Current perspectives on anabolic-androgenic steroid abuse

TiPS - February 1993 [Vol. 141

61

Scott E. Lukas For the past 40 years alzabolic-androgeuic steroids have been used by a wide variety of afkfe~es with the hope of i~?zprovj~gfkeir frainjug, enduraizce and ~erf~r~an~~. ~roponenfs of their use claim that the drugs increase ~ruscfe sf?e~gfk and mass, endurance, decrease recu~e~~ time bef~ee~ lookouts and improve pkys~~ue. Critics claim fkaf these beneficial effects are due pri~arjly to expecfancy and other factors associated with ~rainjng; rnarty doctors also claim tkat their use is actually quite dangerous. ~~egardless of their efficacy, the use and abuse of anabo~ic-audroge~ljc steroids has esca~afed suck fkat in 2990 the US Congress enacfed the Anabolic Steruids Confro~ Act re~l~iringtkaf anabolic steroids be added to Sckedule 111of fke Controlled Substances Act. This action placed co~pot~?~dssuck as fesfos~erone cj~~onafe and na~zdrofo~e ~ecanoa~e in the company of various opioid drugs, a~pketa?ujnes and burbi~t~rates. As chair of tks A~erjcan Society for Pkffr~ac~log~ and ~xpe~i~enta~ Tkerapeutics‘ Co~~iftee on Substance Abuse, Scott Lukas advocates cont~~~e~research on the effectiveness, foxicity and natural history of anaboi~c-a~~rogenic steroid abuse.

Anabol~~androgenic steroids are a group of natural and synthetic compounds that are chemically similar to cholesterol. The most familiar of these, testosterone, is the natural male gonadotrophic hormone synthesized principally in the Leydig cells of the testes (9~~) and adrenal cortex’. A small amount of testosterone is also produced in the ovaries of women. There are a number of analogues and derivatives of testosterone, many of which have been developed for veterinary use, that possess a wide range of effects that are believed to impart greater anabolic or androgenic efficacy or both. In the bloodstream, testosterone is metabolized to one of two classes of hormones: the Sew-reduced androgens such as androstanolone, which are primarily androgenic, and estrogens such as estradiol, which enhance some androgenic effects but antagonize or block other effects. Because of this inte~elationship among structurally similar hormones that possess very different physio~~~c~ properties, the effects of secreted (and exogenously ad-

~~inistercd) testosterone are related to the p~po~ion of the endogenous testosterone to its metabolites. Castration was, and continues to be, used by farmers to domesticate male livestock and improve meat production. riisto~~ally, castration was also practised by the Church to retain the soprano voices of choir boys and by ancient civilizations to create asexual servants (eunuchs) to guard the harems of kings*. The cause of the resultant loss of both fertility and secondary male characteristics was not realized until 13erthold3conducted a series of experiments with castrated roosters. When the testis was implanted in the abdomen of the bird, the loss of the comb was prevented. Berthold and others deduced that a substance produced by the testes was transported via the b~~s~earn to the target tissues. Moore4 isolated extracts from the testis that, when injected into a castrated male, prevented the effects of castration. This substance was later identified as testosterone (see Ref. 5 for a more detailed review of the history of the anaboli~and~genic steroids). The masculinizing (androgetlic) effects of testoste~ne are coupled with an anabolic effect (tissue building). Since all andro@;enicho~ones also exert anabolic effects to some depz, the tetm steroid is ~n~~ii~nd~~enic preferred,

Clinically, androgens are used to treat adult men with androgen deficiency, anaemia in patients with chronic renal failure, aptactic anaemia and patients suffering from a number of diseases that reduce protein synthesis or enhance the breakdown of proteins (e.g. malignancies, burns, major trauma and acquired immune deficiency syndrome). However, it is the nonmedical use of these steroids by athletes that has evoked considerable concern, and is the focus of this article. ~echal~ism of action of anabolicandrogenic steroids Although very Iarge oral doses of testosterone can have physiological effects, much of what is absorbed travels to the portal blood supply and is immediateIy metabolized in the liver, preventing significant amounts from reaching the systemic circulation. Oral preparations with significant activity have structural modifications that retard hepatic metabolism, Parenterally administered testosterone is also rapidly metabolized. However, the metabolic product of testosterone, androstanolone is active and acts as the intracellular mediator of its effects. The testoste~ne molecule can also be modified to impart resistance to metabolic deactivation. Most commonly, alkylation in the 17orposition resuks in orally effective preparations while esterification at the 17@position produces compounds that can be injected (see Fig. 1). Testosterone is not the most active form of the hormone in the body. It is converted by a 5orreductase in many tissues (testes, liver, brain, prostate gland and external genitalia) to the more active compound androstanolone. This more potent metabolite is most likely responsible for many of the physiological effects typically attributed to testosterone. The liver transforms testosterone to a nUm* ber of other active compounds including estradiol, androsterone, ~~-hydroxy-S~-and~stan-~7-one, and~stenedione and to glucuronide for excretion. The mechanism of action of steroid hormones in general, and testosterone in particular, is fairly well unde~tood, Once in the bloodstream (either after being secreted from the testes or after

TPS - February 2993 IVol. 141

62

~~

o&

[&

methyltestosterone

stanozolol ”

.&

l&cScn

.

Compeund

R

TestosterOne

-On

Testosterone pmpionale

.O-COCHaCH,

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metandienone

Nandrolone deeencale

-OCO(CH,)sCH, ,I%2melhyl qa”P Bf pclwon 18)

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oxandroione Rg, 1. Sfructures

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of sume common parenteral (/eff) and oral {right) anabolic-androgenic steroids.

exogenous administration), testosterone (and other anabolicsteroids) passes androgenic through the cell wall of its target tissue and attaches to steroid receptors located in the cytoplasm. The binding to these receptors is highly specific, but of relatively low affinity. This hormonereceptor complex is translocated to the nucleus of the cell and attaches to sites on the nuclear chromatin. Transcription ensues, resulting in the production of specific messenger RNA. Ribosomal translation of the code results in highly specific new proteins that mediate the function of the hormones. This process is depicted in Fig. 2. Effects on performance The effects of physioIogica1 amounts of anabolic-androgenic steroids are well known. The anabolic-androgenic steroids are secreted by the gonads and exert a myriad of effects on a number of different target tissues. The sensitivity of a tissue to these compounds varies depending upon the organism’s stage in life when exposed to the hormone (i.e. before, during or after puberty). Androgens control the development of the urogenital tract during the embryonic life of males, but during puberty they are responsible for the development of secondary sex characteristics. The con-

sequent growth-promoting

effects on bone and muscle result in a rapid increase in body height, weight and physical vigour. Exogenous administration of low-to-moderate doses of androgens has modest effects on the average adult. This fact probably explains why the literature contains discrepant reports of the effectiveness of anabolic-androgenie steroids6*7. The effects of anabolic-androgenic steroids on the strength and muscle mass of inexperienced weightlifters are negligible when compared with the effects due to a newly adopted weight-training programme. However, significant gains in lean body mass and strength and decreases in body fat can be obtained when anaboIic-androg~nic steroids are taken by weightlifters who have reached a plateau in size and strength’,“. Even greater gains in muscle and strength occur in those who have the most intense training programme and who use higher doses of steroids. In addition to increasing muscle size and strength, anabolicandrogenic steroids also possess anticatabolic effects, a property many scientists believe to be the most important for increasing muscle massf’*‘. Anticataboiism appears to occur by reversing the catabolic effects of glucocorticoids that have been secreted in re-

sponse to stress or as a result of improved use of ingested protein and increasing nitrogen retention. Increases in aerobic capacity after anabolic-androgenic steroid use are theoretically plausible because of their ability to stimulate erythropoiesis’. However, reports to date are not compelling, and since many studies used an indirect measure af oxygen uptake, direct correlations with enhanced endurance performance cannot be made. The effects of anabolic-androgenie steroids on women are not we11 understood. As noted by Strauss et al.*O, female bodybuilders do take these drugs. These women experience typical masculinizing effects including an increase in facial and body hair growth, a lowered voice, enlarged clitoris and coarser skin. These effects appear to be permanent but others, such as menstrual cycle cessation or irregularity, increased libido, aggressiveness and acne, all disappear when anabolic-androgenie steroid intake is stopped”, Unfortunately, the data describing the effects of ana~lic-Andygenie steroids on performance are not conclusive and may well remain as such until better methods for measuring athletic pe~o~ance without confounding factors (e.g. level of conditioning, skill, diet, psyche, opponent, arena, sleep,

TiPS - February 2993 [Vol. 14f

recreational drugs and genes) are developedi3. An issue related to the performance-enhancing properties of these drugs is their effects on altering aggressive behaviour. Extreme cases of aggressive behaviour have also appeared in the popular press” and have contributed to the term ‘mid rage’ (see below). There is extensive literature on testosterone levels and aggressive behaviour1’,i2, much of which is directly related to the abuse of exogenous anabolic-androgenic steroids. As noted in the review by Haupt and Revere’, 13 studies have included assessments of subjective effects. Of the 155 subjects in these studies, 16 expressed increased aggression as an effect of anabolic-androgenic steroid use, However, the doses used in these studies were quite modest and are far lower than those currently reported by most athletes. Research with laboratory animals indicates that elevated aggression is a very reliable behaviouraf outcome following anabolic-androgenie steroid administration”. Findings with animals therefore support the many observations of increased aggression in humans. Thus for some sports, such as football, these steroids may serve the dual purpose of increasing strength and performance as well as enhancing combativeness. Adverse and toxic effects The adverse effects of short- and long-term administration of anabolic-androgenic steroids on basic bodily functions are still not completely understood. Almost all of our information is derived from anecdotes although there is now some new data indicating that the use of these steroids can adversely affect cardiovascular, liver and reproductive function. It also appears that the majority of the adverse effects are due to the oral rather than the injectable preparations. One of the main reasons why these toxic effects occur in athletes who use ana~olic~ndrogeni~ steroids rather than in individuals

who receive them therapeutically is that athletes use doses that are 10-30 times higher than those needed for ~~lacement therapy’*. For example, 7MOO mg per week of testosterone enantate suffices as a replacement dose for hypogonadal men, while weekly doses

63

new proteins D

>

steroid hormone

plasma membrane extracellular fluid

J

F/g. 2. ~h~tsrn of action of steroid us on celts. The ~~e passes thigh the ceil watt of its tergettissueand bindsto steroid recet#ors in the cvtoolasm. The hormonr+receplor &?pleX moves info thenucleus and bids to sites on?he chrometOt, which is transcribed to give specific messenger RNA (mRNA). The mRNA is translated into specifk new pmtelns that mediate the function of the hormone.

of 1000 mg’” and 2100 mg of metandienonei6 have been reported by weightlifters and bodybuilders. In addition, many athletes use multiple drugs simultan~usIy in either a ‘stacking’ or a ‘cycling’ regimen ‘?. Thus, not only are the doses higher but also many different steroids can be used over the same training interval. The most significant adverse effect of anabolic-androgeni~ steroid abuse is the reduction of serum hi h-density lipoprotein cholesterol q 4. This effect occurs soon after steroid use begins and usually subsides about one month after cessation of steroid use. The reduction in high-density lipoprotein cholesterol is often accompanied by an elevation of low-density lipoprotein cholesterol. This disruption in the balance of cholesterol fractions suggests that athletes who use these hormones are at greater risk of suffering from coronary heart disease. However, there has been only one published case of heart disease in an athlete who was using androgens”, Other evidence of an association between these steroids and an increased risk of heart disease comes from animal studies in which the steroids cause platelet clumping, thereby increasing the riskof blood clot formation that may result in strokes or heart attacks. However, Ferenchlck ct al,iYfound that there

is also an association between increased platelet aggregation and age in weightlifters who use anabolic-androgenic steroids. Documenting direct correlations between the use of these steroids and heart disease will remain a difficult task because there are many risk factors that must first be considered before such clear associations can be made. The use of oral steroid preparations has also been associated with an increased risk of liver disorders, especially jaundice and tumours. Although the association between anabolic-androgenic steroid use and jaundice was first found in 1952 (Ref. 20) and continues today, the evidence for hepatocellular carcinoma is not so clear”. About half of the reported 91 cases of androgen-related hepatic tumoun were not substantiated histologically or were associated with Fanconi’s anaemia’“. Feminizing side-effects, particularly gynecomastia, can develop in young men who take anabolicandrogenic steroids. As noted previously, androgens can be converted to estrogens in nonglandular tissues. Thus, the feminizing effects may be due to the direct effects of the female hormot~e estrogen. Men with liver disease are especially prone to this side-effect because they cannot disperse the androgens and the excess is shunted to

TiPS - Febrl~~r~ 2993 {Vol. 241

64 .BOXl

Concepts and definitions of abuse and dependence Traditional concepts and definitions of drug abuse and drug dependence have evolved to incorporate a more operational aspect to the terms’. For example, the distinction between physical, psychic and psychological dependences has outlived the theoretical basis upon which they were originally established. The recommendations stated in the World Health organization Memorandum on Nomenclatu~ and Classification2 clearly make a distinction between primary processes, such as drug seifadministration, and secondary consequences of such intake. The use of experimentally or clinically operational terms that are devoid of value judgments (such as ‘addiction’) is desirable from the perspective of drug testing. In this regard, it is useful to define ‘abuse liability’ as the events that precede or accompany strong drug-seeking behaviour as it relates to the social context in chnicai studies and to the operant schedule in animal then, refers to the physiological and studies. ‘Physical dependence’, behavioural alterations that develop consequent to drug exposure, and is measured by quantifying the signs and symptoms that appear when drug administration is terminated. The relevance and importance of the distinction between physical dependence and abuse habihty reside in the fact that while both are of obvious public health concern, they are not mutually inclusive and can occur independent of one another. For example, ~thdrawal signs are observed after terminating a number of drugs (e.g. propranolot and clonidine), yet these drugs are not abused, Conversely, animals will selfadminister very low doses of cocaine and morphine that fail to result in

physical dependente3”. Applying these principles to the anabolic-androgenic steroids must be preceded by the establishment of standards with which the various steroid analogues can be compared - a task that has yet to be completed. ‘This process of comparing the pharmacological equivalence of various drugs fo a standard prototypic drug has been used successfully over the past 60 years and remains the most reliable approach

for assessing

the abuse liability

and dependence potential of drugs belonging to a variety of pharmacological classes. References 1 Brady, J. V. and Lukas, S. E. (1984)Tesrirr$Drugs for Plrysiral Dependence Pokwlial and Abuse ~iabi~ify, NlDA ResearchMonograuh No. 52

2 World Health O$anization (19Bl) Bull. W&d 59,22B-242 3 Jones, 8. E. and Prada, J. A. (1977) Drug Alcohol Deprd. 2,237-294 4 Johanson,C. E., Balstor,R. L, and Bonese,K. (1976) ~~~u~~tf~c~~, gj~ck~~. ~~~~~u, 4, 45-51

extraqandular sites. JInne ’ has suggested

However, that high

doses of certain androgens, particularly mibolerone binds to the human progesterone receptor with greater affinity than progesterone. This finding might explain why even individuals with healthy livers who take high doses of exogenous androgens may exhibit secondary female characteristics. In general, the toxic effects described above appear to disappear once the anabolic steroid is stopped. Side-effects such as in-

ducing female characteristics (enlarged breasts) in male users, and male characteristics (faciai hair, thickened vocal cords, malepattern baIdnes~) in female users are especially deleterious to tccnage users because they are still

undergoing natural deveiopment and growth (e.g. of bone). Unlike many of the effects on the heart, liver and reproductive system, these latter effects may be permanent. Abuse ~iabili~ and dependence potentiai The growing use of anabolicandrogenic steroids by both athletes and nonathletes represents a significant health problem that must be addressed by systematically evaluating the causes and consequences of such abuse. This task will be difficult because the steroids are often obtained via illicit means. As such, the user cannot be certain about the chemical composition of the preparation purchased and since

multiple drugs are often used concurrently it is difficult to determine which drug and dose is responsible for eliciting abuse and producing the physical dependence. Thus, effects (either desired or not) may be attributed to a specific error in preparation. in addition, veterinary preparations are sometimes used, meaning that the clinical data on the effects of these drugs wit1 be limited. These difficulties must be overcome if effective treatment programmes are to be developed. If anabolic-androgenie steroid abuse and dependence resemble abuse and dependence on other drugs, then existing treatment strategies may be useful in treating this population as well. Traditionally, animal models and behavioural testing procedures have been used with excellent success in predicting the abuse liability (i.e. drug-seeking) and dependence potential in humansz2, and have served as the standards for the scheduling process. Unfortunately, the techniques that have been used to quantify these tendencies with respect to classical drugs of abuse such as ethanol, cocaine and opiates may not be useful for testing the anabolicandrogenic steroidsz3. Procedures such as self-administration, tolerance, drug discrimination or physical dependence have not been successful in measuring anaboticandrogenic steroid abuse liability and physical dependence potential in animals. Because studies with human subjects generally lack app~priate controls, suffer from subject selection inadequacies and are confounded by expectancy effects, they do not presentiy provide information on the abuse liability of these steroids (Box 1). One possible explanation for the lack of a clear abuse liability in animal studies is the time delay between drug administration and the appearance of the desired effect. Although there are scattered anecdotal reports of elevated mood during high-dose steroid administration, the anabolic~ndrogenie steroids do not generally produce an immediate elevation in mood or a feeling of euphoria, Steroid hormones can act quite rapidly (within minutes or hours) at receptor sites on cell membranes, but the perceived beneficial effects (eg. changing the

7’iPS - February 1993 [Vol. 241

65

production of proteins) appear to take some time. This factor alone can confound traditional selfadministration studies. The abuse of anabolic-androgenic steroids appears to span many social and physiological factors that are not easily duplicated in studies of more traditional drugs of abuse. The fact that individuals continue to take these drugs and seem to have lost the ability to stop suggests that steroid-seeking behaviour exists. Indeed, the perception of the user that he or she is not big or strong enough may, in fact, reflect a greater vulnerability to subsequent abuse. This perception seems to prevail at the junior and senior high school level: in one study about a quarter of the male high school seniors who reported using anaboiic-androgenic steroids said they would refuse to stop taking them even if the association between their use and the increased incidence of liver cancer, permanent sterility or early heart attacks were proved beyond a doubtz4. However, it is difficult to put this info~atlon into perspective because those surveyed did not actually experience the adverse consequences. There is evidence that physical dependence induced by these steroids can develop, although the doses and duration of exposure required are unknown. The observations of a number of clinical studies suggest that clearly discernible withdrawal signs appear upon termination of anaboiicandrogenic steroid USP~“*~~. Brower et ~1.27surveyed 49 male weightlifters and found that the most frequently reported withdrawal symptoms were, in decreasing order of appearance, steroid craving (52%), fatigue (43%)‘ depressed mood (41%), restlessness (29%), anorexia (24%), insomnia (20%), decreased libido (20%) and headaches (20%). However, the overall impression that 57% of those surveyed might be physically dependent on the steroids may be too liberal given the fact that there was a tremendous selection bias and that answers could not be corroborated. Furthermore, the fact that there has not been a single reported case of anabolicandrogenic steroid dependence in

further suggests that physical dependence on these steroids may not be widespread. Regardless of the scope of dependence on steroids, it does appear to exist in some individuals, and the treatment of such dependence presents a relatively new challenge to the ciinicianz8. Based on the above data, it might be expected that the most difficult aspect of treating anabolic-androgenie dependence is obtaining a thorough case history to detect the steroid abuse problem (see Box 2). Bodybuilders are known to be rather secretive about their drug use, and since these drugs are banned from competition and are scheduled by the Drug Enforcement Agency, individuals may be more reluctant to admit to using them. The clinician must use a variety of findings from physical, mental and laboratory examinations to make a correct diagnosisz9. However, once diagnosed, there is no information regarding the proper procedure for treating an individual who is dependent on steroids. Presently, techniques involving education plus providing alternatives to steroid use and pharmacotherapy to manage withdrawal, and relapse-prevention techniques used with other drugs of abuse, show the greatest promise29.

women or among patitmts who have been prescribed these drugs for le~itlmate tl~erapeutic masons

Although rumours still abound, more accurate estimates of anaboli~and~genic steroid use are

Incidence of nonmedical use In 1938, the physiologicat action of the sex hormones suggested that they might increase muscle growth30 and by 1944, data were available from studies of both animals and humans that supported this notior?. The initiation of systematic use of anabolicandrogenic ste~ids in sports has been attributed to reports of their use by weightlifting teams in the early 1950s”. Soon afterwards, elite American strength athletes began using these drugs on a relatively wide scale. Within a few years the use of anabolic-androgenie steroids diffused to endurance sports, such as long-distance running and swimming, and eventually to recreational use3i. Until the mid-1970s, information on the incidence of the nonmedical use of steroids was based on anecdotes, testimonials and rumours.

due to the results of a few systematic surveys15*24*32-36. There are, however, a -number of limitations associated with obtaining accurate self-reports of steroid use (see Ref. 31). The increased use of drug testing during athletic competitions has also identified new patterns of use; however, the results of such tests - particularly those announced in plenty of time often significantly unde~stimate the incidence of steroid use. A review of the findings of these surveys of steroid use can be summarized as follows: 0 Nonmedical use of anabolicandrogenic steroids occurs in adolescents and adults. it is believed that between 3 and 12% of male and approximately 1% of female high school students have used these steroids during their life. In a survey of high school seniors, lifetime prevalence of steroid use was reported by 2.9% of those interviewed, while 0.2% reported daily use during the previous 30 days”. Less information is available on patterns of use in adult populations. 8 Anabolic-androgenic steroid use is not geographically related and abuse is reported in schools located in the suburbs as well as in the cities. a Significant variations in the incidence of steroid use have been noted among high schools and colleges as well as among different sports. Football players report the highest use while track and field athletes use them least. l The level of anabolicandrogenie steroid use among ail groups has increased over the past two decades. l Steroid use by women appears to be significantly less than that for men, but is slowly increasing: ~1% in the mid-1980s and between 1.5 and 4% in the 1990s. o The incidence of use increases to about 14% of athletes in Division 1 of the National Cob legiate Athletic Association and 30-75% of professional athletes or competitive bodybuilde~3’l Recreational and noncompetitive athletes appear to be using these drugs to improve their physical :*ppearance. l Data that are based on selfreports are likely to underrepresent the level of anabolicand~genic steroid use. available

TilJS - February 1993 [Vol. 141

66 Patterns of use Yesalis3’ has compiled an extensive database on the patterns of anabolic-androgenic steroid use among athletes. The typical pattern of use by bodybuilders and power lifters is a cycle of 6-12 weeks in duration, although some power lifters may use them on a continuous basis=. Athletes also tend to use more than one steroid at a time. This method, called stacking, frequently involves steroids with slightly different pharmacological profiles. The commonly held theory for this practice is that more steroids will engage more receptors, resulting in greater gains than if each drug were taken alone”. The doses are gradrially increased and then decreased over the course of the cycle, a practice called Tolerance, or ‘pyramiding‘. ‘plateauing’, is often avoided by staggering the different drugs in either a brief overlapping pattern or by stopping one drug and then starting anothe?‘. In general, power athletes prefer stacking while bodybuilders favour cycling. Since the doses used are so high, athletes may also use other drugs to boost their athletic performance or, more importantly, block the steroid-induced side-effects3Y. In contrast to the power athletes, endurance runners use these drugs for their putative anticatabolic effects; therefore, they tend to use doses in the physiological range”O. Sprinters, however, have greater strength and power requirements than endurance runners and so tend to use doses that are 1.5-2 times the typical therapeutic doses4’. Psychiatric effects Anabolic-androgenic steroids have been used by athletes for many years but their association with psychiatric side-effects was not recognized until recently. The mechanism by which these psychiatric effects are induced is not known. However, it has been shown that glucocorticoid administration can result in psychiatric symptoms4’, and the higher anabdic-androgenic steroid doses may explain the differential incidence of psychiatric symptoms, Controversy also exists as to the severity of these psychiatric symptoms. For example, anecdotal case reports (see below) note the condition called roid rage, in which

,Box2

Urine testing for Formal testing for the presence of anabolir-androgenic steroids in body Buids beean in the mid-1970s durinlr the Montreal Olvmuic Games’. Today, testing is routinely performed f& international, nafion& collegiate and even high school athletic programmes as well as in military and law enforcement agencies. While the most publicized reason for testing has been for detecting these compounds in athletes, tests also are now being performed during screening for employment and in the medical environment. The primary analytical procedure used for detecting anabolic-androgenic steroids in urine is gas chromatography/mass spectrometry (GUMS). The accuracy is generally from good to excellent, but there are still a number of false positives and false negatives that have precluded widespread acceptance of these procedures. This is especially problematic because the amount of drug being measured is very low and the only method of detecting exogenously administered testosterone is by examining the peak height of the testosterone : epitestosterone ratioz. Generally a ratio of 6 : 1 is required before a positive identification is made.

Since the number of laboratories performing these tests is increasing there is an immediate need for standard laboratory procedures and accreditation programmes. Currently, the lnte~ational Olympic Committee operates the only formal accreditation pro~amme in the world, but the College of American Pathologists is currently developing a programme of their own. Regardless of the experience of the laboratory personnel, there are still inadequate analytical standards for many anabolic-androgenic steroids and their metabolites so that the tests cannot even be performed. This makes it difficult to develop the necessary protocols for accurate identification of compounds other than testosterone. Even if the technical issues in the laboratory are overcome, the problem of implementing a testing procedure that accomplishes the ultimate goal (i.e. preventing anabolic-androgenic steroid abuse) remains. It is clear that many athletes use steroids during training periods so that their presence in the body is not necessary for competition. In fact, the beneficial effects remain for many weeks after the individual has stopped taking the steroid. Long-lasting injectable steroids such as nandrolone decanoate (which could be detected up to six months after a single injection) are no longer used. The use of announced,drug tests gives the athletes additionat time to stop taking the drugs to ensure a negative test. Most athletes now discontinue oral preparations Z-4 weeks, and injectable preparations &6 weeks, before competition, which is when they are at greatest risk of being

the individual erupts into a frenzy of violent behaviour after a course of anabolic-androgenic steroid use. There are presently no definitive controlled studies demonstrating the incidence, or even existence, of this phenomenon. Numerous case reports have identified psychiatric symptoms in individuals who had taken anabolic-androgenic steroids4M7. Although the details of the case reports are sometimes sketchy, there have been a few controlled studies linking psychiatric symptoms to steroid use48*49.In a structured interview of 41 bodybuilders and football players, 22% of the subjects dispIayed a full affective syndrome, while 12% displayed psychotic symptoms that appeared in association with steroid use4* These distributions were significantly higher than during the con-

trol period and greater than the incidence of psychiatric problems normally occurring in this age group. The authors note that their data are descriptive rather than quantitative, but because of the reluctance of these athletes to volunteer information on their steroid-using behaviour, the authors are unsure whether their observations are representative of the entire steroid-using culture, In another study, 20 male weightlifters who used anabolicandrogenie steroids had significantly more somatic, depressive, anxious, hostile and paranoid complaints compared with weightlifters who had never used steroids4%. None of the symptoms was severe enough to be classified on the basis of DSM-IIIR criteria. Examination of the symptoms reported by there two group~~~.~~ suggests that

TiPS - February 1993 [Vol. 241

67

anabo~j~-andro~en~~ steroids tested3. This practice allows the athlete to experience the beneficia1 effects of the drug while minimizing the chances of being caught. Finally, the use of other substances such as somatropin, erythropoietin and somatomedin present especially difficult problems for the clinical testing laboratory. These compounds are cleared from the body so quickly th,at they may be impossible to detect using currently available methods. Because of the difficulties surrounding urine testing, another strategy for detecting the use of these drugs may need to be developed. One possible solution may be to focus on the biochemical changes induced by these steroids that are frequently observed in blood. Great care must be exercised in such a technique because alterations in blood chemistry can occur via a multitude of disease states and nutritional imbalances, many of which have nothing to do with anabolic-androgenic steroid use. Although many of these changes are observed in nonusers who are exercising, the degree of change is much greater when individuals use anabolic-androgenic steroids, Given the myriad of changes observed, and the fact that the results are usually computerized, a positive test for steroid use might be indicated when a specific profile of changes in numerous biochemical markers is observed. This strategy has the added advantage of being an easily conducted test and, unlike the other tests for anabolic-androgenic steroids, the results are quickly available. Potential biochemical markers include liver function tests (e.g. lactate dehydrogenase, alkaline phosphatase and alanine aminotransferase), muscle enzymes (e.g. creatine phosphokinase), high-density lipoprotein cholesterol to low-density lipoprotein cholesterol ratio, hematocrit and haemoglobin levels, serum luteinizing hormone and follicular-stimulating hormone Ievels, and sperm count and motility measures. Any suspected blood chemistry profiles could then be followed with a urine screen for a positive identification of the anabolic-androgenic steroid involved. Overall, this plan could be more cost-effective by reserving the more expensive urine screening tests for confirmation of the less expensive, more easily conducted biochemical tests.

References 1 Catlin, D. (1987)in Drugs and ~er~~r~u~ce ls Sparts (Strauss, R. H,, ed.), pp. 10%120, W. 8. Saunders 2 Catkin, D., Krammerer, R., Hatton, C., Sekera, M. and Merdink, J. (1987) Ctipr. Chem. 33,319-327 3 Yesalis, C. E., Anderson, W. A., Buckley, W. E. and Wright, J. E. (1990) NIDA Ros, Monagr. Ser. 102,97-111

similar profiles were observed, and that perceived differences in

the degree of psychopathology are related to the different thresholds for assigning a psychiatric diagnosisso. To summarize,

it appears

that

naboli~-andro~e~ic steroids

can cause hypomania and perhaps even psychotic symptoms while they are being used, whereas major depression may develop in some individuals upon discontinuation of treatment. Psychiatricsymptoms do occur after the use of these drugs, but because of the low

chronic steroid use more fully, this interpretation remains conjecture, Ethical considerations may pre-

clude the conduct of clear, doubleblind studies in which high doses of anabolic-androgenic steroids are given to volunteers. Thus, the conduct of naturalistic studies will most likely continue, but irnp~v~ methods and standardized criteria for detecting and verifying the frequency and severity of the psychiatric symptoms will need to be adopted. cl

cl

cl

inciderfm of reported cases and the purported widespread use, it must be assumed that many users can

tolerate them without significant difficulty. However, without the benefit of prospective, controlled clinical studies to document the psychiet~c effects of acute and

Basic research

examining the of anasteroid use and

causes and consequences bolic-androgenic

misuse is presently in its infancy. Specific areas in which additional information is needed include detailed epidemiological studies of

the health consequences of acute and chronic steroid use, welfdesigned and well-controlIed studies of performance changes, better models and standards to study the abuse liability and dependence potential, determination of the psychological and behavioural effects of acute and longterm use, and more precise and standardized methods for detecting these compounds (and their metabolites) in urine and blood samples. Since many anabolicandrogenic steroids are now scheduled, a shift in patterns of use to somatropin, somatomedin and ~-hyd~xybutyric acid must be met with reliable information on the physiological and toxic effects of these and other drugs. Acknowledgement This research was supported by Research Scientist Award DA1lO115. References 1 Winters, S. J. (1990) Nl5A Ra. Mormagr. Ser. 102. 113-130 2 Hoskins, R. C. (1941) Eadocritmlo~y: The Glands and Their hrcfiotrs, W. W. Norton 3 Berthold, A. A. (18491 Arrh. Atfat. Physiof. Wiss.Med. 16, 4i-46 4 Moore, C. R. (1939) in Sex atfd f~rf~r~~ff~ Secrctio~rs(Allen, E,, Danforth, C. H. and Doisy, E. A., eds), pp. 354-t51, Williams & Wilkins 5 Kochakian, C. D. (1990) NIDA Kcs. Mormlqr. Ser. 102, 29-59 6 Haupt, H. A. and Rovere, C. D. (1984) Afar,J. Syorls Med. 12, 4691184 7 Lombardo, J. A. and Sickles. R. T. (1992) Psyclri(l~~ Am. 22, 19-23 8 Hervey, G. R. rt al. (1981) C&t. Sri. 40, 457-461 9 Kochakian, C. D. (1976) Arra(?nlic’ArfdragctticStfraids, Springer-Verlag 10 Strauss, R. H., L@ett. M. T. and Lanese, R. R. (1985) j.A.M.A. 253, 2871-2873

11 Svare, 8. B. (1990) N/DA Rn. Mow,qr. Ser. 102,224-241 12 Bahrke. M. S., Yesalis. C. E., II1 and Wright; J. E.. (1990) Sports Mrl. IO, 303-337 13 Lombardo, J. A, (1990) NfDA RP$. Mortogr. Sm. 102, 60-73 14 Fried& K. E. (1990) NIDA Res. Mot~o~r. Ser. 102, 142-176 15 Yesalis, C. cl al. (1988) Phys. Sporfstttrd. 16, 91-100 16 Freed, D. L. J.. Banks, A. J,, Longson, D. and Burley, D. M. (1975) Dr. Med. 1, 2, 471-973 17 Windsor, R. E. and Dumitru, D. (1988) Postgrad. Med. 84, 37-49 18 McNutt. R. A., Ferenchick, C. S., Kirlin, P. C. and Hamlin, N. J. (1988) Am: I. Cnrdiol. 62. 164 19 Ferenchick, G.. Schwartz, D., Ball, M. and Schwartz, K. (1992) A#N.J. Med. Sn. 303,7&-82 20 Lloyd-Thomas, H. G. L. and Sherlock, S.

TiPS - February 2993 [Vol. 141

68 (1952)

21 lime.

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jer. 102, I?%I86 22 Griffith% R. R.. Big&w, G. E. and H~nningfield, Jo E. (1980) in Adzwtces it!

23 24 25

26 27

28 29 30

Srrbstance Abrtse: Brhnviornl md Biologicnl Resenrch (Vol. 1) (Mello, N. K., ed.), pp. l-90, JAl Press Cicero, T. J. and O’Connor, L. H. f 19YO) NIDA Rcs. Monogr. Ser. 102,1-28 Yesalis, C. E. et RI. (1990) NIDA Res. Monogr. Ser. 102, 196-214 Brewer, K. J.. Eliopulos, G. A., Blow, F. C., Catkin, D. H. and Beresford, T. P. (1990) Am. j. Psychintry 147, 510-512 Brower, K. J. (1992) Rychinfry Ann. 22, 3x34 Brewer, K. j., Blow, F. C., Young, J. P. and Hill, E. M. (1991) Br. f. Addict. 86, 759-768 Kashkin, K. 8. and Kleber, H, D, (1989) I.A.M.A. 262,3166-3170 Brower, K. J. (1992) Psychiatry Am. 22, 35-40 Kenyon, A. T., Sandiford, I., Bryan, A. H., Knowlton, K. and Koch, F. C.

(1938) E~~~ocri~~o~og~ 23, 135-153 31 Yesaiis, C. E. (1992) ~s~c~~~?r!/ Am. 22, 7-H 32 Anderson, W. A., Aibrecht, M. A., McKeag, D. B., Hough, D. 0. and McGrew, C. A. (1991) Piqs. Sporfsnred. 19,91-104 33 Burkett. L. N. and Falduto, M. T. (1984) Plrys. Spurtsnred. 12.49-74 34 Buckley, W. E. et al. (1988) I.A.M.A. 260, 3441--3&i 35 Cohen, j. C., Noakes, T. D. and Spinnler Benade; A. j. (1988) i%ys, Sparjs~led. 16, 49-56 36 PO&, H. G., Jr, Katz, D. L. and Champoux, R. (1988) Phys. Sportsmed. 16,75-%1 37 foknston, L. D., O’Malley, P. M. and Bachman, J. G. (1991) &t&g Use Awong Americmr ffigh Scboul SE?I~OIS. College Stjidcnts mrd Ymg Ad&, 29751990 tCo!iegr Shdcnts and Youq Adults, Vol. II), National Institute on Drug Abuse 38 Duchaine, D. (1989) UlrdcrgrurrrrdSteroid Hmdbouk If, Technical Books 39 Di Pasquafe, M. G. (1984) 5rg Use nrtd

Nonchiral, homochiral and composite chiral drugs E. J. Arigns Ch~rality and the im~iicif sfereoselec~iu~fy in ph~r~ucod~n~nyic~ and p~~armacokinefics, in parficuIuy of rncemic f~era~euf~~5, RYCinfeyesfing from boflt scientific and applied points of view. There is much literature on the subject, including B series of papers on c~lirulify in TiPS in 2986 {Vol. 7, pp. t&23, 60-64, 212-116, X5-158, ZOO-205and 281-285). The choice between single stereoisomers fhomochiral drugs) and composite chiral drugs (mixtures of stereoisomers) depends upon fherRpeufic adva~~fages (such us II redi~ct~o~iin xenobio~ic toad), possible adverse sjde-effects and der~elo~men~costs. There is a need for critical evaluation of existing and new composite chiral drugs, while the potential of nonchiru~ drugs is hardly discussed in the ~ifera#ure. This review by E. J. Aril;ns considers current informa~jon on composite, home- and nonchiral drugs, with particular regard to drug development.

In prebiotic

‘organic’ chemistry (carbon chemistry), chirality was inevitable. As in laboratory chemistry, in the absence of particular stereospecific tools, only composite chiral products, such as racemates, could occur. The driving forces in prebiotic carbon chemistry were temperature, eiectrical discharges (lightning), photochemical reactions and, possibly, catalysis on mineral surfaces. Without stereospecific events, prebiotic chemistry would have E. /* AriBns is Emeritus fJro@ssor,lastitufe of Pharmacology arrd Toxicology, University of IVijmegefl, Groenewmtdsaweg 45, 6524 TP Ni~~cge~, The Ne&rlands.

been restricted to nonchiral and composite chiral products. Life, however, is predominantly homochiral. Single stereoisomers, such as the L-amino acids, and a few nonchiral agents, such as purines and pyr~mid~nes, predominate in biochemistry and physiology. Composite chiraP products, such as racemates, are rare. This is true for both flora and fauna, and products exchanged between them. For instance, plant toxins are homochiral and seldom nonchiral, These secondary metabelites (including various alkaloids) serve as defence against predators and are aometimee used as medicines,

Defectiotr in Spark, MGD Press J. E. and 40 Yesalis, C. E., Wright, Lombardo, J. A. (1969) C/in. Sports Med. 1,109-134 41 Francis, C.

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Perry, P. J. and Tsuang, M. T. (1961) Arch. Gcn. Psyclrinfry 38, 471-477 Ann&to, W. R. and Layman, W. A. (1980) I. Clin. Psychiatry 41,143-144 Freinhar, J. P. and Alvarez, W, (1985) I_ Clin. ~s~c~ti~:ry 46, 354-355 Conacher, G. N. and Workman, D. G. (1989) A~I. 1. Psychiatry 146, 679 Pope, H. G., Jr and Katz, D. L. (1987) Luncet 1,863 Wilson, 1. C., Prange, A, J., Jr and Lara, P. P. (1974) Am. f. Psychiatry 131,21-24 Peny, P. J., Yates, W. R. and Anderson, K, H. (1990) Ann. C&a. Psyc~lifftry 2, X1-17 Pope, H. G., Jr and Katz, D. L. (1988) Ant. J. Psychiatry 145, 487-490 Pope, H. G., Jr and Katz, D. L. (1992) Psycfzjfft~ Atm, 22, 2629

Composite chiral products such as Rs-atropine are formed by racemization of the original homochira1 plant product. With few known exceptions, composite chiral products isolated from living organisms are artefacts or the result of exposure to synthetic, anthropogenic, xenobiotics. Of all the drugs on the market about 75% are synthetic, of which about 60% are nonchiral and 40% chiral. Of the chiral drugs, about 12% are homochiral and about 88% composite chiral, racemic mixtures’. How did the change from ,the prebiotic composite chiral to the biological homochiral state come about? One suggestion is photochemical reactions. In the morning there is a significant ‘L’ circular polarized component in light; in the afternoon it reverses to *R’.Since in the afternoon temperatures are appreciably higher than in the morning, a shift in the proportions of enantiomers, from composite to homochiral, occurs2. This is assumed to be the basis for biological homochira~ity and identity in configuration (isosterism), for example the L-amino acid composition of proteins. Natural stereoselective tools were generated in the form of biological enzymes to maintain homo~hirali~; simiiarly receptors that operate on a homochiral basis. Life would be much more cornplicated if it were based on cornposit@ chiral mixtures of DBand ~-amine acids, Xomochirality in