Cardarine or Clenbuterol: what is the difference

Cardarine and Clenbuterol fall into the same “fat burner” category in sports folklore, although they affect the body in fundamentally different ways. Clenbuterol is a β2-adrenergic receptor stimulant; Cardarine is a modulator of gene expression through the PPARδ receptor. The editorial team explains what the difference between them is and why each substance has its own, very serious risk profile.

What these substances are

Clenbuterol is a bronchodilator from the group of long-acting β2-adrenergic receptor agonists. In some countries it is used to treat bronchial asthma in humans, but most widely in veterinary medicine, in particular for horses. Athletes’ interest in clenbuterol arose because of its ability in animals to increase the proportion of muscle tissue and reduce fat — the so-called “repartitioning effect”.

Cardarine (GW501516, or GW1516) is a synthetic agonist of the PPARδ receptor (the delta receptor activated by peroxisome proliferators), created in the 1990s within a collaboration between Ligand and GlaxoSmithKline. It was developed as a potential agent for treating dyslipidemia and metabolic disorders.

The fates of the substances turned out differently. Clenbuterol is a registered medicine in a number of countries (with specific indications), whereas Cardarine never became a drug: the development program was halted after the development of tumors in many organs was found in long-term studies in rodents.

Both substances are banned by WADA, but in different classes: clenbuterol among “other anabolic agents” (S1.2), Cardarine among hormone and metabolic modulators (S4). This reflects the difference in their mechanism.

Mechanism of action: a receptor on the membrane versus a receptor in the nucleus

Clenbuterol binds to β2-adrenergic receptors on the surface of cells. Through a G protein and the enzyme adenylate cyclase this raises the level of cAMP inside the cell, which triggers relaxation of the smooth muscle of the bronchi, enhanced lipolysis in adipose tissue and increased thermogenesis. But β receptors are also present in the heart, so at high concentrations the stimulation spreads to the myocardium.

Cardarine acts more deeply — at the level of genes. PPARδ is a nuclear receptor that, once activated, changes the transcription of genes related to fatty-acid oxidation, mitochondrial biogenesis and lipid metabolism. In a well-known paper by Narkar and colleagues (2008) in mice, the combination of a PPARδ agonist with an AMPK activator increased endurance, which led such compounds to be called “exercise mimetics”.

So clenbuterol gives a fast, “acute” stimulatory effect characteristic of the sympathetic nervous system, while Cardarine gives a slower effect of remodeling metabolism that develops through changes in gene expression.

From this difference follows a difference in risks too: clenbuterol’s are predominantly acute (cardiovascular), Cardarine’s are delayed and potentially carcinogenic, found in long-term animal studies.

What the studies say

For Cardarine there are small human studies with metabolic aims. Thus, in a paper by Sprecher and colleagues (2007) a PPARδ agonist favorably changed the ratio of triglycerides to HDL in healthy volunteers. However, large and long-term clinical studies were not conducted, because development was stopped over data on carcinogenicity in rodents.

There are no controlled-study data showing that Cardarine causes significant fat loss or improves athletic performance in humans. Popular claims of “endurance several times greater” come from experiments in mice and cannot be transferred directly to humans.

For clenbuterol there is no quality evidence of a notable anabolic effect in humans: the known “repartitioning” of mass has been demonstrated mainly in animals, at doses exceeding therapeutic ones. On the other hand, the toxicological data in humans are quite rich — unfortunately, thanks to numerous poisonings.

Reports from toxicology centers (Spiller et al., 2013; Brett et al., 2014) describe a typical picture: tachycardia, palpitations, tremor, agitation, hypokalemia, hyperglycemia, and in severe cases myocardial ischemia and arrhythmias. A significant share of such presentations is linked precisely to use for weight loss and bodybuilding.

Risk profiles

The risks of clenbuterol most often appear quickly. The drug has a long half-life in humans — on the order of a day or more — so its action accumulates and an overdose lasts a long time. A heart working under constant adrenergic stimulation may respond with arrhythmias, and in susceptible people with ischemia even at a young age.

In addition, clenbuterol shifts potassium into cells, lowering its level in the blood, which further raises the risk of rhythm disturbances. Chronic stimulation of β receptors in animal models was associated with myocardial hypertrophy.

The risks of Cardarine are different in nature. After tumors were found in rodents with prolonged use, GSK halted development, and in 2013 WADA issued a separate warning to athletes about the toxicity of GW501516. Whether this effect is reproduced in humans is unknown, but precisely because no one has conducted long-term safety studies.

The uncertainty about Cardarine does not mean “probably safe”. For a substance whose development was stopped over carcinogenicity, the absence of data in humans is grounds for maximum caution.

• Clenbuterol:tachycardia, tremor, insomnia, hypokalemia, hyperglycemia, arrhythmias, myocardial ischemia.
• Cardarine:carcinogenicity in animal models, unknown long-term profile in humans, product adulteration.

Anti-doping control

Clenbuterol is banned in sport at all times. A peculiarity of this substance is the risk of inadvertent entry into the body through the meat of animals that were illegally given clenbuterol to increase muscle mass. Such cases have been described for several countries, and anti-doping organizations have specifically warned athletes about this risk during competitions in the relevant regions.

Cardarine and its metabolites are also reliably detected in doping samples; methods for their detection have been published by anti-doping laboratories. Positive samples for GW501516 have been recorded, in particular, in cycling and athletics.

For both substances the principle of strict liability applies: the athlete is responsible for any prohibited substance in their sample. Therefore the use of unverified “fat-burning” products is a separate risk of disqualification.

In a number of countries the circulation of clenbuterol for humans is controlled as a prescription drug, and the sale of Cardarine for human consumption is not permitted.

Editorial conclusions

Cardarine and clenbuterol are united only by the marketing niche of “fat burning”. Clenbuterol is a β2-adrenergic agonist with acute cardiovascular risks, well documented in toxicology centers. Cardarine is a PPARδ agonist whose development was halted over carcinogenicity in animal studies.

Neither substance has proven safe effectiveness for weight loss in humans, and both are banned in sport. Reliable tools for reducing fat mass — a moderate calorie deficit, sufficient protein, strength and aerobic training — do not carry such risks.

We also recommend our materials “Cardarine vs Clenbuterol: what to choose and for whom”, an overview of stimulant overdose symptoms and an article on safe strategies for reducing fat mass.

References

1. Narkar VA, Downes M, Yu RT, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008;134(3):405–415.
2. Sprecher DL, Massien C, Pearce G, et al. Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist. Arterioscler Thromb Vasc Biol. 2007;27(2):359–365.
3. Spiller HA, James KJ, Scholzen S, Borys DJ. A descriptive study of adverse events from clenbuterol misuse and abuse for weight loss and bodybuilding. Subst Abus. 2013;34(3):306–312.
4. Brett J, Dawson AH, Brown JA. Clenbuterol toxicity: a NSW poisons information centre experience. Med J Aust. 2014;200(4):219–221.
5. Pope HG Jr, Wood RI, Rogol A, et al. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement. Endocr Rev. 2014;35(3):341–375.
6. World Anti-Doping Agency. The World Anti-Doping Code International Standard: Prohibited List. Montreal: WADA; чинна редакція.