Harm Reduction Intervention for Anabolic-androgenic Steroids Users: a Randomized Controlled Trial

1. Scientific Context and Rationale:

The abusive use of anabolic-androgenic steroids (AAS) for aesthetic and physical performance enhancing purposes (i.e., non-clinical) is a global problem that negatively affects the health of men and women of various age groups. In fact, the World Drug Report reinforced the concern about the non-clinical use of these drugs (World Drug Report, 2023). It is estimated that the global prevalence of AAS use is 6.4% and 1.6% among physically active men and women (Sagoe et al., 2014), respectively, and can reach 30% in bodybuilding gyms (Abrahin et al., 2014).

In short, AAS are synthetic substances similar to the hormone testosterone and are part of the list of performance and image enhancing drugs (PIED). The AAS promotes androgenic effects, such as spermatogenesis, deepening of the voice, increased libido, and changes in mood, along with anabolic effects, such as greater synthesis and lower protein degradation, and increased lipolytic activity. However, the abusive and prolonged use of AAS can negatively affect several health parameters. For example, AAS users are more prone to arrhythmias and sudden death, elevated mean arterial pressure over 24 hours, increases in the amount of calcium in the coronary arteries, and volume of atheromatous plaques (Baggish et al., 2017) . Additionally, the use of high concentrations of AAS (i.e., ≥ 200 mg per week) is associated with decreased endogenous testosterone production, spermatogenesis, and gonadal atrophy (Nieschlag \& Vorona, 2015). The seriousness of this global problem is aggravated when we consider that 32% of abusive users develop addiction (Pope, Kanayama, et al., 2014).

It is important to emphasize that the investigation of the effects of AAS abuse in health parameters is not methodologically trivial. The conduct of randomized and controlled studies is not possible because the obvious ethical impossibility of prescribing such substances to healthy humans, especially in the use schemes that are seen in the real world, which combine several drugs (a technique known as polypharmacy) in supraphysiological doses and in a chronic manner. In addition, as described, the use of AAS affects several systems in the human body, which requires a multidisciplinary evaluative approach. As a result, the current evidence on the damage caused to health by AAS is mostly of low scientific quality, and comes from cross-sectional studies, retrospectives, case studies, and opinion articles. Together, the conduction of better quality studies are needed in order to increase understanding about harm reduction strategies for abusive users. In this scenario, prospective cohort studies involving individuals planning to self-conduct the use of AAS emerge as an ethically viable and methodologically appropriate option for investigating the topic. (Bonnecaze et al., 2021; Rops et al., 2022)

Despite the advances achieved by prospective cohort studies with habitual users of AAS, several gaps remain regarding the development of harm reduction interventions in this population. Briefly, the harm reduction strategy aims to decrease and/or cease the use of AAS in the long term. However, it is worth noting that ceasing the use of these drugs is extremely complex, as most users are affected by post-use withdrawal syndrome, which is characterized by symptoms of depression, a sharp drop in libido, and anhedonia, which stimulates the continuous and recurrent use of AAS. Therefore, harm reduction also aims to guide the user to (i) reduce the frequency and dose of AAS, (ii) minimize health complications due to the misuse of additional substances and/or contaminated material, and (iii) provide specialized multidisciplinary support for long-term monitoring of health parameters. Thus, controlled clinical trials aimed at evaluating new strategies to minimize the harm caused by the abusive use of AAS are urgent (Anawalt , 2019; Bonnecaze et al., 2021; Pope, Wood, et al., 2014). 2. Study Justification and Objective:

Given the ethical constraints of conducting interventional studies that involve administering supraphysiological anabolic- androgenic steroids (AAS) doses to healthy individuals, there is a need for research that engages directly with current AAS users in their real-world context. Therefore, this study is designed to investigate the feasibility and impact of a harm reduction intervention specifically developed to habitual AAS users.

General objective: to investigate the efficacy of harm reduction intervention in reducing the short and long-term use of non-clinical AAS use in habitual and abusive users. Secondary objectives include evaluating the intervention's impact on health parameters (i.e., blood and cardiovascular variables), quality of life, sleep quality, body image, eating behavior, depression, anxiety, fatigue, aggressiveness, muscle strength and body composition outcomes. 3. Study Population:

This randomized controlled trial (RCT) will recruit anabolic-androgenic steroids (AAS) habitual users, who declare the intention to self-administrate AAS for aesthetic and physical performance enhancing purposes.

In total, 32 participants will be recruited and randomly assigned into either the harm reduction intervention (HR) (n = 16) or the control (CTRL) group (n = 16). The sample size was calculated based on a previous study (Veerdegaal et al., 2026) which investigated the effect of a harm reduction intervention on the total AAS amount utilized compared to the initial plan, reflecting the expected longitudinal interaction between the intervention and control groups on cumulative anabolic steroid exposure. This effect size was computed using the Morris'd method for pretest-posttest control group designs, which standardizes the between-group difference in change scores using the pooled baseline standard deviation to account for initial imbalance (Morris, 2008). The resulting standardized mean difference (Morris d = -1.167) was converted to Cohen's f (f = 0.584) for use in ANOVA-based sample size estimation. Under a repeated-measures framework with four assessments, a two-sided alpha of 0.05, and 90% power, the calculated minimum sample size was 8 participants. However, this estimate was conservatively increased by a factor of four to account for the high dropout rates reported in the Veerdegaal (2026) study (53.9% in the harm reduction group and 45% in the historical control group), as well as to improve the sensitivity and robustness of the statistical analyses. Given the very large effect size observed, this inflation strategy also aims to mitigate potential overestimation of effects, enhance the precision of estimates for secondary and exploratory outcomes. 4. Outcomes:

The primary outcome is the change in total anabolic- androgenic steroids (AAS) utilized (i.e., expressed in mg) compared to the initial plan (i.e., planned AAS amount for the self-conducted use) in long-term (one year after the cycle's end). As for secondary outcomes, the current study will evaluate the harm reduction intervention effects on health parameters (i.e., blood and cardiovascular variables), quality of life, sleep quality, body image, eating behavior, depression, anxiety, fatigue, aggressiveness, muscle strength and body composition in the short (i.e., 8 weeks from AAS's cycle onset) and long-term (i.e., one year after the AAS's cycle end).

• Short-term effects on cumulative use of anabolic-androgenic steroids and short- and long-term effects on general health parameters [Срок оценки: Eight weeks after AAS cycle's onset (short-term) and one year after the end of the AAS cycle (long-term)]
• Short-term and long-term effects on cumulative use of anabolic-androgenic on quality of life and sleep quality [Срок оценки: Eight weeks after AAS cycle's onset and one year after the end of the AAS cycle.]
• Short-term and long-term effects on cumulative use of anabolic-androgenic on body image [Срок оценки: Eight weeks after AAS cycle's onset and one year after the end of the AAS cycle.]
• Short-term and long-term effects on cumulative use of anabolic-androgenic on eating behavior [Срок оценки: Eight weeks after AAS cycle's onset and one year after the end of the AAS cycle.]
• Short-term and long-term effects on cumulative use of anabolic-androgenic on depression, anxiety, fatigue and aggressiveness [Срок оценки: Eight weeks after AAS cycle's onset and one year after the end of the AAS cycle.]
• Short-term and long-term effects on cumulative use of anabolic-androgenic on cardiovascular parameters [Срок оценки: Eight weeks after AAS cycle's onset and one year after the end of the AAS cycle.]
• Short-term and long-term effects on cumulative use of anabolic-androgenic on muscle strength [Срок оценки: Eight weeks after AAS cycle's onset and one year after the end of the AAS cycle.]
• Short-term and long-term effects on cumulative use of anabolic-androgenic on body composition and muscle cross-sectional area [Срок оценки: Eight weeks after AAS cycle's onset and one year after the end of the AAS cycle.]