Polypharmacy among anabolic-androgenic steroid users: a descriptive metasynthesis

Background As far as we are aware, no previous systematic review and synthesis of the qualitative/descriptive literature on polypharmacy in anabolic-androgenic steroid(s) (AAS) users has been published. Method We systematically reviewed and synthesized qualitative/descriptive literature gathered from searches in electronic databases and by inspecting reference lists of relevant literature to investigate AAS users’ polypharmacy. We adhered to the recommendations of the UK Economic and Social Research Council’s qualitative research synthesis manual and the PRISMA guidelines. Results A total of 50 studies published between 1985 and 2014 were included in the analysis. Studies originated from 10 countries although most originated from United States (n = 22), followed by Sweden (n = 7), England only (n = 5), and the United Kingdom (n = 4). It was evident that prior to their debut, AAS users often used other licit and illicit substances. The main ancillary/supplementary substances used were alcohol, and cannabis/cannabinoids followed by cocaine, growth hormone, and human chorionic gonadotropin (hCG), amphetamine/meth, clenbuterol, ephedra/ephedrine, insulin, and thyroxine. Other popular substance classes were analgesics/opioids, dietary/nutritional supplements, and diuretics. Our classification of the various substances used by AAS users resulted in 13 main groups. These non-AAS substances were used mainly to enhance the effects of AAS, combat the side effects of AAS, and for recreational or relaxation purposes, as well as sexual enhancement. Conclusions Our findings corroborate previous suggestions of associations between AAS use and the use of other licit and illicit substances. Efforts must be intensified to combat the debilitating effects of AAS-associated polypharmacy.


Introduction
Anabolic-androgenic steroid(s) (AAS) refer to testosterone and its synthetic derivatives mainly used nonmedically for enhancing muscle growth and strength, boosting physical activity or sports performance, and for aesthetic purposes as well as for enhancing psychological well-being [1]. AAS are typically used in phases referred to as 'cycles': 'on cycles' referring to specific periods when the users administer AAS and 'off cycles' referring to an AAS-free phase intended to prevent tolerance towards AAS, lessen the possibility of side effects, and allow recovery of natural hormonal functioning. During 'on cycles' users sometimes combine different injectable and oral AAS. This phenomenon is referred to as 'steroid stacking' or simply 'stacking' [2].
There is also a trend referred to as 'blast and cruise' or 'bridging'a continuous 'on cycle' whereby many users never go off AAS but alternate between periods of high dose intake during a 'blast' phase, and low dose intake during a 'cruise' phase. Another way of administering AAS is called 'blitz-cycles', which implies rapidly changing AAS with the aim of preventing tolerance and androgen receptor down-regulation. Moreover, many users complement AAS use or stacking with the use of other substances. In this respect, AAS use has been found to be associated with the use of both licit and illicit substances in systematic reviews of predominantly quantitative literature [3,4].
It has been noted that one of the major drawbacks to successful AAS interventions is public health officials' failure to recognize AAS users' extensive pharmacological regimen [2]. A synthesis of the qualitative or descriptive literature on polypharmacy by AAS users is, both from a clinical and research perspective, important in order to increase the understanding of the polypharmacy often associated with AAS use. Such a literature review and synthesis is also valuable in terms of the development and strengthening of AAS use and harm reduction interventions as such investigation will deepen existing knowledge on the various substances used and the specific function they serve, which in some cases deviates significantly from their formal medical indications. Furthermore, results of such investigation would complement evidence emanating from a systematic review of mostly quantitative evidence [3] in the effort to elucidate the phenomenon of polysubstance use by AAS users. However, as far as we are aware, a systematic review and synthesis of the qualitative or descriptive literature on polypharmacy by AAS users has not been published.
Against this backdrop, we conducted the first systematic review and synthesis of the qualitative or descriptive studies presenting data on the use of other licit and illicit substances among AAS users. The research questions guiding the present study were: (a) what substances do AAS users report consuming prior to their AAS debut? (b) what ancillary or supplementary substances do AAS users report using? and (c) what reasons do AAS users assign for using these substances?

Search strategy and inclusion criteria
We searched in PsycINFO, PubMed, ISI Web of Science, and Google Scholar for literature. For searches in PubMed and ISI Web of Science, 'anabolic steroid', 'doping', and 'performance enhancing drug', were each combined with 'interview', 'focus group', and 'qualitative'. These combinations were not practical in PsycINFO and Google Scholar as they produced voluminous redundant hits. Thus, 'anabolic steroid + doping + performance enhancing drug + interview + focus group + qualitative' was used in searches in PsycINFO and Google Scholar. From a total of 10,106 hits, 7,720 articles were assessed after the removal of duplicates. We also inspected references of relevant studies and searched in online databases and websites.
This search yielded 15 new articles. Based on titles and abstracts, 106 full-text papers were retrieved for screening after initial evaluation of the 7,735 papers. After screening of the 106 full-text papers, 79 papers were deemed relevant for inclusion. Thus, of the 79 papers scrutinized, 50 studies satisfied the following inclusion criteria: (a) studies used qualitative approaches (interviews, focus groups, or case studies) in data collection, (b) studies delineated or described licit and illicit substances used nonmedically by AAS users, and (c) studies were published in English.
We again inspected the characteristics of extracted studies for similarities to curb duplicate extraction and synthesis. The literature search was completed in June 2014. The literature search strategy adhered to Shaw et al.'s [5] recommendations for qualitative literature search as well as the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [6]. Figure 1 presents the literature search process.

Data extraction and synthesis
The first author conducted the study scrutiny and selection. Analysis of the studies was conducted using Smith et al.'s [7] Interpretative Phenomenological Analysis (IPA). Each full-text paper was regarded as a transcript. The first author (DS) read through the full-text papers several times, gaining an overall sense of the themes in the studies through this process. These themes were then highlighted. Using a standardized data extraction form, the first author and another reviewer independently extracted the following data from the included studies: author name and publication year, country, study type, type of AAS users involved in the study, and recruitment site or mode. To assess the quality of the extraction, we calculated inter-reviewer reliability for the two reviewers in SPSS version 20 (IBM Corp.) [8]. DS then independently coded the full-text papers by substance used and reason(s) or motive(s) for use. Study characteristics are presented in Table 1. We have presented all the studies that fall under each substance.

Classification of substances
We sought to classify the various non-AAS substances used by AAS users into meaningful groups. First, SP provided a functional categorization of the substances. Acknowledging that some AAS users self-administer these substances for purposes contrary to their conventional use, DS built on SP's classification by allocating the substances into SP's groups based on motives for use as presented by users in the literature. For substances for which motive for use was not delineated in the literature, DS grouped them based on Evans-Brown et al.'s [2] classification of human enhancement substances and a classification by the Norwegian Institute of Public Health [59]. JM inspected the grouping and provided further advice. Next, DS allocated substances that at this stage could not be allocated into groups based on the three previous methods by referring to Medscape Drug Reference and Wikipedia [60]. We reached consensus on the classification through further review and discussion.

Results and discussion
Description of studies and inter-reviewer reliability A total of 50 studies were included in the metasynthesis. Participants' ages ranged from 14 [34] to 66 years [51].

Substances used prior to AAS initiation
Before their AAS use debut, some users had experimented with or were regular users of other substances. This was presented by ten studies [17,21,24,[26][27][28][29]34,47,53]. The most prominent of these substances were alcohol, amphetamine, cannabis, and cocaine. Others were analgesics/opioids, heroin, stimulants, and dietary/nutritional supplements such as creatine, and protein powder as well as other unspecified licit and illicit substances (see Table 2).
In Kanayama  Furthermore, it is important to note that our data also suggested that AAS use may precede the use of other substances for some individuals. In Hoff 's study [24]:     We relied on the qualitative results generated from the interview.
Respondent 8 reported using narcotics after he had started using AAS. In this case, alcohol and drug abuse cannot explain why he started doping [using AAS]. However, AAS use seems to have led him into drug use and criminality in order to finance his extensive AAS use and investment in elite powerlifting. This respondent became aggressive and violent when he combined AAS and alcohol. Due to these side effects he changed from alcohol to cocaine as his primary social drug when he was on AAS (p. 63).
Use of supplementary/ancillary substances AAS users often engaged in stacking and the use of various licit and illicit substances during their 'on cycles' as previously shown. For instance, in a study by McBride [39], "…Mr B had initially used nalbuphine in conjunction with anabolic steroids, clenbuterol, ephedrine, and tamoxifen, all to aid bodybuilding" (p. 69). Indeed, in a study [46] of 100 AAS users: "A number of other drugs were used in addition to AAS as part of their training routine by 49% of the sample" (p. 49). The most popular supplementary/ancillary substances declared by AAS users in multiple studies were: alcohol, amphetamine/meth, aspirin®, caffeine, cannabis/cannabinoids, clenbuterol, clomiphene citrate, cocaine, codeine, creatine, ephedra/ephedrine, erythropoietin, furosemide, gamma hydroxybutyrate (GHB), growth hormone, heroin, human chorionic gonadotropin (hCG), insulin, insulin-like growth factor 1 (IGF-1), melanotan, nalbuphine/nubain®, protein powder, tamoxifen, thyroxine, and tobacco. Other popular classes of substances presented were analgesics/opioids, anti-oestrogens, benzodiazepines, dietary/nutritional supplements, diuretics, hallucinogens, and stimulants (see Table 3).

Groups of non-AAS substances used by AAS users
Our classification of the various substances used by AAS users resulted in 13 main groups: analgesics/non-steroidal anti-inflammatory drugs/opioids, anti-oestrogens, cardiovascular drugs, central nervous system depressants, central nervous system stimulants, cosmetic drugs, dietary/
nutritional supplements, diuretics, fat burning/weight loss drugs, muscle/strength-enhancement hormones, non-hormone muscle/strength-enhancement drugs, recreational substances/drugs, and sexual enhancement drugs (see Table 4). These groups of substances are briefly discussed below.
Analgesics/non-steroidal anti-inflammatory drugs/opioids These drugs include aspirin®, codeine, and oxycodone. This group of drugs was used for relieving inflammation, pain, and fever emanating from exercise, sports participation or the recreational and occupational activities of AAS users.

Anti-oestrogens
Anti-oestrogens include aminogluthimide, clomiphene, and tamoxifen. These drugs were used for reducing the oestrogen-like side effects of AAS use such as preventing gynecomastia. They were also used for endurance, improved testosterone production, and burning body fat.

Cardiovascular drugs
These drugs such as captopril, carvedilol, and digoxin were used for improved functioning of the cardiovascular system such as lowering blood pressure and reducing the risk of myocardial infarction, as well as burning body fat.

Central nervous system depressants
Examples of depressants are buprenorphine, hydrocodone, and oxycodone. The purposes for which these drugs were used were improved sleep, relaxation, and elevation of mood.

Central nervous system stimulants
Stimulants including epinephrine, amphetamine/methamphetamine, and yohimbine were used for alertness, boosting training, burning body fat, increased aggression and strength (including sexual), and psychological wellbeing.

Cosmetic drugs
Cosmetic or aesthetic drugs such as esiclene, melanotan II, and thiomucase were used in order to deal with acne, and for: inflammatory effects on smaller muscles, skin tanning, and a leaner physique thus enhancing physical appearance.

Dietary/nutritional supplements
These supplements such as calcium, glutamine, and potassium were consumed to provide essential nutrients to supplement the diet and combat the risk of illness.

Diuretics
Diuretics such as furosemide, hydrochlorothiazide, and spironolactone were used for combating side effects of AAS use such as water retention, together with masking the use of AAS and other doping agents.

Fat burning/weight loss drugs
These drugs include 2,4-dinitrophenol (DNP), conjugated linoleic acid, and teroxin (T3) and were used for suppression of appetite, increased metabolism, and reduced absorption of body fat as a means to burning body fat and losing weight.

Muscle/strength-enhancement substances
Two types of muscle/strength-enhancement substances were presented in the literature: hormones and nonhormones. Examples of muscle/strength-enhancement hormones are growth hormones, growth hormone releasing peptide (GHRP), and insulin. Non-hormone muscle/strength-enhancement drugs include clenbuterol used by some in an attempt to enhance the size and structure of muscles, as well as boosting strength.

Recreational substances/drugs
Recreational substances/drugs such as cannabis/cannabinoids, cocaine, and lysergic acid diethylamide (LSD) were used to alter experiences, elevate mood, and create psychological wellbeing as well as for relaxation.

Sexual enhancement drugs
These drugs such as phosphodiesterase-5 inhibitors (PDE5i), melanotan II, and sildenafil were used for dealing with testicular atrophy, improved sexual desire or arousal as well as erectile functioning.
In sum, the above groups of substances were used to enhance the effects of AAS, combat the side effects of AAS, and for recreational or relaxation purposes, as well as sexual enhancement. It is important to note that there is overlap between some of the groups. For instance, some central nervous system depressants may be misused for promoting sleep as well as their analgesic properties. Again, some muscle/strength-enhancement hormones are used for direct muscle enhancing properties and others for counteracting shutdown of endogenous testosterone production. Additionally, some of the substances are used for multiple purposes. For instance, melanotan II is used for tanning the skin and also as self-treatment for erectile dysfunction resulting from long-term AAS use. Others may use melanotan II to self-treat specific conditions such as rosacea or fibromyalgia and others may use melanotan for the self-reported weight loss effects due to appetite suppression. It is also important to note that some of the alleged properties or uses are not scientifically well documented such as the use of insulin for burning body fat [54]. Furthermore, the quality, safety, and efficacy of substances obtained from the illicit market cannot be known, with adulteration usually commonplace [2,63].        [54]. There may be overlap between classes (e.g. CNS depressants may be used for promoting sleep and for analgesic properties). Some of the drugs do not have well documented efficacy for their alleged motives for use.

Implications for policy and practice
The present study has highlighted various licit and illicit substances used by AAS users. Evidence abounds that some of the substances identified in our study, especially dietary and nutritional supplements, may be contaminated with AAS and other pharmacological elements thus, potentially, playing a role in the decision to initiate AAS use [2,[64][65][66][67]. Preventive efforts should therefore highlight the potential role licit and illicit substance use, especially dietary and nutritional supplement use, may play in the initiation of AAS use as well as the role AAS use may potentially play in the use of other substances, together with the potential negative consequences individuals who engage in such behavior may encounter.
AAS-associated polypharmacy is dangerous for several reasons. First, it has been associated with violent and criminal behavior as well as various forms of pathology and mortality [68][69][70]. Second, chemical interactions from AAS-related polypharmacy may have adverse psychophysical effects on individuals engaged in such behavior. Thus, the main and combined effects of the use of these substances must attract the attention of clinicians, policymakers and public health officials. Indeed, physicians may inadvertently administer medication to AAS-using polydrug users thereby triggering unintended adverse chemical interactions that may be harmful to AAS-using patients. Accordingly, gathering correct and comprehensive substance use histories of AAS users is important in the effective pharmacological and psychological treatment of AAS users [67,71] as such information may guide clinicians in the diagnosis and prescription of 'safe' drugs during treatment.
Additionally, most AAS users obtain the substances identified in the present study from the illicit market [1,2]. Because many of these substances are controlled or illegal [2], they may be produced in unsterile 'underground laboratories' leading to inadvertent and sometimes deliberate incorrect dosing, substitution of ingredients and contamination with additional pharmaceuticals, toxic chemicals and pathogens. Furthermore, some users resort to unsterile injection equipment for the administration of these products, resulting in injecting site injuries as well as bacterial and fungal infection [72] and the potential transmission of blood borne viruses such as hepatitis B/C and HIV [25]. Stakeholders must take our findings into consideration in the development of preventive and therapeutic interventions for AAS users. There is also the need for the strengthening of harm reduction interventions to combat the harmful consequences of AAS-related polydrug use.

Implications for research
There is the need for further investigations to elucidate better the pathway to AAS-associated polysubstance use. Further studies are also necessary to examine the main and complementary enervating consequences of the use of different dosages of these varied substances, plus their addictive potential and trajectories. Moreover, there is a dearth of knowledge regarding the spread of these substances due to the fact that most of these substances are relatively new. So far most focus has been directed toward AAS in particular. Thus, the use of ancillary and associated substances has mainly escaped the attention of clinicians, public health officials, policymakers, and researchers [2]. There is therefore the need for studies examining the emergence of these substances in the pharmacopoeia of substance users as well as their diffusion into other substance-using populations.
There is the need for the collection and analysis or testing of these substances, to ascertain their content and potential contaminants. Additionally, apart from the Iranian study [10], all studies were conducted in Western countries. Nonmedical AAS use is a global public health problem [4] and researchers are encouraged to extend their investigations to non-Western nations. Finally, investigations of AAS-associated polypharmacy must be a continuous process requiring updates as evidence accumulates.

Strengths and limitations
As far as we are aware, the present study is the pioneering international systematic review and synthesis of qualitative studies on AAS use and polypharmacy. The inclusion of both peer-reviewed and grey literature, as well as literature published before 1995 and after 2009, also distinguishes this review from a previous review [3]. The present study also has some limitations that ought to be taken into consideration when interpreting our findings. First, due to the nature of the present study, it was not statistically possible to establish 'gateway' or causal associations between AAS use and use of the other substances. In addition, we were unable to establish the prevalence of the use of these substances by AAS users. Third, some of the studies included in the present study did not specifically investigate AAS users' intake of other licit and illicit substances. Although these studies present very useful data in respect of the present study, it is plausible that these studies do not present a comprehensive picture of the variety of substances ingested by AAS users. Similarly, the case reports included in the present study may have been published because they are 'extraordinary' and may therefore not be representative of the 'typical' AAS user. With the relative paucity of literature in this field [73], the inclusion of these studies is in our view still defendable. Finally, there is the possibility that our exclusion of non-English language literature may have biased our results. It should be noted however that this very common practice in terms of reviews and meta-analyses might not necessarily affect findings [62].