Why drugs are abandoned in development: examples from sports pharmacology
Many substances sold online to gym-goers were once serious pharmaceutical projects that never made it to approval, or were withdrawn soon after. Our editorial team looks at how drug development works and what the stories behind these compounds reveal about their risks.
How a medicine reaches the market
Every licensed medicine has travelled a long road. It begins with laboratory work identifying a target, such as a receptor or enzyme, followed by tests in cells and animals. Only then do human trials begin: Phase I in small numbers of volunteers to study safety and how the body handles the compound, Phase II to look for signs of benefit and suitable dosing, and Phase III in large populations to confirm efficacy and detect less common harms.
Most candidate molecules never finish this journey. An analysis by Wong, Siah and Lo of thousands of development programmes found that the probability of a compound progressing from Phase I to approval is low and varies considerably by therapeutic area. The reasons for failure fall into a few broad categories: lack of efficacy, unacceptable safety signals, commercial decisions and manufacturing problems.
Even approval is not the end. Post-marketing surveillance, through schemes such as the MHRA Yellow Card scheme in the UK, can uncover rare or delayed harms that trials of a few thousand patients missed. When the balance of benefit and risk shifts, licences can be suspended or withdrawn.
This process matters to people in sport because a striking number of substances circulating in gyms are compounds that failed this very process. Understanding why they failed is one of the best ways to understand their risks.
Cardarine: abandoned after animal studies
GW501516, sold online as "Cardarine", is a PPAR-delta agonist developed by GlaxoSmithKline in the 1990s with a view to treating lipid disorders and metabolic disease. Early studies were promising: in animals, it shifted muscle metabolism toward fat burning and improved endurance.
Development was halted in the late 2000s after long-term rodent studies reportedly found that the compound caused cancers in multiple organs. Carcinogenicity findings in animals do not always translate to humans, but when they appear across several tissues, few companies will take the risk of exposing large patient populations.
The World Anti-Doping Agency took the unusual step of issuing a public warning about GW501516 in 2013, stressing that it had not received clinical approval and pointing to the serious toxicity seen in preclinical work. Despite this, it continues to be sold online as a "research chemical", and anti-doping laboratories, as described by Sobolevsky and colleagues, have developed methods to detect it and its metabolites.
The lesson is simple: a product that a major pharmaceutical company chose to abandon after investing heavily in it is not made safer by being repackaged and sold without a licence.
SARMs and growth hormone secretagogues
Selective androgen receptor modulators were designed to deliver the muscle and bone benefits of testosterone while sparing the prostate and other tissues. Enobosarm (ostarine) showed increases in lean body mass in a Phase II trial by Dalton and colleagues in older adults. However, later Phase III trials in cancer-related muscle wasting did not meet their primary endpoints combining lean mass and physical function, and the compound has not been licensed for that indication.
The story illustrates an important point: changing a lab number such as lean mass is not the same as delivering a meaningful patient benefit. Regulators require improvements in outcomes that matter, like function or survival.
Ibutamoren (MK-677), an oral growth hormone secretagogue, was studied by Merck for several indications. In a trial in older patients recovering from hip fracture, reported by Adunsky and colleagues, the study was stopped early, and a higher number of patients receiving the drug developed heart failure. That safety signal, combined with modest benefits, ended its path to approval.
Neither SARMs nor ibutamoren are licensed medicines in the UK, and both are prohibited in sport at all times under the WADA code. Products sold online have repeatedly been found to contain different substances or amounts from those on the label.
Weight-loss drugs withdrawn after approval
Some failures come after a medicine has already been on the market. Rimonabant, a cannabinoid receptor blocker, was licensed in Europe for obesity in 2006. A meta-analysis by Christensen and colleagues in The Lancet found an increased risk of psychiatric adverse events, including depression and anxiety. The European Medicines Agency recommended suspension in 2008.
Sibutramine, an appetite suppressant, was withdrawn across Europe in 2010 after the SCOUT trial, published by James and colleagues, found an increased risk of non-fatal heart attacks and strokes in people with pre-existing cardiovascular disease.
| Compound | Intended use | Main reason development or marketing stopped |
|---|---|---|
| GW501516 | Lipid and metabolic disorders | Cancers in long-term animal studies |
| Enobosarm | Cancer-related muscle wasting | Phase III endpoints not met |
| Ibutamoren | Recovery after hip fracture | Heart failure signal, trial stopped early |
| Rimonabant | Obesity | Psychiatric adverse effects |
| Sibutramine | Obesity | Cardiovascular events in SCOUT |
Both drugs continue to turn up as undeclared ingredients in "herbal" slimming products seized by authorities. The MHRA has warned repeatedly about unlicensed weight-loss products bought online.
Why this matters for anyone who trains
When a compound is abandoned, the safety research usually stops too. There are no long-term human data, no quality-controlled manufacturing and no pharmacovigilance system to pick up harms. People who buy such products are effectively joining an uncontrolled experiment.
- "Research chemical" labels mean a product is not approved for human use.
- Animal data on muscle growth or fat loss do not prove safety or benefit in people.
- Early trial results are often not confirmed in larger studies.
- Most of these substances are prohibited under anti-doping rules.
Our editorial team does not provide dosing information for unapproved or prescription compounds. If you have used any of the substances discussed and have symptoms such as chest pain, breathlessness, swelling, mood changes or jaundice, seek medical help and be open about what you have taken.
For those looking to improve body composition, evidence-based training, nutrition and, where medically appropriate, licensed treatment prescribed by a doctor remain the safer routes.
Editorial conclusions
Most drug candidates fail, and they fail for good reasons: lack of benefit, unacceptable harm or both. Several popular gym compounds are exactly those failures.
Cardarine, ostarine and ibutamoren were all studied by major companies and did not reach licensing, while rimonabant and sibutramine were withdrawn after real-world risks emerged.
Knowing the development history of a substance offers a useful reality check on marketing claims.
Readers may also want to explore our articles on how clinical trial phases work, the WADA Prohibited List explained and the risks of buying medicines online.
References
- Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Biostatistics. 2019;20(2):273–286.
- Dalton JT, Barnette KG, Bohl CE, et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle. 2011;2(3):153–161.
- Adunsky A, Chandler J, Heyden N, et al. MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study. Arch Gerontol Geriatr. 2011;53(2):183–189.
- Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet. 2007;370(9600):1706–1713.
- James WPT, Caterson ID, Coutinho W, et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med. 2010;363(10):905–917.
- Sobolevsky T, Dikunets M, Sukhanova I, Virus E, Rodchenkov G. Detection of PPARδ agonists GW1516 and GW0742 and their metabolites in human urine. Drug Test Anal. 2012;4(10):754–760.
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