showing that high doses of GW501516 given to mice dramatically improved their physical performance; the work was widely discussed in popular media, and led to a black market for the drug candidate and to its abuse by athletes as a doping agent. Concerns were raised prior to the 2008 Beijing Olympics that GW501516 could be used by athletes as a performance-enhancing drug that was not currently controlled by regulations or detected by standard tests. One of the main researchers from the study on enhanced endurance consequently developed a urine test to detect the drug, and made it available to the International Olympic Committee.
Cardarine has no history of traditional use in any herbal medicine tradition, ethnobotanical context, or folk medicine system, as it is an entirely synthetic pharmaceutical compound that did not exist before the 1990s.
Cardarine, also known as GW501516, is one of the most well-known yet controversial research chemicals in the world of performance enhancement. It is often incorrectly labeled a SARM, but it is, in fact, a Peroxisome Proliferator-Activated Receptor delta (PPARδ) agonist. Cardarine is non-hormonal and does not affect androgen receptors. Often advertised as a selective androgen receptor modulator (SARM), GW1516 is actually a PPARδ agonist, prohibited under the WADA Prohibited List. Substances in this category modify how the body metabolizes fat, and GW1516 was originally synthesized and evaluated for the treatment of obesity, diabetes, and other disorders caused by metabolic problems.
GW501516 is a selective agonist of the PPARδ receptor. It displays high affinity (Ki = 1 nM) and potency (EC50 = 1 nM) for PPARδ with greater than 1,000-fold selectivity over PPARα and PPARγ. It has been extensively cited in the primary literature as a reference PPAR-δ ligand in studies of lipid metabolism, fatty acid oxidation, mitochondrial function, and inflammatory and metabolic signaling pathways. GW501516 is widely characterized as one of the most potent and selective PPAR-δ agonists described, with reported binding affinity in the low-nanomolar range and substantial selectivity over the other PPAR subtypes.
Cardarine binds to and activates the PPARδ receptor, a transcription factor that plays a key role in the body's energy metabolism. In rats, binding of GW501516 to PPARδ recruits the coactivator PGC-1α. This recruitment of PGC-1α is central to downstream gene expression changes governing mitochondrial biogenesis, fatty acid oxidation gene programs, and slow-twitch muscle fiber specification.
PPAR-δ ligands, including GW501516, have been shown to boost the body's ability to use fat as a source of fuel instead of glucose. PPAR-δ receptor activation plays a role in metabolism and promotes the burning of fatty acids via the mechanism of up-regulation of fatty acid uptake and oxidation. GW501516 increases expression of PGC-1alpha and CPT-1 and stimulates fatty-acid oxidation in muscle cells. CPT-1 (carnitine palmitoyltransferase 1) is the rate-limiting enzyme for mitochondrial fatty acid import, and its upregulation by PPARδ activation is a principal mechanistic step.
Research has described the engineering of a mouse capable of continuous running of up to twice the distance of a wild-type littermate. This was achieved by targeted expression of an activated form of PPARδ in skeletal muscle, which induces a switch to form increased numbers of type I muscle fibers. Treatment of wild-type mice with PPARδ agonist elicits a similar type I fiber gene expression profile in muscle. It is known that endurance training can increase the number of type I fibers, and this is accompanied by an increase in PPAR-δ expression. The increase in type I fibers correlated with increased exercise endurance in transgenic mice.
Numerous studies demonstrated that GW501516 treatment and skeletal muscle-specific PPARδ expression in mice ameliorated diet-induced obesity, enhanced metabolic rate, lipid oxidation, reduced intramuscular triglycerides, and increased mitochondria in skeletal muscle. Moreover, anatomical analysis revealed the resistance to increased body weight was largely due to reduced mass of visceral and epidermal fat depots.
The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as resveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. Testing the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test found that PPARβ/δ agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. PPARδ overexpression increases AMPK activity, and PPARδ activity is also stimulated by AMPK. PPARδ appears to interact with AMPK and synergistically regulates exercise endurance genes.
Small molecule ligands that specifically activate PPARδ, including GW501516, have revealed multiple beneficial metabolic effects including increased energy expenditure, elevated fatty acid oxidation, reduced obesity and insulin resistance, exercise-induced muscle remodeling, and collectively enhanced running endurance by 80% or more (Narkar et al., 2008).
Some researchers have concluded that PPARδ activation blocks substances involved in inflammatory responses and reduces the activity of inflammatory genes. In rats, cardarine consumption was associated with reduced inflammatory markers including MCP-1, TNF-alpha, IL-6, and NF-κB. GW501516, evaluated for its effect on fatty acid-induced inflammation in cardiomyocytes, was also found to reduce expression of the NF-κB target genes MCP-1 and TNF-α in both human cardiac cells stimulated by palmitate and hearts of mice fed a high-fat diet. This implies that PPAR-δ may counteract NF-κB activity.
Peroxisome proliferator-activated receptor-delta (PPARdelta) activation enhances skeletal muscle fatty acid oxidation and improves whole-body glucose homeostasis and insulin sensitivity. GW501516, a selective PPARdelta agonist, was reported to increase glucose uptake in human skeletal myotubes by an AMPK-dependent mechanism that may contribute to improved glucose tolerance. However, another study found conflicting results: while GW501516 increases expression of PGC-1alpha and CPT-1 and stimulates fatty-acid oxidation in L6 myotubes, it fails to enhance insulin sensitivity, AMPK activity, or glucose uptake and storage in that cell line, leading to the conclusion that sarcolemmal glucose transport is not a definitive target for the therapeutic action of PPARdelta agonists in all skeletal muscle models.
Administration of GW501516 to mice increased fatty acid β-oxidation in skeletal muscle, reduced obesity in diet-induced models, and improved running endurance by reprogramming muscle fiber types toward oxidative metabolism. These preclinical results highlighted GW501516's role in attenuating features of metabolic syndrome, including elevated triglycerides and insulin resistance, through PPARδ-dependent mechanisms.
GW501516 entered clinical development in the early 2000s as a potential treatment for metabolic disorders, including dyslipidemia, metabolic syndrome, and related conditions such as diabetes and hyperlipidemia, under the sponsorship of GlaxoSmithKline (GSK) in collaboration with Ligand Pharmaceuticals. Phase I trials, initiated around 2000–2002, focused on assessing safety, tolerability, and pharmacokinetics in healthy volunteers, with two such studies completed to evaluate single and multiple ascending doses.
A key Phase II dose-finding study administered GW501516 to a large patient population. GW501516 (2.5, 5.0, or 10.0 mg) or placebo was given for 12 weeks to patients (n=268) with HDL cholesterol below 1.16 mmol/L. Fasting lipids/apolipoproteins, insulin, glucose, and free fatty acid were measured. A second smaller exploratory study (n=37) in a similar population was conducted using a sequence of 5 and 10 mg dosing for the assessment of lipoprotein particle concentration. GW501516 demonstrated HDL cholesterol increases up to 16.9% (10 mg) and apoA-I increases up to 6.6%. Reductions were observed in LDL cholesterol (−7.3%), triglycerides (−16.9%), apoB (−14.9%), and free fatty acids (−19.4%).
A separate crossover lipoprotein kinetics study investigated the mechanism behind these lipid changes. In a randomized, double-blind, crossover trial involving 13 dyslipidemic men with central obesity, the study investigated the impact of GW501516 on lipoprotein metabolism. The results revealed that GW501516 effectively lowered plasma triglycerides, fatty acid, and various apolipoprotein concentrations, while increasing HDL cholesterol levels. This was achieved by enhancing the clearance of very low-density lipoprotein (VLDL) particles and increasing the production of beneficial HDL particles. Additionally, GW501516 reduced cholesteryl ester transfer protein activity, leading to favorable changes in lipid content within lipoprotein particles.
An earlier smaller study in healthy volunteers also showed directionally consistent results. Serum triglycerides trended downwards (P=0.08, 10 mg), whereas triglyceride clearance post-fat-feeding improved with the drug (P=0.02). In this small study, GW501516 significantly influenced HDLc and TGs in healthy volunteers. Enhanced in vivo serum fat clearance and the first demonstrated in vitro upregulation in human skeletal muscle fat utilization and ABCA1 expression suggest peripheral fat utilization and lipidation as potential mechanisms.
Evidence Strength: The lipid-modifying effects of GW501516 are among the best-supported human findings for this compound. The largest study enrolled 268 participants over 12 weeks in a placebo-controlled design, providing moderate-quality human evidence of beneficial effects on the lipid profile. However, all of these trials were short (≤12 weeks), and the compound's clinical development was terminated before confirmatory long-term efficacy or cardiovascular outcome studies could be completed.
Caucasian men (age 18–50 years, n=18) were randomly assigned to treatment with GW501516, GW590735 (a PPARα agonist), or placebo for two weeks while residing in a clinical research facility. A meal tolerance test, skeletal muscle biopsy, and blood/breath sampling were conducted. The study reported that treatment with GW501516 ameliorated multiple metabolic abnormalities associated with metabolic syndrome including oxidative stress, obesity, dyslipidemia, and insulin resistance, all while increasing fatty acid oxidation. Notably, no adverse effects were reported. However, the restricted living conditions and/or diets that the participants were subjected to likely do not resemble their normal lifestyle.
In a double-blind, randomized trial involving moderately overweight individuals, GW501516 was compared to a PPARα agonist and a placebo. GW501516 led to significant reductions in fasting triglycerides, apolipoprotein B, LDL cholesterol, and insulin levels, along with a decrease in liver fat content and oxidative stress. These changes were not observed with the PPARα agonist. GW501516 increased fat oxidation in skeletal muscle and the expression of carnitine palmitoyl-transferase 1b (CPT1b). These findings suggest that GW501516 can mitigate metabolic syndrome-related abnormalities through enhanced fat oxidation in muscles without increasing oxidative stress.
Evidence Strength: Preliminary to moderate. The available human studies are short-term (two weeks in most cases), small in sample size (n=18 in the best-characterised metabolic syndrome study), and conducted in controlled inpatient settings. Results are directionally consistent but insufficient to draw firm clinical conclusions.
Overexpression of a constitutively active PPARδ (VP16-PPARδ) in skeletal muscles of transgenic mice preprograms an increase in oxidative muscle fibers, enhancing running endurance by nearly 100% in untrained adult mice (Wang et al., 2004). In the landmark 2008 study by Narkar and colleagues published in Cell, PPARβ/δ agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. In the original study, GW501516 combined with exercise produced a 70% endurance improvement. However, GW501516 required exercise to achieve its full effect, while AICAR worked without exercise. GW501516 alone was insufficient.
Selective PPARδ agonist GW501516 increased the number of oxidative myofibers and the level of running endurance in adult mice. Exercise-induced performance improvement was attenuated in PPARδ-deficient mice. These effects are attributed to PPARδ-induced suppression of glucose catabolism; glucose sparing delays hypoglycemia and extends running time.
No controlled human trials have directly evaluated the endurance-enhancing effects of GW501516. GW501516 has attracted significant attention in both animal research and early human clinical trials for its potential to address a range of metabolic and cardiovascular conditions. While initial clinical investigations provided limited early data, the vast majority of findings to date come from preclinical and mechanistic studies conducted in animals and in vitro models.
Evidence Strength: Preclinical evidence in rodents is compelling for endurance enhancement, particularly when combined with exercise. There is no controlled human evidence for endurance effects. The compound's appearance in athlete doping cases provides circumstantial evidence of perceived performance benefit in humans, but this cannot substitute for clinical trial data.
In high fat-fed rats and mice, cardarine improved insulin response, which in turn reduced blood sugar levels. In a mouse model of metabolic syndrome, cardarine administration ameliorated insulin resistance. In monosodium L-glutamate-induced metabolic syndrome mice, cardarine treatment improved glucose intolerance, normalized fasting blood glucose levels, and increased high-density lipoprotein cholesterol. These effects are attributed to enhanced fatty acid oxidation and improved insulin sensitivity.
Human data on glycaemic effects is limited and indirect. The two-week Risérus et al. study cited above reported reductions in fasting insulin and improved insulin sensitivity as secondary endpoints in overweight men, but long-term glucose outcomes were not assessed. GW501516 was reported to increase glucose uptake in human skeletal myotubes by an AMPK-dependent mechanism that may contribute to improved glucose tolerance.
Evidence Strength: Preclinical evidence is consistent across multiple animal models. Human evidence is limited and derives from secondary measurements in short metabolic trials. No dedicated clinical trial on glycaemic control has been completed.
In a high-fructose rodent model, GW501516 activated PPAR-beta/delta and its target genes PDK4 and CPT-1. Despite showing no effects on the ACE/AT1r axis or renin expression, GW501516 improved the inflammatory state in the kidney, eliciting an expressive reduction in the expression of inflammatory genes such as IL-1β, IL-6, MCP-1, and Cd68. However, no differences were found in oxidative stress.
Applied on the skin, cardarine was associated with improved healing of diabetic wounds in mice, possibly due to reduced inflammation. Cardarine may also have antioxidant potential: mice given cardarine produced more of the antioxidant enzymes SOD1 and catalase.
Evidence Strength: Evidence is entirely preclinical (animal and cell-based). Cardarine has been associated with lower inflammation, reduced oxidative damage, and improved wound healing in animal trials. Human studies have not been conducted for inflammatory endpoints.
The hepatic effects of GW501516 are mixed in the preclinical literature. On one hand, early human metabolic studies reported a decrease in liver fat content. On the other, cardarine was thought to prevent liver damage by stimulating fat-burning, improving insulin resistance, and relieving inflammation; however, it may also worsen liver disease and was found to cause liver cell death and liver damage, further demonstrating potential danger. Cardarine increased cell death in liver cells and caused liver damage in some mice with liver disease. These conflicting signals mean the net hepatic effect of GW501516 cannot be characterised as uniformly protective.
Evidence Strength: Mixed preclinical data; limited and indirect human data from short metabolic trials. No dedicated human hepatology study has been completed.
The following dosages appear in peer-reviewed publications or government regulatory documents and are reported here as stated in those sources:
GW501516 has been prohibited by the World Anti-Doping Agency (WADA) under section S4.4.1 of the Prohibited List as a PPARδ agonist, a category of hormone and metabolic modulators, since 2009. It remains banned at all times, both in- and out-of-competition, in the 2025 Prohibited List with no changes to its status. It falls under category S4.4, metabolic modulators, alongside other PPARδ agonists. It is classified as a non-specified substance, which is the more serious designation under WADA rules, meaning athletes who test positive face harsher default sanctions than they would for many other banned substances. Multiple athletes across cycling, track and field, and other endurance sports have received bans after testing positive.
In 2013, WADA took the rare step of warning potential users of the compound of the possible health risks, stating that "clinical approval has not, and will not be given for this substance."
The U.S. Food and Drug Administration (FDA) classifies GW501516 as an unapproved new drug, prohibiting its marketing or use in humans outside investigational settings, as evidenced by FDA warning letters targeting products containing it. In addition to being prohibited at all times under the WADA Prohibited List, GW1516 is not legally permitted in any medications, supplements, or foods. Athletes should be aware that dietary supplements may be contaminated with this compound. Similarly, the marketing of this compound as a medication or dietary supplement is not legal.
Since June 2018, the TGA has classed cardarine under Schedule 10, which means that it is considered such a danger to health that it is prohibited by law from sale, supply and use. A TGA statement on cardarine states that the "public health risk substantially outweighs the benefit" of "public access to any proposed or known cardarine products." GW1516 is associated with high frequency of carcinogenicity and reproductive toxicity. The TGA lists GW1516 under Schedule 10 — substances of such danger to health as to warrant prohibition of sale, supply and use. A Therapeutic Use Exemption (TUE) would not be granted for the use of GW1516.
GW501516 entered into clinical development as a drug candidate for metabolic and cardiovascular diseases, but was abandoned in 2007 because animal testing showed that the drug caused cancer to develop rapidly in several organs. It later emerged that the drug was discontinued because animal testing showed that the drug caused cancer to develop rapidly in several organs, at dosages of 3 mg/kg/day in both mice and rats. Long-term administration of high doses of cardarine on rats and mice resulted in multiple tumor growths — including colorectal and uterine cancer.
Due to the early termination of its clinical development, data on side effects of GW501516 in humans is limited. Short-term clinical trials did not report significant adverse effects. The primary established risk comes from preclinical animal studies, which demonstrated carcinogenicity at high doses, leading to the discontinuation of pharmaceutical development.
Some of cardarine's proponents argue that cancer risks have not been proven in humans, but this is only because it was never found safe enough to justify long-term safety studies in humans. In fact, most carcinogenic substances usually don't cause cancer in these types of animal studies because they are not sensitive enough to pick up compounds that only slightly increase the chance of developing cancer. They are designed to pick up on the worst compounds so we don't risk the lives of human subjects in early clinical work.
Without long-term clinical studies, the carcinogenic effect of cardarine in humans cannot be proven or disproven, but it cannot be considered to be safe.
Single oral administration of GW501516 on gestational day 10 was studied in animals. Fetal poor growth was observed. Single oral administration of GW501516 on GD 10 induced cystic degeneration associated with cellular lysis of glycogen cells. In animals, cardarine was not safe to use during pregnancy, as high doses over an extended period of time posed risks to fetal development.
Cardarine may also worsen liver disease and was found to cause liver cell death and liver damage. The net hepatic effect is context-dependent: in models of metabolic liver disease, PPARδ activation may have anti-steatotic effects, but in models of pre-existing hepatic disease, liver cell toxicity has been observed in preclinical settings.
USADA urgently advises athletes not to use this dangerous substance and WADA has also issued a safety warning about GW1516. GW1516 is not available anywhere as an approved medication and has no recognised therapeutic uses. The primary rationale for these prohibitions stems from preclinical studies revealing serious safety risks, including carcinogenicity in multiple organs observed in rats and mice at doses comparable to those used by athletes, leading to the termination of its development by GlaxoSmithKline.
Athletes should be aware that dietary supplements may be contaminated with this compound. In 2015 and 2016, there were fewer than six positive tests for GW1516 globally each year. In 2017, however, the number of positive tests rose to 31, an increase of 183.33 percent. This sharp increase in doping violations coincides with its growing availability through online vendors marketing it as a research chemical or purported dietary supplement.
Cardarine (GW501516) is a peroxisome proliferator-activator receptor-delta agonist investigated for the potential treatment of dyslipidemia, obesity, lipid disorders, and cardiovascular disease. No specific drug–drug interaction studies in humans have been published in the peer-reviewed literature. Given GW501516's broad transcriptional effects on energy metabolism—including upregulation of CPT-1, PDK4, and fatty acid oxidation genes—interactions with anticoagulants, lipid-lowering agents, antidiabetic drugs, and hepatically-metabolised medications are biologically plausible but have not been characterised in controlled human studies. The compound's marked effects on the lipid profile (reductions in LDL, triglycerides; increases in HDL) would be expected to interact pharmacodynamically with statins and fibrates.
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