Cardiovascular Implications of the Enhanced Games: Performance Enhancing Drugs in Competition and Recreation

The Enhanced Games (TEG) initiative-an event that permits the off-label use of FDA-approved drugs for performance enhancement under medical supervision-represents a revolutionary yet highly controversial disruption in modern sport. Although the excessive use of certain performance-enhancing drug (PED) classes is associated with clear health risks, current evidence on PED-related cardiovascular (CV) risk is primarily derived from retrospective reports, small cohorts, or illicit use, leaving major gaps in mechanistic understanding and dose-response relationships in performance enhancement, well-being, and rehabilitation purposes. MAIN: This review synthesizes existing data on the ergogenic mechanisms and CV toxicity of key PED classes relevant to TEG athletes, including anabolic-androgenic steroids (AAS), growth hormone and IGF-1, erythropoiesis-stimulating agents (ESAs), stimulants, β₂-agonists, diuretics, metabolic modulators, and emerging incretin-based weight management therapies. Across these agents, ergogenic effects are inconsistently demonstrated, whereas CV harm is not rare, and may be cumulative and irreversible. AAS and ESAs exhibit the strongest ergogenic signals but are also associated with myocardial remodeling, arrhythmia, and thrombotic events. Other agents provide limited or unclear performance benefits yet may disrupt autonomic balance, metabolism, or myocardial integrity. With the emergence of availability through compounding pharmacies and a rapid increase in PED use among the general population, there is an urgent need for high-quality, prospective data to inform about health risks. Since the recreational and well-being use of PEDs is on the rise among the general population, PEDs' dose-dependent detrimental effects must be carefully evaluated. By applying rigorous pre-participation screening and long-term follow-up, TEG may provide high-quality, longitudinal data not previously available with PEDs.

TEG's potential to provide valuable scientific insights should not be interpreted as a proof-of-concept for safe, extreme-level performance enhancement, but rather as a high-risk observational setting that demands exceptional ethical scrutiny, transparency, and long-term accountability. While ethical and regulatory debates dominate public discourse, TEG also presents a research opportunity to systematically evaluate the CV effects of PED use under controlled conditions. A dedicated, risk-adapted pre-participation screening and longitudinal monitoring framework will be essential for characterizing PED-associated CV effects and informing harm-reduction strategies.