Anabolic Androgenic Steroids: Emerging Use Disorder, Mechanisms of Action, and Clinical Considerations for Pharmacotherapy.

Debate on the psychoactive nature of AAS has existed for decades, with increasing evidence showing a likely AAS use disorder that is mediated directly and indirectly through classical reward pathways. AAS likely affect dopaminergic, opioid, and serotonergic pathways. Chronic anabolic steroid treatment in rats increases beta-endorphin and opioid receptor expression in limbic regions. Animal studies have further shown that the opioid agonist naloxone is able to reverse testosterone-induced locomotor impairment in hamsters, indicating that testosterone may partially activate opioid receptors and that AAS reinforcement may be dependent on opioid receptor activity ( 22 ). In humans, administration of oral methyltestosterone to healthy men results in increased 5-hydroxyindoleacetic acid (5-HIAA) levels in the cerebrospinal fluid. As a major metabolite of serotonin, 5-HIAA has been linked to behavioral changes observed in AAS use ( 23 ) and is indicative of the impact of AAS on serotonergic pathways. Serotonin and serotonergic pathways in the brain have been shown to modulate drug reward and reinforcement ( 24 ). AAS have additional robust pathways to addiction, with secondary positive and negative reinforcement mechanisms. These secondary effects are not how the drug directly stimulates either euphoria or withdrawal but how the use of the substance results in behavior-associated rewards and the fear of loss of those rewards ( 25 ). AAS have both anabolic and androgenic effects through the androgen receptors ( 26 ) that form the biological underpinnings of these secondary addiction pathways (see Figure 1 ). The anabolic mechanism of action of AAS involves increasing DNA transcription to induce the formation of steroid-receptor complexes that then stimulate protein synthesis ( 27 ), resulting in hypertrophy of preexisting muscle fibers ( 28 ), an increased number of muscle progenitor cells ( 29 ), and increasing oxygen delivered to tissues ( 30 ). The result is that AAS contribute to increased lean muscle mass and strength ( 31 ), but most gains are appreciable only when combined with extensive amounts of exercise ( 32 ). Ongoing AAS use is often required for maintenance of muscle mass. In some ways, this could be considered the development of tolerance, whereby doses of AAS that previously resulted in increased muscle gains instead result in muscle maintenance and a plateauing of gains. The anabolic nature of AAS contributes to a few distinct pathways of addiction. First, PWU-AAS at supratherapeutic doses are often driven by a desire for muscle mass, and they often see relatively quick muscularity gains upon initiation of use when combined with exercise. This positive reinforcement results in a reward cycle: increased gym attendance and physical activity result in the release of endogenous opioids (endorphins), which can increase mood and self-esteem ( 33 – 36 ). Increased mood, self-esteem, and additional performance enhancement from AAS make exercise more rewarding, resulting in even more physical activity and thus a continuing pattern of positive reinforcement. For individuals with underlying muscle dysmorphia, relief from self-criticism and negative feelings by seeing supranatural muscularity can itself be a form of positive reinforcement. External factors also provide positive reinforcement related to AAS use. PWU-AAS who use the drugs for performance enhancement reasons receive external validation (e.g., from coaches) through an increased ability to compete in and win competitions. Individuals who use AAS for aesthetic reasons similarly see benefit in their social contexts through being perceived as more attractive by others. This can result in socially mediated positive reinforcement from peers, but for others it can result in more quantifiable benefits, such as increased sexual activity or increased financial opportunities (especially for those working as models, sex workers, or in the adult film industry) ( 21 ). Cessation of AAS use frequently results in a withdrawal-type phenomenon called AAS-induced hypogonadism (ASIH), which primarily affects the androgenic aspects of AAS and is discussed at length later in this review. From an anabolic perspective, gains from AAS are difficult to maintain upon cessation, with PWU-AAS noticing that continued training and exercise are insufficient to preserve strength and appearance. Inability to continue regimens leads to a decrease in self-confidence and decreased affirmations from others, increased anxiety and fear about a loss of gains and confronting an unenhanced version of the self, and reduced endorphins from decreased exercise capacity. These forces often result in a return to use, with repeat future cycles. Similarly, an allostatic model of AAS use suggests that PWU-AAS often paradoxically seek health benefits from AAS yet develop health consequences and impairments from use ( 37 ). This can result in a negative reinforcement system whereby PWU-AAS may continue to use or use higher doses, other IPEDs, or both, to try and overcome these negative health impacts. Planning AAS use, obtaining AAS, and researching AAS comorbidity treatments and polypharmacological interventions require significant amounts of time and money ( 38 ). Both neurobiological and sociocultural frameworks indicate that cessation of AAS results in adverse symptoms that serve as negative reinforcement and can contribute to a return to use. The androgenic effects are mediated by the enzyme 5α-reductase, which is predominantly expressed in the testes, epididymis, seminal vesicles, prostate, liver, kidney, pancreas, skin, and brain ( 39 ). It metabolizes AAS into 5α-dihydrotestosterone (DHT), an even more potent binder of the androgen receptor. DHT does not appear to play a role in the anabolic effects of testosterone and does not result from the metabolism of commonly used non-testosterone AAS ( 40 ). However, from an androgen perspective, DHT affects facial and pubic hair growth, male pattern balding, acne, and voice deepening ( 41 ). Testosterone is heavily involved in male sexual function, including libido, ability to obtain and maintain erections, and ejaculation and orgasms ( 42 ). Notably, the androgenic mechanism of AAS affects women differently. Endogenous androgens in women are generated from the adrenal glands and ovaries and involved in sexual desire, cardiovascular health, cognitive function, bone health, and musculature ( 43 ). These levels are often minimal and have limited impact on estrogen and hormonal function; however, when there is an excess of testosterone caused by exogenous AAS use cisgender women start to develop usually unwanted masculinizing effects, including deepened voice, changes in menstruation, clitoral enlargement, and increased libido ( 44 , 45 ). Literature about women using AAS remains limited, and additional research is warranted. For men with late-onset hypogonadism (low T) and sexual dysfunction, exogenous testosterone often results in improved sexual desire and function ( 46 ). For men with baseline normal levels of testosterone, supraphysiological doses of testosterone likely increase arousability without changing the frequency of sexual intercourse, masturbation, or erections ( 47 ). Interestingly, surveys of PWU-AAS often describe men as reporting favorable impacts of AAS on their sexual function ( 21 , 48 – 51 ). Similarly, although men with low levels of testosterone and resulting impaired mood may see an improvement with AAS use, the relationship between mood and supraphysiologic doses of testosterone remains ill defined, with men experiencing both improvements and impairments in mood ( 52 ). Again, these data contrast with those related to self-perception noted on surveys of PWU-AAS who report high rates of improvement in energy level ( 53 ). In addition to some of the traditional reward pathways found in psychoactive substances, AAS use results in changes to endocrinological function through the suppression of the HPG axis ( 54 – 56 ). AAS are converted into estradiol, which, along with testosterone itself, signals the hypothalamic-pituitary axis to suppress secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus through a negative feedback system. Decreased GnRH results in decreased release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland, which results in decreased endogenous testosterone production from the testes. This suppression is most visible through testicular atrophy in men and changes in menstruation for women. Exogenous testosterone can be administered; however, this suppression of endogenous testosterone persists for some time even after cessation of AAS use and results in an induced hypogonadal state. ASIH persists for a minimum of 3–12 months and results in a period of profound hypogonadism, often with testosterone levels <50 ng/dL ( 54 ). Symptoms of ASIH include activation of the sympathetic system (including headaches, tremors, palpitations, and nausea), neuropsychiatric symptoms (depressed mood, body dysmorphia, cravings for AAS, insomnia), and hypogonadism (low libido, erectile dysfunction, fatigue, and myalgias) ( 57 ). More than 95% of individuals who routinely use AAS have at least one symptom of ASIH after cessation, most frequently low mood and fatigue, with almost 15% reporting suicidal thoughts ( 58 ). These symptoms often contribute to a negative reinforcement mechanism of AAS dependence ( 22 ). On physical exam of A’ you notice a bulky, muscular-appearing man with a blood pressure of 142/91, an S4 and laterally displaced point of maximum impulse, and hepatomegaly. His mental status exam, which reveals a dysphoric mood with suicidal ideations, is concerning.

Complications related to AAS use are common and become more frequent with both higher doses and longer duration of use. PWU-AAS face an increase in overall mortality, with an adjusted hazard ratio of 3.64 for unnatural deaths and 2.24 for natural deaths ( 59 ). AAS use increases cardiovascular risks, especially cardiomyopathies, heart failure, and acute myocardial infarction ( 60 ). Other common complications from AAS include hyperlipidemia, coronary artery disease, hypertension, transaminitis and hepatic steatosis, acne, alopecia, gynecomastia, testicular atrophy, sexual dysfunction, secondary hypogonadism, erythrocytosis, cellulitis and abscesses, HIV, hepatitis C, and tendon ruptures. A comprehensive review of medical risks is available elsewhere ( 61 ). An overview of medical risks is presented in Figure 2 . Many psychiatric implications from AAS use have been reported, with PWU-AAS shown to have more than twice the odds of exhibiting psychopathic traits and substance use risk-taking behaviors, as well as an increased odds of experiencing anger problems, difficulty with emotional stability, depressive symptoms, and impulsivity ( 62 ). Mania, hypomania, anxiety, paranoia, and violent behavior have all been reported as related to AAS use among PWU-AAS ( 62 – 64 ). Depression and suicide risk appears to increase, especially during withdrawal from AAS ( 65 , 66 ). DSM-5 does not recognize AAS use disorder as a diagnosis; however, a body of research depicts clinical scenarios consistent with an AAS use disorder. The prevalence of addiction-related phenomena in select studies ( 10 , 14 , 25 , 34 , 38 , 45 , 53 , 62 , 64 , 67 – 76 ) is summarized in Table 1 . Overall, a cohort of PWU-AAS appears to demonstrate use patterns consistent with other substance use disorders. Most studies have found that men binge on AAS use, often taking more AAS than intended or using for longer than planned. Tolerance to AAS is commonly reported, with individuals needing increasing amounts of AAS to obtain similar results, and withdrawal symptoms are present among most PWU-AAS who have developed tolerance. Interestingly, all of the studies listed in Table 1 demonstrated participants’ continued use of AAS despite medical and psychiatric harm. It becomes clear to you and A’ that he has demonstrated difficulty controlling his AAS use, is demonstrating symptoms of withdrawal from AAS cessation, and has continued using despite related consequences on his cardiovascular health. To help treat his current symptoms related to AAS withdrawal, you discuss the use of PCT and harm-reduction methods. Treatments for PWU-AAS with ASIH, an AAS use disorder, or both, remain ill defined. A 2019 scoping review found no studies that explored the effectiveness of any approaches to encourage cessation or treat dependence ( 77 ). Given the current exclusion of AAS use disorder from DSM-5 , research specific to the management of an AAS use disorder instead of related to AAS use itself remains limited. Given the role of muscle growth in AAS use and its strong overlap with muscle dysmorphia, cognitive-behavioral therapy (CBT) provides promise as a therapeutic intervention. A recent randomized controlled trial that included 59 men who use AAS and experience both muscle dysmorphia symptoms and associated psychological distress investigated a manualized CBT protocol among PWU-AAS and found significant improvements in depressive symptoms, psychological distress, disordered eating, and exercise addiction ( 78 ). The authors postulated that CBT may have treated both underlying cognitive distortions that lead to AAS use as well as impacts of AAS on mood dysregulation. Unfortunately, data on the AAS usage patterns were not provided, and the study did not assess participants for the presence or absence of addiction-type behavior. For individuals who do develop ASIH, symptoms can last months to years ( 79 ). There are no guidelines for the management of ASIH, but there is likely a role for the management of symptoms of comorbid conditions (e.g., depression, erectile dysfunction). Many PWU-AAS report the use of PCT, or the use of medications, such as clomiphene or human chorionic gonadotropin (HCG), to trigger the anterior pituitary to release LH and FSH. Although clomiphene and HCG have been shown to be successful at increasing testosterone levels in hypogonadal men ( 80 , 81 ), their efficacy for ASIH remains unclear. There currently is an ongoing pilot study protocol on the off-label use of clomiphene in this population ( 82 ). Another consideration is the use of prescription testosterone for individuals with a history of using nonprescribed and supratherapeutic doses of AAS. Prescribed testosterone has been considered for both individuals who are currently using AAS and for those with persistent hypogonadism after use. Prescribed testosterone for PWU-AAS without the intention of cessation is considered a possible harm-reduction method whereby providers can ensure a safe and uncontaminated supply of testosterone for patients, help guide them in dosing decisions, and monitor them for ongoing complications. Limited data exist to support this practice, with some PWU-AAS reporting that prescribed testosterone would not replace their use of nonprescribed AAS if doses are only physiologic. Among patients with ASIH, prescribed testosterone is likely helpful in obtaining physiologic testosterone levels, although when testosterone therapy should be started remains unclear. Some individuals with ASIH eventually do develop the ability to create endogenous testosterone months to years after cessation, and the use of prescribed testosterone during that interval makes this less likely. However, the period of profound hypogonadism is intolerable for many, and some find the alternative—resumption of low-dose nonprescribed AAS— more appealing. Additional well-designed and -powered randomized controlled trials in this area are necessary to determine whether a certain time interval or biological marker can help indicate who is likely to regain testosterone production and when production may be expected. Similarly, the use of patches and gels that deliver a constant dose, instead of intramuscular injections, may result in different treatment outcomes. Clinicians caring for PWU-AAS have few evidence-based tools to provide to their patients, yet they may be concerned about many of the harms that have been outlined in this review. PWU-AAS report they often feel alienated from medical settings and that they distance themselves from seeking professional help because of the heavy emphasis on abstinence-focused care. Thus, many PWU-AAS focus primarily on the prevention of AAS-related harms. The use of harm-reduction techniques to optimize patient health has been described, with a focus on multiple levels of prevention ( 6 ). In the primary prevention of AAS-related harms, PWU-AAS are encouraged to plan cycles in advance and turn to peers who have experience using AAS to learn (unproven) best practices. In secondary prevention, providers and patients together can screen for common complications of AAS use, such as erythrocytosis and hepatotoxicity. With tertiary prevention, patients and providers can treat AAS-related health impacts, such as hypertension and hyperlipidemia, with appropriate medical regimens. Given the sociocultural landscape in which AAS is used as a performance-enhancing drug, certain populations are at disproportionate risk of use and require specific clinical considerations. Among PWU-AAS who engage in extreme physical activity, the transition from AAS use to AAS dependence has been associated with age at onset of strength training, age at onset of AAS use, lifetime weeks of AAS use, maximum weekly dose of AAS used, and lifetime use of other performance-enhancing drugs ( 83 ). Supplements have been proposed as a gateway to AAS use for adolescent boys ( 84 – 86 ). Screening for extensive supplement use may help detect individuals at risk of AAS use to allow for a conversation about exercise goals and to serve as a segue to screening for body image disorders, such as muscle dysmorphia. In addition, screening for supplement use can help detect important drug-drug interactions and risks. The presence of muscle dysmorphia itself is likely a risk factor for AAS use. In DSM-5 , muscle dysmorphia is a subtype of body dysmorphia characterized by a negative preoccupation with body size and muscularity that results in compulsive behaviors to achieve a desired physique. Several screeners for muscle dysmorphia have been proposed, most frequently the Muscle Dysmorphic Disorder Inventory ( 87 ). Use of these instruments has been predominantly limited to research settings, but they may also be helpful in clinical settings. Risk factors for muscle dysmorphia and resulting AAS use include childhood weight-related problems (either being underweight or overweight) along with a desire to meet unrealistic body ideals. Additionally, normalization and encouragement of AAS use by partners and peers are frequently reported as motivators for use ( 21 ). Screening for underlying muscle dysmorphia may be necessary to address problematic AAS use. It is possible that combining CBT and PCT, or prescribed testosterone, may be beneficial for individuals with a likely AAS use disorder, but this remains unknown. Many gay, bisexual, and cisgender queer men report that their use of AAS is due to increased rates of community exposure and peer pressure, unrealistic ideals of masculinity, and the desire for additional sexual attention from other gay, bisexual, or queer men ( 21 , 88 , 89 ). Within this community, individuals working in the adult film industry or sex work find AAS use necessary to generate continued income. Given the overlaps of sexual health with AAS use, clinicians should screen patients for risk factors for HIV and other sexually transmitted infections and connect them to appropriate care for pre-exposure prophylaxis for HIV or treatment of HIV infection. More comprehensive discussions of the management of sexual health for men who have sex with men have been published elsewhere ( 90 ). Last, middle-age men frequently report andropause, or late-onset hypogonadism, a phenomenon of decreased energy, libido, and sexual function that patients often attribute to lower testosterone levels ( 91 , 92 ). Although some of these men have late-onset hypogonadism or diagnostically low testosterone levels because of chronic medical conditions, many continue to have testosterone levels that are within normal limits but lower than they had at younger ages. These men may use AAS to self-medicate for these age-related changes. Additional research into management of this population is warranted.

The aim of this narrative review is to summarize the mechanistic and clinical aspects of AAS use for health care professionals; it is not meant to serve as a systematic review. We conducted comprehensive searches through PubMed and Google Scholar to identify existing research and the current gaps in the literature on AAS use disorders. This review has limitations in light of the current state of published knowledge regarding AAS as a potential use disorder. As a thematic review, it is not meant to summarize all the available literature on AAS use or its addictive potential. Prevalence statistics are quite limited and dated and may over- or underrepresent the full impact of AAS use today. Most of the literature focuses on the use of AAS among cisgender men, which limits the current understanding of the impact of AAS use on women and on transgender individuals who are outside the realm of gender-affirming care. Additional research on these topics is warranted. Given the exclusion of AAS use disorder from DSM-5-TR , current research has been unable to differentiate between management of AAS use versus addiction to AAS. Overall, decades of research on AAS are allowing a picture of their addictive potential to emerge. High rates of AAS use are continuously reported internationally, along with descriptions of increasing ease in obtaining access through online distributors, the continuing rise of social media and its impact on body image and self-esteem, and continued difficulty managing ASIH. Consideration of AAS use as a classified substance use disorder is warranted to facilitate diagnosis and disorder characterization. In addition, research on possible treatments for PWU-AAS and people with an AAS use disorder is urgently needed to provide an evidence-based foundation for diagnosis and suitable interventions.