Performance-Enhancing Supplements: Adverse Events

By Dónal P. O'Mathúna, PhD. Dr. O'Mathúna is Senior Lecturer in Ethics, Decision-Making & Evidence, School of Nursing, Dublin City University, Ireland; he reports no financial relationship relevant to this field of study.

Performance-enhancement supplements, also called ergogenic aids, remain popular among athletes. Up to 3 million people in the United States are believed to use anabolic-androgenic steroids (AAS).1 However, the profile of those using such drugs is broadening. A web-based survey of almost two thousand men using AAS found that the typical user was Caucasian, highly-educated, professionally employed, approximately 30-years-old, and not active in organized sports.2 Users were motivated to increase their muscle mass, strength, and physical attractiveness.

Use of performance-enhancing supplements by athletes is discouraged or banned for several reasons. Foremost amongst these is concern about adverse effects and toxicity. This will be the focus of this review.

Athletes are sometimes highly knowledgeable about performance-enhancing supplements, but not always. For example, a survey of competitors in the Ironman Triathlon World Championships found that 73% believed caffeine improved their endurance performance and 84% believed it improved their concentration.3 However, 53% could not identify how much caffeine was needed to improve performance, nor did they know how much caffeine was in common foods. Information on caffeine was most commonly gained through self-experimentation and talking to other athletes.

Users of AAS view physicians as uninformed about these drugs, with 58% lacking sufficient trust in their physicians to report using AAS.2 To build such trust, healthcare professionals should be able to provide reliable evidence about the potential risks and benefits of popular performance-enhancing supplements.

Anabolic-Androgenic Steroids (AAS)

AAS are a group of more than 30 steroids related to testosterone. Although their effectiveness has been debated over the years, the current consensus is that they do increase muscle mass and strength. Even more debate has occurred over their adverse effects. Their illicit status makes them difficult to study. Many case reports have been published, but almost all AAS users maintain that the public has a highly exaggerated perception of their adverse effects.2

Nonetheless, nearly 30% of AAS users report mild adverse effects.1 These include loss of libido, mood changes, reduced testicular volume, and acne, especially on the back and chest. More serious adverse effects have been reported, but causation is difficult to reliably establish. The incidence mortality of 62 Finnish powerlifting champions suspected of using AAS was compared with 1094 population controls.4 Over a 12-year period, 12.9% of the powerlifters died compared to 3.1% of the controls. The risk of death was 4.6 times higher for the AAS users (P = 0.0002). The causes of death among the AAS users were suicide (3), acute myocardial infarction (3), hepatic coma (1), and non-Hodgkin's lymphoma (1).

AAS are believed to cause cardiac toxicity via several mechanisms.5 Studies have found that AAS cause profound changes in lipid metabolism, reducing HDL levels and raising LDL levels. They appear to promote platelet aggregation and directly promote coagulation. Direct damage of coronary arteries and myocardial cells has been noted. In a small study (58 subjects), 29% of current AAS users and 37% of past AAS users had hypertension, compared to 8% of potential users (matched controls).6 Other serious adverse events reported include liver toxicity, liver cancer, masculinization in women, and gynecomastia in men.7

Surplus plasma androgens are converted into estrogen. To prevent or treat unwanted estrogen effects, AAS users often take other drugs to block this conversion (aromatase inhibitors) or block estrogen receptors (clomiphene or tamoxifen).2 The impact of combining these drugs with AAS is unknown.

The psychiatric effects of AAS are less well understood and harder to study.7 When 88 athletes using AAS were compared with 68 non-using athletes, 23% of the users were found to have major mood symptoms (including mania, hypomania, and depression) compared to 6% of non-users.7 In controlled studies, most subjects given AAS did not have mood changes, but some did. Those given physiological doses did not display mood changes, but higher doses elicited mania and hypomania.

Anecdotal reports of increased aggression and violence with AAS have been coined "roid rage." When the bodies of professional wrestler, Chris Benoit, and his wife and son were found in June 2007 in an apparent double murder-suicide, AAS were alleged to have played some role in the tragic events. However, observational and controlled studies of AAS and aggression have been equivocal.7 Addiction to AAS can develop, with an incidence ranging from 14% to 57% of users. AAS use is often associated with use of other illicit drugs.


Androstenedione (or andro) came to prominent public attention in 1998 when Mark McGwire broke Roger Maris' home run record and announced that he used this and other dietary supplements. Over the next few years, a number of studies reported no evidence of performance enhancement and reported no adverse effects.8 However, subjects given andro had elevated estrogen levels and reduced HDL, which are associated with higher risks for diseases. Studies on the long-term effects of androstenedione usage are not available. As a result of concerns about adverse effects and lack of efficacy, the FDA in 2004 banned the distribution of androstenedione in the United States.9


Ephedra is the only herbal remedy among those discussed here. Ephedra products contain various Ephedra species and were banned by the FDA in 2004.10 Most of these contain ephedrine and related compounds which have a- and b-adrenergic agonist activity.11 These compounds increase blood pressure, heart rate, cardiac output, peripheral vascular resistance, and stimulate the central nervous system. Although used as ergogenic aids and weight loss supplements, a meta-analysis of controlled trials that led to the FDA ban found no studies of athletic performance using herbal ephedra.12 The review found 8 trials assessing the effects of synthetic ephedrine on athletic performance. No benefits were found when ephedrine alone was used, although 20% to 30% improvements in performance were found when ephedrine and caffeine were taken together.

Prior to the ephedra ban, almost two-thirds of all herb-related adverse events reported at US poison control centers involved ephedra. One review examined over 17,000 cases of adverse events reported to the FDA and manufactureres.12 At the same time, ephedra was one of the most popular herbal remedies in the United States. In 1999, it was estimated that 12 million people in the United States used 3 billion doses of ephedra.11 Ephedra use was associated with stroke, cardiac arrhythmias, tachycardia, acute myocardial infarction, tachycardia-induced cardiomyopathy, and sudden death.5 Another review of adverse events reported to the FDA found that hypertension was the most common adverse event, with sudden death reported more frequently than myocardial infarction or arrhythmia.13

Ephedra is also associated with psychiatric effects through its stimulation of adrenergic receptors and of dopamine release. The meta-analysis of controlled trials found that ephedra users had 3.64 times the risk of mild psychiatric symptoms compared to placebo.12 These included euphoria, neurotic behavior, agitation, depressed mood, giddiness, irritability, and anxiety. A review of all 1,820 ephedra-related adverse events reported to the FDA as of September 2001, identified 57 serious psychiatric events.14 Over half the reports were of psychosis, with severe depression, mania, hallucinations, and suicidal ideation also reported. Although adverse event reports cannot demonstrate cause and effect, their frequency, and a number of high-profile deaths of professional athletes connected to ephedra use, contributed to the ephedra ban. Since that time, however, other herbs, like bitter orange, have been added to "ephedra-free" products. While little is known of its toxicity or efficacy, some fear it will have similar adverse effects as ephedra because it contains related active stimulant ingredients.5


Arguably one of the most popular ergogenic aids, creatine differs from the other substances discussed here in that it is not banned by any major sporting organization. Numerous studies have shown that creatine is effective in enhancing power output during short, intense exercise, especially when repeated intermittently (interval training).15 Its effectiveness in enhancing other forms of exercise is not well established. Some data are showing that creatine supplementation may be beneficial for elderly people who exercise.16

The adverse effects with creatine are relatively few and generally mild. They include weight gain (probably through water retention), muscle cramping, and gastrointestinal disturbances. More serious concerns have been raised about muscle tears, electrolyte imbalance, dehydration, and kidney damage. While these have been identified in a small number of case studies, larger and longer studies in healthy adults have found creatine to be safe and well-tolerated.17


Interest in complementary and alternative medicine is connected to the recognition that health involves more than just the physical. In recognizing the contribution of emotional, relational, and spiritual factors to health, the potential for harm in those areas must be acknowledged. Thus, the broader implications of performance-enhancing drugs should be recognized. Use of these drugs flourishes when sports over-emphasize winning.

Rob Garibaldi, a talented college baseball player who never quite made it to the professional leagues, flew into a rage when his father confronted him about drugs. Rob yelled, "I'm on steroids, what do you think? Who do you think I am? I'm a baseball player, baseball players take steroids. How do you think Bonds hit all his home runs? How do you think all these guys do all this stuff? You think they do it from just working out normal?"18 A few months later, he committed suicide at age 24. Many factors contributed to his death. Perhaps foremost was his belief that the only way he could be a college or professional athlete was by using steroids.

Sports can contribute much to people's lives. Winning itself is good, but the pressure to win can become destructive. A "win at all cost" mentality can contribute to someone's life unraveling. That is part of why sports organizations ban certain drugs. Another reason is the adverse effects of these substances. The banned performance-enhancing agents discussed here have serious adverse effects. Little is known of their frequency, but the risks involved warrant discouraging the use of these drugs. No longer can this be limited to concerns that top athletes might get banned from competition. Given their increased prevalence in the general population, healthcare professionals should be alert to symptoms among those who exercise regularly.


Doctors who care for teenagers and college-age athletes should be watchful for signs of use of these supplements, and especially for their more common adverse effects. Given the results of the survey of AAS users, vigilance should be broadened to all young adults. Healthcare professional should be open in speaking with patients about these drugs, and test and treat accordingly. While creatine is the one drug that appears to be somewhat effective and relatively safe, users should be encouraged to allow doctors to monitor its impact, especially on their renal function.


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