Cardarine (GW-501516) or anabolic steroids: a comparison of risks

Cardarine (GW-501516) and anabolic steroids often end up in the same "basket" of sports pharmacology, and sometimes Cardarine is even advertised as a safer alternative. Comparing these substances is not simple: they have different mechanisms, different goals and a completely different quality of evidence base. The editorial team compared their risk profiles as far as the available data allow.

Different substances — different goals

Anabolic-androgenic steroids (AAS) are testosterone and its synthetic derivatives. They act through androgen receptors, enhance muscle protein synthesis and increase muscle mass and strength. Their efficacy has been proven in randomized studies, in particular in the classic work of Bhasin and co-authors (1996).

GW-501516 is an agonist of the nuclear receptor PPAR-delta. It does not build muscle but changes energy metabolism: it enhances the oxidation of fatty acids and, according to studies in mice, increases the proportion of oxidative muscle fibers. In the work of Narkar and co-authors (2008), in mice it increased endurance in combination with training.

Thus, these substances are not interchangeable. AAS are used for the sake of mass and strength, GW-501516 for the sake of endurance and fat reduction. The comparison of "which is safer" makes sense only in general terms: what risks a person takes on by choosing each of them.

Another fundamental difference: testosterone and some other steroids are registered medications with clear medical indications, whereas GW-501516 was never approved by any regulator.

Known risks of anabolic steroids

The risks of AAS are described in detail. The Endocrine Society review (Pope et al., 2014) systematizes them by system: cardiovascular (dyslipidemia, hypertension, cardiomyopathy, arrhythmias), endocrine (suppression of one's own testosterone, infertility), liver (for oral 17-alpha-alkylated compounds), psyche (irritability, aggression, depression after withdrawal, dependence).

Suppression of the hypothalamic-pituitary-gonadal axis is one of the most frequent consequences. The review by Rahnema and co-authors (2014) shows that recovery after prolonged use can take months, and in some men testicular function does not fully recover.

For women a specific risk is virilization: deepening of the voice, hirsutism, clitoral enlargement, cycle disturbances. Some of the changes are irreversible even after discontinuation.

Oncological risks of AAS also exist: known associations of oral steroids with adenomas and, more rarely, with liver cancer. However, most AAS effects are characterized by dose dependence and, in many cases, partial reversibility after discontinuation.

Risks of GW-501516: the main question is tumors

Unlike steroids, little is known about GW-501516. Short clinical studies lasting about two weeks (Sprecher et al., 2007; Risérus et al., 2008) found no serious acute side effects and showed favorable lipid changes. However, they were too short and small to assess long-term safety.

The main event in the drug's history is GlaxoSmithKline's halt of development in 2007 after long-term carcinogenicity studies in rodents. According to reports, tumors arose in many organs and at various doses. Regulators require that the dose causing tumors in animals significantly exceed the therapeutic dose for humans, and GW-501516 did not meet this requirement.

In 2013 WADA issued a separate warning for athletes, in which it emphasized the substance's serious toxicity. For an anti-doping organization such a step is atypical: usually the agency simply adds substances to the list without publishing separate warnings.

It is important to understand: at present there is no evidence that GW-501516 causes cancer in humans. But it is precisely the absence of studies that makes this risk impossible to quantify, and this fundamentally distinguishes it from the risks of AAS.

Comparison by body systems

If we juxtapose the data by individual systems, the picture turns out to be heterogeneous. In some respects GW-501516 has obvious advantages, in others — an absence of data or alarming signals.

The table shows that on a number of "visible" side effects — hormonal, androgenic, lipid — GW-501516 looks milder. It is exactly this that forms its reputation. But on the most serious criterion, carcinogenicity, the signal from GW-501516 is so strong that a pharmaceutical company abandoned a promising drug.

Finally, favorable changes in the lipid panel on GW-501516 cannot automatically be considered a reduction of cardiovascular risk. This requires studies with hard endpoints — heart attacks and mortality — which have not been conducted.

Uncertainty as a separate risk

For AAS the risks are at least known, and a person receiving testosterone for medical indications undergoes regular monitoring: hematocrit, lipids, PSA, blood pressure. The doctor knows what and how to monitor. For GW-501516 no such algorithm exists, because it is unknown what exactly should be monitored to detect a problem in time.

The second component of uncertainty is product quality. Both groups of substances are sold on the illegal market with a risk of counterfeiting, but for GW-501516, which is sold as a "research chemical," not even a legal pharmaceutical source theoretically exists.

• Common to both:WADA ban — AAS in section S1, GW-501516 in section S4.
• Common to both:risk of counterfeit and incorrect dosing.
• Different:for AAS the risks are described in detail, for GW-501516 they are not.
• Different:AAS have legal medical indications, GW-501516 has none.

The widespread practice of combining GW-501516 with steroids to "protect lipids" does not reduce risks but sums them: to the well-known complications of AAS is added the uncertain oncological risk of GW-501516.

The editorial team believes it is correct to formulate the conclusion as follows: neither steroids nor GW-501516 are safe for non-medical use, and the difference between them lies not in the level of safety but in the nature of the risks and in how well we understand them.

Editorial conclusions

AAS and GW-501516 are substances with different mechanisms and goals, so speaking of one as a "safe replacement" for the other is incorrect.

Steroids carry well-studied risks to the hormonal system, heart, liver and psyche. GW-501516 lacks androgenic effects and in short studies had a favorable effect on lipids, but its development was stopped due to tumors in many organs in animals.

The notion of Cardarine as the "safer" option is based mainly on a lack of data, not on evidence of safety.

We also recommend reading our materials on the history of Cardarine's development, on the comparison of risks of ibutamoren and anabolic steroids, and on the interaction of Cardarine with other substances.

References

1. 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.
2. Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996;335(1):1–7.
3. Rahnema CD, Lipshultz LI, Crosnoe LE, et al. Anabolic steroid-induced hypogonadism: diagnosis and treatment. Fertil Steril. 2014;101(5):1271–1279.
4. Narkar VA, Downes M, Yu RT, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008;134(3):405–415.
5. 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.
6. Risérus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes. 2008;57(2):332–339.
7. World Anti-Doping Agency. WADA issues alert on GW501516. Montreal: WADA; 2013.