Introduction
Anabolic-androgenic steroids (AASs) refer to the male hormone, testosterone, and many of its natural and synthetic derivatives. All AASs have androgenic (masculinizing) and muscle-specific (anabolic) effects, but some are relatively more anabolic or androgenic than others. Oxandrolone, for example, has greater anabolic activity and less androgenic activity than testosterone. All AASs share a cholesterol-like and -derived chemical structure in common with other classes of steroid compounds, such as corticosteroids, mineralocorticoids, and estrogens. Synthetic selective androgen receptor modulators are nonsteroidal anabolic-androgenic drugs, but little is known about the addiction potential of these premarketed substances.
Although AAS use is widely focused on the illicit uses to increase muscle growth and strength, several established medical uses exist for these substances. The US Food and Drug Administration (FDA)–approved medical uses of AASs include male hypogonadism (androgen deficiency), hereditary angioedema (a dermatological disorder), treatment of weight loss associated with AIDS, burns, and other catabolic states, and relatively rare types of anemias including Fanconi and those related to bone marrow suppression (aplastic anemia). Other uses of AASs, including experimental ones, have included male contraception, postmenopausal hormonal therapy, and treatment of depression and sexual disorders.
AASs are rarely used in isolation. Typical appearance and performance enhancing drug (APED) use involves several synthetic androgens and some combination of legal stimulants, illegal stimulants/thermogenic drugs, illicit nonsteroidal anabolics, and legal supplement use. Within the international sports community, APEDs are commonly referred to as “doping agents” and subject to detection by the World Anti-Doping Agency. The use of APEDs by athletes to increase performance constitutes only a small subset of APED users, and the secrecy of this form of drug use prevents any substantial literature on specific patterns of use among athletes. Unlike recreational users, fear of detection leads athletes to use a range of evasion strategies including use of masking agents, altered drug use schedules, and designer drug use.
AASs have some superficial similarities to so-called classical addictive drugs, such as alcohol, cocaine, nicotine, and opioids. A major difference is that AASs are not taken to induce euphoria and have little interoceptive detectability. Rather, APEDs are often taken in the context of a fitness-focused lifestyle that prohibits use of classical drugs of abuse. Although not part of the motivating salience of APEDS, many of these substances have known psychoactive effects. For instance, the psychoactive influence of testosterone on mood has historically been a source of investigation in medicine that persists. Recent advances in the neurobiology of AASs have further increased overall attention to the neurobiology androgen effects on reward. There is now general consensus that AASs are reinforcing and have important psychiatric effects, including the potential for addiction-like pattern of use.
Epidemiology
AASs first entered the mainstream athletic spotlight with the 1956 World Games. The Russian team was discovered to be using AASs at the Vienna weightlifting championships, leading other teams to introduce this seemingly miraculous drug to their athletes. As elite sports athletes continued to misuse these substances, AASs became banned drugs by the International Olympic Committee in 1975. During the Montreal Olympic Games in 1976, eleven athletes were disqualified as a result of urine steroid screening tests that were instituted.
Since then, AAS use has become more commonplace within the population. A meta-analysis of 271 studies yielded a global lifetime prevalence rate of 3.3%, with males significantly more likely than females to have used (6.4% vs. 1.6%). The highest rates were found in “recreational sportspeople” (18.4%) and athletes (13.4%), followed by prisoners and arrestees (12.4%). In the United States., between 2.9 million and 4 million people have tried AAS. In 1990, Congress passed the Anabolic Steroid Control Act, in an effort to reduce use, and anabolic steroids became a Schedule III controlled substance. Anabolic steroid use had spread from professional athletes and body builders to high school athletes and non-athletes striving to improve strength and physical appearance. According to the National Youth Risk Behavior Survey, the percentage of all high school students who ever took steroids without a doctor’s prescription is 3.5. The prevalence of taking steroids without a prescription was higher among male (4.0%) than female (2.7%) students. According to the results from this survey, the prevalence of having ever taken steroids without a doctor’s prescription increased from 1991 to 2001 (2.7%–5.0%) and then decreased somewhat from 2001 to 2015 (5.0%–3.5%). In addition, the University of Michigan Monitoring the Future study, which conducts an annual survey on substance use among high school students, has collected data on steroid use in 8th, 10th, and 12th grade students since 1989. These data show a fairly stable rate of increase from 1991 to 1998 across these groups in overall annual prevalence rate and a gradual decline in use from 1999 to 2016. Lifetime prevalence of AAS use in 12th graders significantly decreased from 2.3% in 2015 to 1.6% in 2016. A consistent finding is that males outnumber females in prevalence of AAS use, a
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with onset commonly occurring in one’s early 20s, and risk persisting into middle age.Overall, men who train extensively by lifting weights for athletic or aesthetic purposes are at highest risk to use AASs. Most studies also support a correlation with alcohol and other drug abuse, with some exceptions (e.g., Striegel et al. ). Conduct disorder during childhood and adolescence and adolescent body image and muscularity concerns are predictive of AAS use in male weightlifters. Body dissatisfaction commonly co-occurs with AAS use, but this finding is not consistent. A severe form of body dissatisfaction among male AAS users has been called muscle dysmorphia (MD), although women may also have it. Individuals with muscle dysmorphia exhibit a persistent belief that they are too weak or small and whose daily behavior is severely impacted by a preoccupation with increasing muscle mass. This syndrome has been compared to eating disorders—thus historically referred to as reverse anorexia nervosa or bigorexia . Individuals with MD may share patterns of cognitive functioning that are similar to individuals with eating and body image disturbances. Specifically, set-shifting difficulties and weak central coherence are positively associated with the drive for muscularity, a symptom of MD. MD also has features of obsessive-compulsive disorder.
Pharmacology
Chemical Structure
Derived from cholesterol, AASs have a 4-ring structure with 19 carbon atoms. Modifications at C-17 and other carbon atoms are responsible for much of the variety among synthetic AASs. Alkylation at the C-17 atom in its alpha position results in most of the oral forms of AASs, because this structural modification confers resistance to first-pass liver metabolism. The C-17-alkyl-AASs may also be more likely to cause liver toxicity and cholesterol abnormalities. Esterification at the C-17 atom in its beta position results in the commonly injected testosterone esters (testosterone cypionate, testosterone enanthate, and testosterone propionate). Because testosterone is rapidly metabolized by the liver, the testosterone esters were designed as depot medications, and are released slowly from the muscles into which they are injected.
Pharmacokinetics
Most oral forms of AASs are relatively short-acting with half-lives of approximately 24 h, whereas injected AASs are relatively long-acting with half-lives of several days to weeks. Thus testosterone esters when injected for medically indicated replacement therapy are usually administered every 2–4 weeks, whereas oral forms are typically administered daily. Gel forms and transdermal forms of testosterone are applied topically to, and absorbed by, the skin for replacement therapy. Their pharmacokinetics also require daily administration. A buccal form of testosterone is available that is applied to the upper gingiva and requires dosing every 12 h. The topical forms of testosterone are not typically used illicitly, however, because they are difficult to administer in the supraphysiological doses preferred by illicit users.
Testosterone can be viewed as a “prohormone” for both dihydrotestosterone and estradiol. When testosterone is aromatized by the enzyme, aromatase, estradiol is formed and acts on estrogen receptors. When reduced by the enzyme 5α-reductase, dihydrotestosterone is formed and acts on androgen receptors. Testosterone also acts directly on androgen receptors, but dihydrotestosterone is about 10 times more potent. Different organs are genetically programmed to express one enzyme or the other preferentially depending on its function. Thus, 5α-reductase predominates in the testes where spermatogenesis occurs, and aromatase predominates in the female breast causing enlargement. In the human brain, aromatase regulates the androgen-to-estrogen ratio in a tissue-specific manner. Similarly, preferential gene expression may drive the synthesis of either estrogen or androgen receptors depending on the tissue site and function of the organ, in particular, the brain.
Urine Testing
Testing for AASs in the urine, although critical for athletic competitions at the elite level, is rarely performed in routine clinical practice, including addiction treatment settings. One reason is that AAS users are not frequently seen in addiction treatment settings. Another reason is that testing is expensive and requires specialized laboratories that can perform mass spectrometry/gas chromatography across a large number of different AASs ( Table 29.1 ). The detection of AASs in urine has recently been reviewed.
| Injected testosterone esters Testosterone cypionate Testosterone propionate (Testoviron) Testosterone enanthate (Delatestryl) Testosterone ester mixture (Sustanon) Injected veterinary forms Boldenone undecylenate (Equipoise) Stanozolol (Winstrol-V) Trenbolone acetate (Finajet, Finaplex) Other injected forms Nandrolone decanoate (Deca-Durabolin) Nandrolone phenpropionate (Durabolin) Oral forms Methandrostenolone (Dianabol), also known as methandienone Methyltestosterone (Android, Testred) Oxandrolone (Anavar) Oxymetholone (Anadrol) Stanozolol (Winstrol) |
Patterns of Illicit Use
Users often take AAS with the very specific goals of improving physical appearance and athletic abilities. Thus they tend to take these substances in strategic doses and combinations for varying durations. Multiple substances are often combined (“stacked”) to maximize effects and to achieve supraphysiological dosages. These substances are self-administered during the drug cycles that typically last between 4 and 12 weeks. AAS use is sometimes started at low doses and increased to a peak, and then gradually reduced, a pattern referred to as “pyramid” dosing. The polypharmacy of the APED cycle can be complex and relies on recipes passed via expert user circles of an individual trial and error knowledge based in self experimentation. Often ignored, APED users use specific exercise and dietary practices in conjunction with the cycle and postcycle recovery period. Many surveys suggest that AAS users are more likely than nonusers to misuse other addictive drugs. In this regard, it is of interest that AASs can increase sensitivity to alcohol, amphetamine, and opioids. This sensitivity is likely part of a larger adaptation of the central nervous system to rewards of all types.
AASs are readily available through social networks associated with weightlifting gyms. Although classified as Schedule III controlled substances in the Unites States, AASs are available on the Internet, although the real contents may be suspect.
Adverse Medical Effects
Adverse medical effects of AASs have been well reviewed. Adverse medical effects may be transient, relatively reversible, and limited to periods of use and acute withdrawal; or long-term, relatively irreversible, and persistent during periods of sustained abstinence. The short-term effects generate less disagreement among experts than do the long-term effects, because good epidemiological studies of the latter are lacking. The major organ systems that are adversely affected by AASs are endocrine, hepatic, and cardiovascular.
Effects on the Endocrine System
Endocrine side effects result from having too high or too low concentrations of gonadotropins and sex steroids. Given that AAS use involves introducing exogenous androgens to the system, it results in a series of endocrinological events. Increased levels of free androgens through AAS use stimulate the secretion of aromatases, which break down the androgen molecules to be cleared from the system. This process, aromatization, causes circulating androgens to be converted to estradiol and other estrogens, leading to higher levels of estrogens in the system and resulting in unwanted physical feminization effects. For instance, gynecomastia or the development of breast tissue, female-pattern fat deposition, and water retention are common effects of aromatization that occur through AAS use. Gynecomastia, particularly when painful, may require surgical correction. In men, these effects also include testicular atrophy, abnormal and reduced spermatogenesis, premature male pattern baldness, and loss of libido, although these physical effects are most often transient and reverse shortly upon ending AAS use. In addition, most users are aware of the common adverse effects and will often take ancillary drugs to combat these physical changes. In women, the endocrine side effects of AAS use include clitoral hypertrophy, decreased breast size, hirsutism including abnormal facial hair (such as mustache and beard growth), menstrual irregularities, reduction of breast size, infertility, and deepened voice. In females, some of these physical changes may be permanent and irreversible. If taken during pregnancy, AASs can masculinize a female fetus.
Effects on the Hepatic System
Adverse effects on the liver—such as impaired excretion function, cholestasis, peliosis hepatis, and liver cancer—from AAS have been observed through animal studies, raising health concerns for individuals administering AAS in supraphysiological doses. In addition, there have been a number of case studies that have reported the presence of liver disorders in young athletes using AAS. However, it should be noted that these adverse effects have been observed only with the use of orally active 17-alpha alkylated AAS, such as methyltestosterone, oxymetholone, fluoxymesterone, norethandrolone, and methandienone. This type of AAS is less aromatizable and sought out by users who are attempting to avoid the androgenic effects that lead to excessive estrogen. Systematic research has shown mild and reversible elevation of transaminase levels from the use of oral 17-alpha alkylated AAS, although this relationship has never been associated with the use of injectable steroids.
Effects on the Circulatory System
Cardiovascular effects include hypertension, abnormal cholesterol levels, and cardiomyopathy as well as numerous case reports of myocardial infarction or stroke. Some effects may be confounded by strenuous exercise that accompanies AAS use. The lack of controlled trials of the cardiac effects of AAS since it is an illicit substance, combined with polypharmacy, also creates a problem when investigating whether AAS have a direct effect on the circulatory system. Nevertheless, a review of autopsy data from 1990 to 2012 revealed 19 fatalities in AAS users due to cardiac causes.
Although the American College of Sports Medicine concluded that there was a clear relationship between AAS use and hypertension in a position paper, this claim was based on the findings of a single study that has not been replicated. Other studies have not found AAS use to have any effect on hypertension. Possible effects that anabolic steroids may have on hypertension include their potential to increase blood pressure through observed effects on water retention in users, especially with use of oral anabolics. In addition, it is possible that some anabolic steroids with erythropoietic effects, such as boldenone undecylante, raise blood pressure when they increase blood volume to support the higher levels of red blood cells that accrue. This idea could explain symptoms that have been reported in AAS users, such as nosebleeds, which may be caused by the increased blood volume from oral anabolics and boldenone; however, this relationship has not yet been empirically proven, since these substances cannot be legally administered in the United States.
Several studies have established a relationship between some forms of AAS use and decreased serum high-density lipoprotein (HDL) and an increase in low-density levels, which is an identified risk factor for heart disease. Although these effects on serum cholesterol levels have been the most commonly cited negative effect of AAS use, studies have shown that serum cholesterol levels return to normal after stopping AAS use. It is believed that the effects on HDL levels are not from testosterone, but rather the estrogen that it is converted to after aromatization. Thus, using low-aromatization AAS or using antiestrogenics in order to avoid the unwanted androgenic effects of AAS, puts users at a greater risk for lowered HDL.
Other adverse effects include acne, peripheral edema due to water retention, polycythemia, exacerbation of tic disorders, sleep disorders, and infections due to nonsterile injection practices. Taken by children, AASs can cause premature closure of epiphyseal growth plates in long bones, resulting in small stature.
Psychiatric Aspects and Effects
There is general consensus that AASs are psychoactive drugs that can contribute to and cause psychiatric effects in vulnerable individuals. Many factors can influence the development of adverse psychiatric effects to drugs. Such factors include genetic vulnerability, social context, stress, personality characteristics, a past history of psychiatric problems, use of other substances, and expectancies. Case reports, retrospective studies, and psychiatric diagnostic studies of AASs users provide some clues regarding the range of adverse psychiatric effects observed, however, it can be difficult to prove that AASs, rather than coexisting factors (e.g., other drug use, predisposition, or environment) were responsible. Therefore, double-blind placebo-controlled trials that measure psychiatric effects of AASs are more conclusive (see below).
The most frequently described adverse psychiatric effects of AASs are extreme mood reactivity, marked aggression including homicidal thoughts and behavior (roid rage), grandiose and paranoid delusions, and addiction-like behavior. Mania or hypomania, violent aggression, and delusions typically begin during a course of AAS use, whereas depressive episodes and suicide attempts are most likely to occur within 3 months of stopping AAS use, that is, during AAS withdrawal. Fortunately, most psychiatric effects such as mood swings are reversible with medically monitored cessation of AAS use, but suicides and homicides are obviously irreversible. These data are not based on placebo-controlled studies and most recreational users report limited psychiatric complications during their use.
The true rate of adverse psychiatric effects among AAS users is unknown. Studies of illicit AAS users typically include small numbers of participants who may not be representative of all AAS users; and the studies rely on self-report of past events, which may not always be accurate. One controlled study of 160 athletes reported that 23% of 88 AAS users were diagnosed with major mood disorders (i.e., mania, hypomania, or depression) in association with their AAS use, including 11% diagnosed with major depression. That study also suggested that psychiatric effects are dose related: none of the AAS users taking low doses had major depression, whereas medium-dose and high-dose users had rates of 6 and 28%, respectively. Another study found that rates of depression were higher during AAS withdrawal than when actively taking AASs (6.5% versus 1.3%). That study also found that 3.9% of 77 illicit AAS users had attempted suicide during the withdrawal period. An autoptic study found that, compared to deceased amphetamine or heroin users, AAS users are more likely to die at a younger median age and violently, such as through suicide or homicide. Rates of completed suicides, however, are especially hard to estimate. In a series of 34 forensically evaluated deaths among male AAS users, 11 users committed suicide, 9 were victims of homicide, 12 deaths were judged as accidental, and 2 were indeterminate. Another study examined 24 cases of unnatural or unexpected deaths in AAS users and found that the majority (62.5%) were due to drug toxicity, 16.7% suicide, and 12.5% homicide. This finding demonstrates the lack of clear causality in deaths of AAS users, since there is often comorbid polysubstance-related behaviors. Several studies have investigated the link between testosterone levels and suicide with conflicting findings. Some have found significantly low testosterone levels after suicide attempts, which supports the link between AAS withdrawal and depression symptoms. Another study observed no association between testosterone levels and history of suicide attempt in male veterans with posttraumatic stress disorder. Similarly, a comparison of testosterone levels in male suicide attempters and healthy controls found no difference between the two groups. However, results from a study examining testosterone levels in suicide attempters with bipolar disorder found a positive correlation between testosterone and the number of manic episodes and suicide attempts. Thus the precise pathophysiological relationship between testosterone and suicidal behavior remains unclear.
Adverse psychiatric effects appear to be dose related. There are at least four double-blind, randomized placebo-controlled trials that employed relatively high doses of AASs. Three of these studies indicate that some individuals will experience severe, adverse psychiatric effects after high doses of AASs are administered. although one study found no evidence of psychiatric effects. Averaging across studies, recent reviews have concluded that the incidence of prominent irritability or hypomania attributable to steroids during controlled trials is 5%. These gold standard studies, however, are likely to underestimate the incidence and severity of psychiatric effects, because ethical considerations limit the maximum doses of AASs that can be administered to human subjects. Illicit AAS users typically consume 10–100 times the therapeutic doses prescribed legitimately by physicians to restore testosterone levels in patients who cannot make their own. By contrast, the maximum doses administered in the cited controlled trials were 5–6 times the therapeutic dose.
Neurobiology
The following structures have been implicated in the psychoactive properties of AASs: the midbrain, nucleus accumbens, amygdala, hippocampus, and prefrontal cortex. Androgen receptors are prominent in the hippocampus, amygdala, and prefrontal cortex, structures involved in learning and/or aggression. Synaptic density in the hippocampus is androgen-dependent. The size of the medial amygdala is also AAS dependent. More recent studies have examined structural brain imaging in human AAS users.
Neurotransmitter systems altered by AASs include γ-aminobutyric acid, , , glutamate, which correlated with aggressive behavior, dopamine, opioids, norepinephrine, and serotonin.
The mechanism of action of AASs can vary depending on the availability (in different brain regions) of specific enzymes such as 5α-reductase or aromatase, and receptors such as androgen or estrogen. This is because many of the metabolites of testosterone are active. Thus the actions of AASs on the brain can be exceedingly complex. The inherent polypharmacy of AASs also complicates the basic understanding of its neurobiology. Stimulants are commonly used among AAS users and ultimately have less controversial and robust effects on mood and aggression, with known central nervous system effects.
A modern theory of AAS misuse positions these substances as catalysts for allostatic response (i.e., homeostasis maintaining) to the musculoskeletal and stress systems. This adaptation involves increased endorphin/opioid response to exercise stress that produces an exercise high that is highly reinforcing. Over time, this model suggests that the natural allostatic responses in the hypothalamic-pituitary-gonadal axis and adrenal axis eventually reach a state of allostatic overload, where the AAS user would require constant AASs to achieve normal functioning within these respective systems.
Addiction
The term “addiction” is used here synonymously with moderate to severe substance use disorders, as defined by the Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition (DSM-5) criteria. The generally accepted abuse potential of AASs led to their classification in 1991 by the Drug Enforcement Administration as Schedule III Controlled Substances. Addiction to AAS was originally proposed in a peer-reviewed journal in 1989. Repetitive, rigorous weight training activity might be reinforcing in itself, similar to exercise dependence, or psychosocially (if not monetarily) rewarding in terms of winning competitions, or having athletic prowess or a fit-appearing body. It remains true that AASs are not generally used nonmedically in the absence of regular and intense exercise, suggesting that exercise may be essential to any addictive syndrome that includes AASs. Nevertheless, it is now generally accepted that AASs have a potential for addiction.
Rodents will self-administer AASs and show clear evidence of mild reinforcing effects, although self-administration is paradigm dependent. The reinforcing effects appear larger for AASs have moderate aromatizing (i.e., metabolize into estrogens) effects suggesting an estrogenic mechanism is involved in AASs reinforcing properties. The evidence of addiction to AASs from animal studies was a subject of comprehensive review, and the evidence suggests that AASs somehow alter the opiate system.
Frequencies of withdrawal symptoms are shown in Table 29.2 . Pope et al. recently reviewed 10 studies of rates of AAS users who fit DSM-III-R or DSM-IV diagnostic criteria for substance dependence for AAS use. Three of the published studies assessed for lifetime prevalence of AAS dependence, whereas six assessed only for current AAS dependence. Both types of studies produced similar estimates of AAS dependence within users, however, with a mean (95% confidence interval) across studies of 32.5% (25.4%, 39.7%), with a median of 29.5%.
| Symptom | Brower et al. | Midgley et al. | Copeland et al. | ∗ Hildebrandt et al. |
|---|---|---|---|---|
| N = 49 | N = 50 | N = 100 | N = 400 | |
| Anorexia | 24% | – | 33% | – |
| Acne | 57.8% | |||
| Anxiety | – | – | 12% | 21% |
| Body image dissatisfaction | 42% | – | 38% | – |
| Decreased libido | 20% | 10% | 1% | 26.8% |
| Decreased size or weight | – | 52% | – | – |
| Decreased strength | – | 38% | – | – |
| Depressed mood | 41% | – | 31% | – |
| Depressed (due to size loss) | – | 30% | – | – |
| Depression (unexplained) | – | 6% | – | 20.8% |
| Desire to take more steroids | 52% | – | 28% | – |
| Fatigue | 43% | 4% | 24% | – |
| General loss of interest | – | – | 23% | – |
| Headaches | 20% | – | 6% | – |
| Increased aggression | – | 10% | – | 33% |
| Insomnia | 20% | – | – | 47.3% |
| Nausea | – | – | 2% | – |
| Nosebleeds | – | – | 1% | – |
| Restlessness | 29% | – | 10% | – |
| Suicidal thoughts | 4% | – | 2% | – |
| Sweating | – | – | 1% | – |
All reported instances of AAS dependence have occurred in nonmedical or illicit users who took AASs for weightlifting and bodybuilding. It is important to note that no cases of AAS dependence have been reported in patients legitimately taking medically prescribed AASs for clinical indications, which is primarily an issue of dose. Medical indications only require doses to restore normal physiologic function, whereas use for athletic performance or aesthetic appearance require supraphysiological doses of AASs. In contrast to prescription opioid dependence, therefore, the development of addiction to AASs does not appear to start with therapeutic doses that escalate over time as addiction emerges. Rather, dependence on AASs seems to require deliberate self-administration of supratherapeutic doses from the beginning and the co-occurrence of intense exercise. The lack of AAS dependence in individuals taking them for legitimate medical purposes has led to the erroneous conclusion that dependence does not develop without compulsive weightlifting activity, but this conclusion is confounded by the correlation between exercise and supratherapeutic doses.
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