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Original Article |

Effects of Supraphysiologic Doses of Testosterone on Mood and Aggression in Normal Men:  A Randomized Controlled Trial FREE

Harrison G. Pope Jr, MD, MPH; Elena M. Kouri, PhD; James I. Hudson, MD, SM
[+] Author Affiliations

From the Biological Psychiatry Laboratory, McLean Hospital, Belmont; and Department of Psychiatry, Harvard Medical School (Drs Pope, Kouri, and Hudson), and Department of Biostatistics, Harvard School of Public Health (Dr Hudson), Boston, Mass.


Arch Gen Psychiatry. 2000;57(2):133-140. doi:10.1001/archpsyc.57.2.133.
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Published online

Background  Field studies of illicit anabolic-androgenic steroid users suggest that some develop manic or aggressive reactions to these drugs—a potential public health problem. However, controlled laboratory evaluations of these effects remain limited.

Methods  In a randomized, placebo-controlled, crossover trial, we administered testosterone cypionate for 6 weeks in doses rising to 600 mg/wk and placebo for 6 weeks, separated by 6 weeks of no treatment, to 56 men aged 20 to 50 years. Psychiatric outcome measures included the Young Mania Rating Scale (YMRS), the Point Subtraction Aggression Paradigm (a computerized provocation test of aggression), the Aggression Questionnaire of Buss and Perry, the Symptom Checklist-90-R, daily diaries of manic and depressive symptoms, and similar weekly diaries completed by a "significant other" who knew the participant well.

Results  Testosterone treatment significantly increased manic scores on the YMRS (P=.002), manic scores on daily diaries (P=.003), visual analog ratings of liking the drug effect (P=.008), and aggressive responses on the Point Subtraction Aggression Paradigm (P=.03). Drug response was highly variable: of 50 participants who received 600 mg/wk of testosterone cypionate, 42 (84%) exhibited minimal psychiatric effects (maximum YMRS score, <10), 6 (12%) became mildly hypomanic (YMRS score, 10-19), and 2 (4%) became markedly hypomanic (YMRS score, ≥20). The 8 "responders" and 42 "nonresponders" did not differ significantly on baseline demographic, psychological, laboratory, or physiological measures.

Conclusions  Testosterone administration, 600 mg/wk increased ratings of manic symptoms in normal men. This effect, however, was not uniform across individuals; most showed little psychological change, whereas a few developed prominent effects. The mechanism of these variable reactions remains unclear.

Figures in this Article

THE MALE hormone testosterone and its synthetic analogs compose the family of hormones called anabolic-androgenic steroids (AASs). Probably more than a million Americans, primarily young men—including 4% to 7% of male high school students—have used these hormones illicitly to improve athletic performance or personal appearance.14 During the past 10 years, results of a growing literature of field studies1,513 suggest that some illicit AAS users develop marked aggression, hypomania, and occasionally frank mania during AAS exposure, as well as depressive symptoms and even suicidality during AAS withdrawal. The euphoric effects of AAS use and the dysphoric effects of withdrawal may contribute to a syndrome of AAS dependence in some individuals.1,1315 Several articles1,8,1622 speculate that AAS use may precipitate criminal violence. These effects may be dose related, with frequent symptoms in individuals using the equivalent of more than 1000 mg of testosterone per week,57 occasional symptoms at intermediate dosages,6,813 and few symptoms at 300 mg per week or less.6,23 In one field study of 88 illicit AAS users,6 25 (28%) reported using at least 1000 mg of testosterone or the equivalent per week, and another 51 (58%) had used between 300 and 1000 mg per week—often as "stacks" of oral and injectable AAS taken simultaneously. Thus, many illicit users may be at risk for psychiatric morbidity.

However, interpretation of these findings is limited by the problems common to observational studies. For example, selection bias may affect which users will present for study, and information bias may arise in participants recalling psychological effects experienced in the past while taking illicit drugs of uncertain potency or authenticity. The confounding effects of users' premorbid personalities and expectations, concomitant abuse of other substances, and the physiological and psychological effects of weight training might also bias the findings.6,2426

Experimental treatment studies avoid such limitations but ethically cannot use highly supraphysiologic doses of AAS approaching those used illicitly. Endocrinologic,27,28 physiological,2931 and medical3234 studies have typically used at most 300 mg/wk of testosterone2734 or nandrolone29 and have noted few psychiatric effects. However, 3 recent laboratory studies have used higher doses: 2 reported occasional manic or hypomanic reactions in participants administered methyltestosterone35 or testosterone,36 whereas a third study using testosterone did not.37,38

To augment these limited data, we performed a randomized, placebo-controlled, double-blind crossover study of the psychiatric effects of intramuscular testosterone cypionate treatment, at dosages rising to 600 mg/wk, in 56 normal men. We hypothesized that this supraphysiologic dosage of an AAS would increase hypomanic and aggressive symptoms. We also tested the hypothesis that such effects, if present, would be more prominent in men who had previously used AASs illicitly or who lifted weights regularly.

PARTICIPANTS

We advertised at several local colleges and 1 local gymnasium to recruit men aged 20 to 50 years from 3 groups: (1) men who did not lift weights regularly and never used AASs, (2) men who lifted weights regularly (at least 3 times per week for ≥2 years) and never used AASs, and (3) men who formerly used AASs illicitly. We required each participant to furnish a "significant other"—a spouse, sexual partner, or close friend—to rate his behavior in a weekly diary (see the "Study Procedures" subsection) and to alert the investigators if he displayed adverse behavioral changes. We informed each participant and significant other that we were investigating the psychological effects of receiving supraphysiologic doses of testosterone, and required both to sign informed consent forms approved by the institutional review board of McLean Hospital, Belmont, Mass.

At baseline evaluation, we obtained demographic information, psychiatric and substance abuse histories using the Axis I portion of the Structured Clinical Interview for DSM-III-R,39 and medical histories. The evaluation also included a physical examination, determination of body fat using calipers,40 an electrocardiogram, and laboratory tests (see the "Study Procedures" subsection). We excluded participants who (1) met DSM-III-R criteria41 for any substance abuse or dependence within the past year; (2) reported current or past major depression, active suicidal ideation, hypomania, mania, or psychotic symptoms; (3) had ever required use of any regular psychiatric medication; (4) exhibited a clinically significant medical condition; or (5) had used any AASs within the past 90 days, as determined by self-report and baseline urine testing.

STUDY PROCEDURES

Qualifying participants were then seen weekly for 25 weeks. They were randomized to receive intragluteal injections of testosterone or placebo under double-blind conditions forweeks 1 through 6 (the "first treatment period"), a washout for weeks 7 through 12, injections of the opposite treatment for weeks 13 through 18 (the "second treatment period"), and a second washout for weeks 19 through 25. During the testosterone treatment period, participants received 150 mg each of the first 2 weeks, 300 mg the third and fourth weeks, and 600 mg each of the last 2 weeks. Placebo injections consisted of equivalent amounts of the sesame oil vehicle. We assessed psychiatric symptoms at each visit using the Young Mania Rating Scale (YMRS),42 24-item Hamilton Depression Rating Scale,43 Aggression Questionnaire of Buss and Perry (AQ),44 and Symptom Checklist-90-R.45 Weight, pulse, and blood pressure were also measured weekly. Laboratory tests—including standard chemistries, hematological measures, neuroendocrine measures (total testosterone, luteinizing hormone, follicle-stimulating hormone, and prolactin), urinalysis, and urine screening for drugs of abuse (including AASs46,47)—were administered every 3 weeks. Blood and urine samples for these tests were obtained within a few minutes before or after any intragluteal injections. To minimize the possible confounding effects of diet and weight training,24 we asked participants to maintain a stable diet and exercise pattern throughout the 25 weeks, although this behavior was not formally monitored. Virtually all injections and investigator-administered ratings were performed by one of us (H.G.P.); in his absence, they were performed by another physician (J.I.H.). Thus, the raters were aware of when participants were receiving treatment but were unaware of the identity of that treatment.

At home, participants also completed a 17-item daily diary (available on request) covering 12 manic symptoms and 5 depressive symptoms experienced during the past 24 hours. The diaries generated a manic score of 0 to 48 and a depression score of 0 to 20. Participants also marked a 100-point visual analog "liking" scale with 3 anchors: "I dislike the way that I feel on this medication very much" (0 points), "neutral" (50 points), and "I like the way that I feel on this medication very much" (100 points). Total manic, depressive, and liking scores for each week represented the mean scores of all diaries submitted during the preceding 7 days. Significant others rated the participant's behavior weekly in a virtually identical diary. Participants received approximately $50 per week for study participation and significant others received $5 per weekly diary.

In the second study year, we introduced a computerized measure of aggression, the Point Subtraction Aggression Paradigm (PSAP).48 This test was administered to most participants at weeks 1, 5, 7, 13, 17, and 19. We presented this technique in detail in a previous article,49 together with preliminary data from 5 participants in the present study. Briefly, each participant was seated in a booth equipped with a monitor screen and was told that he was playing against an unseen male opponent, which was actually a computer. The participant could accumulate points on the screen—exchangeable for money—by pressing one button, or he could deprive his "opponent" of points by pressing another button. During the session, the opponent provoked the participant by randomly depriving him of points. The participant's aggression score represented the total number of points that he subtracted from his opponent in retaliation to this provocation. In accordance with published scoring methods for this test,48 we excluded participants who guessed that their opponent was a computer. Participants were judged to have guessed correctly if they both (1) failed to deprive their opponent of points during 1 or more sessions, and (2) responded on a poststudy questionnaire49 that their opponent had been a computer.

DATA ANALYSIS

For the primary analysis of each outcome measure, we compared the changes during the testosterone and placebo periods. We defined each period to begin on the day of the first injection and end 1 week after the last injection (when the effects of testosterone would be expected to be greatest). We considered participants to be "fully evaluable" for a given treatment period if they received at least the first 5 of 6 scheduled injections to ensure that all testosterone treatment periods included at least 1 injection of 600 mg of testosterone. In addition to the analysis of fully evaluable participants, we also analyzed participants' responses after adminstration of 300 mg of testosterone, using as the end point the visit 1 week after the second injection of 300 mg (week 5 or week 17).

We used a model for the mean of the response variable derived from Senn50 to analyze crossover studies. This model incorporates terms for treatment and period effects but not for carryover (or residual) effect. The decision to exclude such a term was based on the work of Freeman,51 who showed that models with a term for carryover effect are biased and possess poor power to detect a carryover effect. In any event, a carryover effect seemed unlikely with our design because evidence from kinetic studies52,53 with testosterone cypionate suggests that a 6-week washout period after a 6-week treatment period allows neuroendocrine function to return to baseline. Thus, the model was as follows: E(Yi)= β01 treatment + β2 period, where E(Y) is the expected value of the outcome variable for the ith subject; treatment is an indicator variable for testosterone treatment; and period is an indicator variable for the first treatment period.

To model the covariance, we wanted to allow for both dependence of repeated observations within the same individual and possible dependence of variance of the response variable on the mean. Therefore, we used PROC MIXED in SAS54 to fit 3 models for the "working" covariance: one allowed variance to depend on treatment group, another allowed variance to depend on treatment period, and a third assumed equal variance (compound symmetry). We chose the best-fitting model in each analysis and computed SEs based on empirical variances.

We tested for effects of previous AAS use and/or regular weight lifting by putting terms in the model for the various participant categories (1 indicates no weight lifting, no previous AAS use; 2, regular weight lifting, no previous AAS use; and 3, previous AAS use). Because it was unclear whether this variable should be best treated as a nominal or an ordinal variable, we analyzed it both ways.

We also analyzed data from only the first treatment period using the Wilcoxon rank sum test, 2-tailed. This analysis was free of concern about carryover effect and distributional assumptions but ignored almost half of the data. Thus, it represented an unquestionably valid but overly conservative assessment of treatment effects.

In an a posteriori analysis, we classified participants' responses to testosterone treatment as marked, moderate, or minimal on the basis of YMRS scores (see "Results" section), and then compared attributes of marked or moderate responders with those of minimal responders using the Fisher exact test, 2-tailed. In these and all other comparisons, we considered P<.05 to be statistically significant.

Because the outcome measures in this study are correlated to an unknown degree, it is difficult to calculate an appropriate correction for the effect of multiple comparisons. Results are therefore presented without correction. Thus, some findings, especially those of marginal significance and those that do not test a priori hypotheses, may represent chance associations.

PARTICIPANT CHARACTERISTICS

Of 66 participants recruited, 56 were randomized, 55 were followed up in the first study period; 53 received at least 5 injections and were considered fully evaluable, as defined in the "Data Analysis" subsection of the "Participants and Methods" section (demographic characteristics of these 53 men are shown in Table 1). Forty-nine participants were followed up in the second study period; 47 were fully evaluable.

Table Graphic Jump LocationTable 1. Demographic Characteristics of 53 Evaluable Study Participants
PSYCHIATRIC MEASURES

Manic scores on the YMRS increased significantly with testosterone treatment (Table 2). However, this effect was not uniform: most participants exhibited little change during testosterone treatment, whereas a few displayed marked symptoms (see Figure 1 and the "Comment" section). While taking testosterone, no participant reported actual violence (see definition in Table 1), but several described instances of uncharacteristic aggressiveness; we withdrew one participant from the study after the fifth week because he became alarmingly hypomanic and aggressive (Figure 1). Of 34 participants administered the PSAP at baseline and after at least 1 treatment period, 1 was excluded because he misinterpreted the instructions and 6 because they guessed that their opponent was a computer (see "Study Procedures" subsection of the "Participants and Methods" section). Thus, 27 participants were evaluable for at least 1 study period. Because some participants were not given the PSAP at week 13 (the baseline for the second period), we analyzed this measure using the end-point value (week 7 or week 19) for testosterone vs placebo treatment, with the week 1 value as a covariate. Despite the smaller number of participants in this analysis, aggression scores on the PSAP increased significantly with testosterone treatment. Again, however, this effect was not uniform; most participants showed little change and a few showed marked changes. The manic and liking scores on participants' daily diaries also showed a significant testosterone treatment effect. Diaries from significant others did not show a significant testosterone effect, although manic scores on participants' and significant others' diaries correlated highly at the end of the testosterone treatment period (Spearman Y=0.59; P<.001).

Table Graphic Jump LocationTable 2. Psychiatric Measures at Baseline and End Point With Placebo and Testosterone Treatment in 53 Evaluable Participants*
Place holder to copy figure label and caption

Responses of 6 participants to testosterone cypionate treatment on the Young Mania Rating Scale. Black bars represent testosterone treatment periods; white bars, placebo periods. Asterisk indicates discontinuation of testosterone treatment after week 5 for this participant because of rapidly escalating manic symptoms.

Graphic Jump Location

Self-rating scales showed few drug treatment effects. Only 1 of 4 AQ subscale scores, verbal hostility, increased significantly with testosterone therapy among evaluable participants (P=.03), and this score displayed a significant period effect, with second-period increases greater than those of the first period (P=.01). Only 1 of 9 Symptom Checklist-90-R subscale scores, phobic anxiety, showed a significant increase with testosterone treatment (P=.006). Depression scores on both types of diaries and on the Hamilton Depression Rating Scale remained low, with no changes even approaching significance during testosterone administration or withdrawal. When we expanded our analysis to include the 55 participants who had received at least 1 injection, the effect of testosterone treatment and the levels of significance on all primary psychiatric measures remained virtually unchanged.

We examined whether the categories of weight lifting and previous AAS use (no regular weight lifting and no previous use, regular weight lifting without previous use, previous use, and both weight lifting and previous use groups combined) were associated with a significant effect on outcome measures. We found no significant effect or even tendency toward an effect (P<.10) on any outcome measure in Table 2, regardless of whether these categories were treated as ordered or unordered.

Next, by examining response to testosterone treatment at the 300-mg level, as discussed in the "Participants and Methods" section, we found only a slight effect. The effect of testosterone treatment (mean±SE) was 1.1±0.6 (χ21=3.68; P=.06) on the YMRS, 1.2±0.6 (χ21=4.20; P=.04) on the daily diary manic score, and 3.4±0.1 (χ21=4.49; P=.03) on the daily diary liking score. The effect did not approach significance on the PSAP at 47±39 (χ21=1.41; P=.23), or on the other measures.

Looking at the first treatment period only, the changes on psychiatric measures were similar to those found in the primary analysis but yielded lower levels of statistical significance. Of the 4 measures showing a significant effect for testosterone treatment in the primary analysis, the change in YMRS scores was significantly greater with testosterone than with placebo treatment (median, 2 vs 0; z=2.96; P=.003). All changes on the other 3 measures showed a tendency toward statistical significance in the same direction (PSAP: median, 99 vs 14; z=1.71; P=.09; daily diary manic scores: median, 0.1 vs -1.0; z=1.66; P=.10; liking scores: median, 0 vs 0; z=1.62; P=.11). As with the primary analysis, the difference between testosterone and placebo treatment on the other 4 primary psychological measures was not significant.

Finally, in an a posteriori analysis, we divided the evaluable participants into 3 groups based on maximum YMRS score attained during each treatment: marked responders (YMRS score of ≥20, indicating manic symptoms likely to impair social and occupational functioning), moderate responders (YMRS scores of 10-19, indicating milder hypomanic symptoms), and minimal responders (YMRS scores of <10). Because there were no significant period effects in the analyses of YMRS data, we scored participants' responses to testosterone treatment, regardless of the period during which it was administered. This classification yielded 2 marked, 6 moderate, and 42 minimal responders to testosterone treatment (Figure 1). By comparison, the 50 placebo periods produced no marked, 1 moderate, and 49 minimal responses. Diary scores seemed to be consistent with this classification: manic scores of the 8 moderate or marked responders increased significantly more than those of the 42 minimal responders (median, 6.9 vs 0.2; z=3.90; P<.001 by Wilcoxon rank sum test, 2-tailed), as did liking scores (median, 6 vs 0; z=2.93; P=.003) and manic scores on the significant other diaries (median, 8.9 vs -0.2; z=3.48; P<.001). We then compared the 8 moderate or marked responders with the 42 minimal responders on all baseline variables in Table 1 and on all physiological and laboratory variables in Table 3. The latter were examined at baseline and at the end of the testosterone period. No comparison yielded a significant difference. Also, none of the 11 individuals reporting a first-degree relative with a major mood disorder were among the 8 testosterone responders.

Table Graphic Jump LocationTable 3. Physiological and Laboratory Measures That Changed Significantly With Testosterone Treatment*
PHYSIOLOGICAL MEASURES

Although diet, exercise, and times of blood drawing were not standardized across participants in this primarily psychiatric study, testosterone treatment produced expected changes on physiological and laboratory test results (Table 3).27,37,56 Measures differing significantly between testosterone and placebo treatment among the 53 fully evaluable participants are summarized in Table 3; all other measures on the standard chemistry, hematologic, and urinalysis battery produced no significant differences. No serious laboratory abnormalities or adverse medical events occurred during the study.

In a placebo-controlled, double-blind, crossover study of administration of supraphysiologic doses of testosterone cypionate to normal men, testosterone treatment significantly increased several measures of manic and aggressive symptoms; these effects seemed to be independent of whether the participant had engaged in regular weight lifting or had used AASs illicitly in the past. These effects were largely confined to a small group of "responders"—but this group proved indistinguishable from "nonresponders" on demographic, psychological, physiological, and laboratory measures. The small number of responders in this analysis raises the possibility of a type II error—failure to reject the null hypothesis when a true difference exists. Also, the laboratory measures included total but not free testosterone, leaving open the small possibility that responders might have differed on the latter measure. However, such responses may be idiosyncratic and presently unpredictable.

Several limitations of the study should be considered. First, the crossover design raises the question of a carryover effect.50,51 Although statistical methods have low power to detect a carryover effect, it seems unlikely: among participants who received testosterone in the first treatment period, all psychiatric measures returned to baseline at least 1 week before the beginning of the second treatment period (in other words, no significant differences were found between values at week 1 and at week 12 on any variable using paired t tests). Furthermore, in the analysis of the first treatment period only—which avoids the issue of a carryover effect—testosterone treatment differed significantly from placebo treatment on the YMRS, and showed trends in the same direction on the PSAP and on manic and liking scores on the daily diaries. Nevertheless, a carryover effect cannot be completely excluded in the primary analysis.

Second, study measures did not produce uniformly positive findings: the self-rating scales (AQ and Symptom Checklist-90-R) and diaries completed by the participants' significant others showed few differences, comparable to those found on the YMRS, PSAP, and daily diaries. However, neither the AQ nor the Symptom Checklist-90-R rates hypomania,44,45 and the AQ may also be less sensitive than other measures of aggression.57 The significant others' ratings also seemed to be insensitive, likely as a result of carelessness or noncompliance. Therefore, the YMRS, PSAP, and daily diaries were probably better adapted to measuring effects of testosterone.

Another possible criticism is that some participants might have guessed when they were receiving testosterone and hence displayed bias because of expectational effects.31 However, several observations weigh against this possibility. First, individuals previously experienced with AAS use or with regular weight lifting would presumably be more sensitive to expectational effects than those with no such experience. Yet, as mentioned previously, neither previous AAS use nor regular weight lifting was significantly associated with manic or aggressive responses to testosterone. Second, expectational bias would not easily explain the testosterone treatment effect on the PSAP, in which the participant was not informed that he was being tested for aggression. Third, there was no significant correlation between change in lean body mass and changes on the 8 psychiatric measures shown in Table 2 (P>.10 in all cases by Spearman rank correlation), suggesting that increased size and strength were not associated with elevated mood and aggression scores. These reasons notwithstanding, we cannot exclude the possibility of expectational bias.

Conversely, several methodological limitations may have caused us to underestimate the psychiatric effects of testosterone treatment. First, the modest dose and duration of testosterone treatment in our study, chosen for considerations of safety, did not match the high doses of AAS, frequently comprising several agents taken simultaneously and often ingested, by illicit users.57 Second, we excluded prospective participants with a history of a major psychiatric disorder, but illicit users do not select themselves with similar care. Third, study participants were not permitted to use illicit drugs during the study, and none regularly consumed large amounts of alcohol. Illicit AAS users, lacking such restrictions, might be at higher risk for psychiatric effects than participants taking testosterone alone. Fourth, we withdrew 2 participants from testosterone treatment during the study because of adverse psychiatric effects; had these participants hypothetically continued through the full protocol, the effect of testosterone treatment might have been greater. For these reasons, the findings of the present investigation may represent a "lower bound" for the true rate of psychiatric effects exhibited by AAS users in the field.

In summary, our findings augment the evidence that administration of 300 mg per week of testosterone or the equivalent produces few psychiatric effects,6,23,2734,36 whereas dosages of 500 per week or more produce occasional prominent manic or hypomanic reactions (Table 4). Such reactions are probably more frequent "in the field" than in the laboratory and may represent an underrecognized public health problem. To understand the biological or psychological contexts for these seemingly idiosyncratic reactions, future investigators should consider using larger sample sizes, more sophisticated batteries of neuroendocrine measures, and more detailed assessments of baseline psychological and neuropsychological indices.

Table Graphic Jump LocationTable 4. Placebo-Controlled Studies Examining Psychiatric Effects of Administration of Testosterone, ≥500 mg/wk, or the Equivalent

Accepted for publication March 5, 1999.

This study was supported in part by grant RO1-DA06543 from the National Institute on Drug Abuse, Rockville, Md.

We are indebted to Alicja Skupny and Jack Mendelson, MD, for the performance and interpretation of the neuroendocrine measures; Don H. Catlin, MD, and Caroline K. Hatton, PhD, of the UCLA Olympic Analytical Laboratory, Los Angeles, Calif, for urinary anabolic-androgenic steroid testing; Pharmacia & Upjohn Co, Bridgewater, NJ, for supplying testosterone cypionate and matched placebo; David Katz, MD, for assistance with the design of the study and commentary on the manuscript; David Amato, PhD, and Garrett Fitzmaurice, PhD, for assistance with statistical analyses; and Paul Oliva and John Borowiecki for assistance with data collection and management.

Reprints: Harrison G. Pope, Jr, MD, MPH, Biological Psychiatry Laboratory, McLean Hospital, 115 Mill St, Belmont, MA 02178 (e-mail: pope@mclean.harvard.edu).

Pope  HG  JrKatz  DL Psychiatric effects of exogenous anabolic-androgenic steroids. Wolkowitz  OMRothschild  AJeds.Psychoneuroendocrinology for the Clinician Washington, DC American Psychiatric Press.In press.
Yesalis  CEKennedy  NJKopstein  ANBahrke  MS Anabolic-androgenic steroid use in the United States. JAMA. 1993;2701217- 1221
Link to Article
Buckley  WAYesalis  CEFriedl  KEAnderson  WStreit  AWright  J Estimated prevalence of anabolic steroid use among male high school seniors. JAMA. 1988;2603441- 3445
Link to Article
Durant  RHRickert  VIAshworth  CSNewman  CSlavens  G Use of multiple drugs among adolescents who use anabolic steroids. N Engl J Med. 1993;328922- 926
Link to Article
Pope  HG  JrKatz  DL Affective and psychotic symptoms associated with anabolic steroid use. Am J Psychiatry. 1988;145487- 490
Pope  HG  JrKatz  DL Psychiatric and medical effects of anabolic-androgenic steroid use. Arch Gen Psychiatry. 1994;51375- 382
Link to Article
Parrott  ACChoi  PYLDavies  M Anabolic steroid use by amateur athletes: effects upon psychological mood states. J Sports Med Phys Fitness. 1994;34292- 298
Choi  PYLParrott  ACCowan  D High-dose anabolic steroids in strength athletes: effects upon hostility and aggression. Human Psychopharmacol. 1990;5349- 356
Link to Article
Lefavi  RGReeve  TGNewland  MC Relationship between anabolic steroid use and selected psychological parameters in male bodybuilders. J Sports Behav. 1990;13157- 166
Perry  PJYates  WRAndersen  KH Psychiatric symptoms associated with anabolic steroids: a controlled, retrospective study. Ann Clin Psychiatry. 1990;211- 17
Link to Article
Moss  HBPanzak  GLTarter  RE Personality, mood, and psychiatric symptoms among anabolic steroid users. Am J Addict. 1992;1315- 324
Link to Article
Burnett  KFKleiman  ME Psychological characteristics of adolescent steroid users. Adolescence. 1994;2981- 89
Malone  DA  JrDimeff  RLombardo  JASample  BRH Psychiatric effects and psychoactive substance use in anabolic-androgenic steroid users. Clin J Sports Med. 1995;525- 31
Link to Article
Kashkin  KBKleber  HD Hooked on hormones? an anabolic steroid addiction hypothesis. JAMA. 1989;2623166- 3170
Link to Article
Brower  KJBlow  FCYoung  JPHill  EM Symptoms and correlates of anabolic- and androgenic steroid dependence. Br J Addict. 1991;86759- 768
Link to Article
Conacher  GNWorkman  DG Violent crime possibly associated with anabolic steroid use [letter]. Am J Psychiatry. 1989;146679
Bidwell  MKatz  DL Injecting new life into an old defense: anabolic steroid–induced psychosis as a paradigm of involuntary intoxication. Univ Miami Entertainment Sports Law Rev. 1989;71- 63
Pope  HG  JrKatz  DL Homicide and near-homicide by anabolic steroid users. J Clin Psychiatry. 1990;5128- 31
Dalby  JT Brief anabolic steroid use and sustained behavioral reaction. Am J Psychiatry. 1990;149271- 272
Stanley  A Anabolic steroids—the drugs that give and take away manhood: case with an unusual physical sign. Med Sci Law. 1994;3482- 83
Choi  PYLPope  HG  Jr Violence toward women and illicit androgenic-anabolic steroid use. Ann Clin Psychiatry. 1994;621- 25
Link to Article
Pope  HG  JrKouri  EMPowell  KFCampbell  CKatz  DL Anabolic-androgenic steroid use among 133 prisoners. Compr Psychiatry. 1996;37322- 327
Link to Article
Bahrke  MSWright  JEStrauss  RHCatlin  DH Psychological moods and subjectively perceived behavioral and somatic changes accompanying anabolic-androgenic steroid use. Am J Sports Med. 1992;20717- 724
Link to Article
Bahrke  MSYesalis  CE Weight training: a potential confounding factor in examining the psychological and behavioral effects of anabolic-androgenic steroids. Sports Med. 1994;18309- 318
Link to Article
Riem  KEHursey  KG Using anabolic-androgenic steroids to enhance physique and performance: effects on moods and behavior. Clin Psychol Rev. 1995;15235- 256
Link to Article
Rubinow  DRSchmidt  PJ Androgens, brain, and behavior. Am J Psychiatry. 1996;153974- 984
Bagatell  CJHeiman  JRMatsumoto  AMRivier  JEBremner  WJ Metabolic and behavioral effects of high-dose, exogenous testosterone in healthy men. J Clin Endocrinol Metab. 1994;79561- 567
Anderson  RABancroft  JWu  FCW The effects of exogenous testosterone on sexuality and mood of normal men. J Clin Endocrinol Metab. 1992;751503- 1507
Hannan  CJFriedl  KEZold  AKettler  TMPlymate  SR Psychological and serum homovanillic acid changes in men administered androgenic steroids. Psychoneuroendocrinology. 1991;16335- 343
Link to Article
Forbes  GBPorta  CRHerr  BEGriggs  RC Sequence of changes in body composition induced by testosterone and reversal of changes after drug is stopped. JAMA. 1992;267397- 399
Link to Article
Björkvist  KNygren  TBjörklund  ACBjörkvist  SE Testosterone intake and aggressiveness: real effect or anticipation? Aggr Behav. 1994;2017- 26
Link to Article
Griggs  RCPandya  SFlorence  JM  et al.  Randomized controlled trial of testosterone in myotonic dystrophy. Neurology. 1989;39219- 222
Link to Article
Skakkebaek  NEBancroft  JDavidson  DWWarner  PM Androgen replacement with oral testosterone undecanoate in hypogonadal men: a double-blind controlled study. Clin Endocrinol. 1981;1449- 61
Link to Article
O'Carroll  RBancroft  J Testosterone therapy for low sexual interest and erectile dysfunction in men: a controlled study. Br J Psychiatry. 1984;145146- 151
Link to Article
Su  T-PPagliaro  MSchmidt  PJPickar  DWolkowitz  OMRubinow  DR Neuropsychiatric effects of anabolic steroids in male normal volunteers. JAMA. 1993;2692760- 2764
Link to Article
Yates  WRPerry  PMacindoe  JHolman  TEllingrad  V Psychosexual effects of three doses of testosterone cycling in normal men. Biol Psychiatry. 1999;45254- 260
Link to Article
Bhasin  SStorer  TWBerman  N  et al.  The effect of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996;3351- 7
Link to Article
Tricker  RCasaburi  RStorer  TW  et al.  The effect of supraphysiological doses of testosterone on angry behavior in healthy eugonadal men. J Clin Endocrinol Metab. 1996;813754- 3758
Spitzer  RLWilliams  JBWGibbon  M Structured Clinical Interview for DSM-III-R (SCID).  New York, NY New York State Psychiatric Institute1989;
Jackson  ASPollock  ML Generalized equations for predicting body density of man. Br J Nutr. 1978;40497- 504
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.  Washington, DC American Psychiatric Association1987;
Young  RCBiggs  JTZiegler  VEMeyer  DA A rating scale for mania: reliability, validity, and sensitivity. Br J Psychiatry. 1978;133429- 435
Link to Article
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;2356- 62
Link to Article
Buss  AHPerry  M The Aggression Questionnaire. J Pers Soc Psychol. 1992;63452- 459
Link to Article
Derogatis  LR Symptom Checklist-90-R: Administration, Scoring, and Procedures Manual.  Minneapolis, Minn National Computer Systems Inc1994;
Catlin  DHKammerer  RCHatton  CKSekera  MHMerdink  JM Analytical chemistry at the Games of the XXIIIrd Olympiad in Los Angeles, 1984. Clin Chem. 1987;33319- 327
Aguilera  RBecchi  MCasabianca  H  et al.  Improved method of detection of testosterone abuse by gas chromatography/combusion/isotope ratio mass spectrometry analysis of urinary steroids. J Mass Spectrom. 1996;31169- 176
Link to Article
Cherek  DRSchnapp  WMoeller  FGDoughterty  DM Laboratory measures of aggressive responding in male parolees with violent and nonviolent histories. Aggr Behav. 1996;2227- 36
Link to Article
Kouri  EMLukas  SEPope  HG  JrOliva  PS Increased aggressive responding in male volunteers following the administration of gradually increasing doses of testosterone cypionate. Drug Alcohol Depend. 1995;4073- 79[published correction appears in Drug Alcohol Depend. 1998;50:255].
Link to Article
Senn  S The AB/BA crossover: past, present and future? Stat Methods Med Res. 1994;3303- 324
Link to Article
Freeman  PR The performance of the two-stage analysis of two-treatment, two-period crossover trials. Stat Med. 1989;81421- 1432
Link to Article
Schulte-Beerbuhl  MNieschlag  E Comparison of testosterone, dihydrotestosterone, luteinizing hormone, and follicle-stimulating hormone in serum after ingestion of testosterone enanthate or testosterone cypionate. Fertil Steril. 1980;33201- 203
Nankin  HR Hormone kinetics after intramuscular testosterone cypionate. Fertil Steril. 1987;471004- 1009
SAS Institute Inc, SAS/GIS Software [computer program]: release 6.12.  Cary, NC SAS Institute Inc1997;
Kouri  EMPope  HG  JrKatz  DLOliva  PS Fat-free mass index in users and non-users of anabolic-androgenic steroids. Clin J Sports Med. 1995;5223- 228
Link to Article
Kouri  EMPope  HG  JrOliva  PS Changes in lipoprotein-lipid levels in normal men following increasing doses of testosterone cypionate. Clin J Sports Med. 1996;6152- 157
Link to Article
Allen  TJDougherty  DMRhoades  HMCherek  DR A study of male and female aggressive responding under conditions providing an escape response. Psychol Rec. 1996;46651- 664

Figures

Place holder to copy figure label and caption

Responses of 6 participants to testosterone cypionate treatment on the Young Mania Rating Scale. Black bars represent testosterone treatment periods; white bars, placebo periods. Asterisk indicates discontinuation of testosterone treatment after week 5 for this participant because of rapidly escalating manic symptoms.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic Characteristics of 53 Evaluable Study Participants
Table Graphic Jump LocationTable 2. Psychiatric Measures at Baseline and End Point With Placebo and Testosterone Treatment in 53 Evaluable Participants*
Table Graphic Jump LocationTable 3. Physiological and Laboratory Measures That Changed Significantly With Testosterone Treatment*
Table Graphic Jump LocationTable 4. Placebo-Controlled Studies Examining Psychiatric Effects of Administration of Testosterone, ≥500 mg/wk, or the Equivalent

References

Pope  HG  JrKatz  DL Psychiatric effects of exogenous anabolic-androgenic steroids. Wolkowitz  OMRothschild  AJeds.Psychoneuroendocrinology for the Clinician Washington, DC American Psychiatric Press.In press.
Yesalis  CEKennedy  NJKopstein  ANBahrke  MS Anabolic-androgenic steroid use in the United States. JAMA. 1993;2701217- 1221
Link to Article
Buckley  WAYesalis  CEFriedl  KEAnderson  WStreit  AWright  J Estimated prevalence of anabolic steroid use among male high school seniors. JAMA. 1988;2603441- 3445
Link to Article
Durant  RHRickert  VIAshworth  CSNewman  CSlavens  G Use of multiple drugs among adolescents who use anabolic steroids. N Engl J Med. 1993;328922- 926
Link to Article
Pope  HG  JrKatz  DL Affective and psychotic symptoms associated with anabolic steroid use. Am J Psychiatry. 1988;145487- 490
Pope  HG  JrKatz  DL Psychiatric and medical effects of anabolic-androgenic steroid use. Arch Gen Psychiatry. 1994;51375- 382
Link to Article
Parrott  ACChoi  PYLDavies  M Anabolic steroid use by amateur athletes: effects upon psychological mood states. J Sports Med Phys Fitness. 1994;34292- 298
Choi  PYLParrott  ACCowan  D High-dose anabolic steroids in strength athletes: effects upon hostility and aggression. Human Psychopharmacol. 1990;5349- 356
Link to Article
Lefavi  RGReeve  TGNewland  MC Relationship between anabolic steroid use and selected psychological parameters in male bodybuilders. J Sports Behav. 1990;13157- 166
Perry  PJYates  WRAndersen  KH Psychiatric symptoms associated with anabolic steroids: a controlled, retrospective study. Ann Clin Psychiatry. 1990;211- 17
Link to Article
Moss  HBPanzak  GLTarter  RE Personality, mood, and psychiatric symptoms among anabolic steroid users. Am J Addict. 1992;1315- 324
Link to Article
Burnett  KFKleiman  ME Psychological characteristics of adolescent steroid users. Adolescence. 1994;2981- 89
Malone  DA  JrDimeff  RLombardo  JASample  BRH Psychiatric effects and psychoactive substance use in anabolic-androgenic steroid users. Clin J Sports Med. 1995;525- 31
Link to Article
Kashkin  KBKleber  HD Hooked on hormones? an anabolic steroid addiction hypothesis. JAMA. 1989;2623166- 3170
Link to Article
Brower  KJBlow  FCYoung  JPHill  EM Symptoms and correlates of anabolic- and androgenic steroid dependence. Br J Addict. 1991;86759- 768
Link to Article
Conacher  GNWorkman  DG Violent crime possibly associated with anabolic steroid use [letter]. Am J Psychiatry. 1989;146679
Bidwell  MKatz  DL Injecting new life into an old defense: anabolic steroid–induced psychosis as a paradigm of involuntary intoxication. Univ Miami Entertainment Sports Law Rev. 1989;71- 63
Pope  HG  JrKatz  DL Homicide and near-homicide by anabolic steroid users. J Clin Psychiatry. 1990;5128- 31
Dalby  JT Brief anabolic steroid use and sustained behavioral reaction. Am J Psychiatry. 1990;149271- 272
Stanley  A Anabolic steroids—the drugs that give and take away manhood: case with an unusual physical sign. Med Sci Law. 1994;3482- 83
Choi  PYLPope  HG  Jr Violence toward women and illicit androgenic-anabolic steroid use. Ann Clin Psychiatry. 1994;621- 25
Link to Article
Pope  HG  JrKouri  EMPowell  KFCampbell  CKatz  DL Anabolic-androgenic steroid use among 133 prisoners. Compr Psychiatry. 1996;37322- 327
Link to Article
Bahrke  MSWright  JEStrauss  RHCatlin  DH Psychological moods and subjectively perceived behavioral and somatic changes accompanying anabolic-androgenic steroid use. Am J Sports Med. 1992;20717- 724
Link to Article
Bahrke  MSYesalis  CE Weight training: a potential confounding factor in examining the psychological and behavioral effects of anabolic-androgenic steroids. Sports Med. 1994;18309- 318
Link to Article
Riem  KEHursey  KG Using anabolic-androgenic steroids to enhance physique and performance: effects on moods and behavior. Clin Psychol Rev. 1995;15235- 256
Link to Article
Rubinow  DRSchmidt  PJ Androgens, brain, and behavior. Am J Psychiatry. 1996;153974- 984
Bagatell  CJHeiman  JRMatsumoto  AMRivier  JEBremner  WJ Metabolic and behavioral effects of high-dose, exogenous testosterone in healthy men. J Clin Endocrinol Metab. 1994;79561- 567
Anderson  RABancroft  JWu  FCW The effects of exogenous testosterone on sexuality and mood of normal men. J Clin Endocrinol Metab. 1992;751503- 1507
Hannan  CJFriedl  KEZold  AKettler  TMPlymate  SR Psychological and serum homovanillic acid changes in men administered androgenic steroids. Psychoneuroendocrinology. 1991;16335- 343
Link to Article
Forbes  GBPorta  CRHerr  BEGriggs  RC Sequence of changes in body composition induced by testosterone and reversal of changes after drug is stopped. JAMA. 1992;267397- 399
Link to Article
Björkvist  KNygren  TBjörklund  ACBjörkvist  SE Testosterone intake and aggressiveness: real effect or anticipation? Aggr Behav. 1994;2017- 26
Link to Article
Griggs  RCPandya  SFlorence  JM  et al.  Randomized controlled trial of testosterone in myotonic dystrophy. Neurology. 1989;39219- 222
Link to Article
Skakkebaek  NEBancroft  JDavidson  DWWarner  PM Androgen replacement with oral testosterone undecanoate in hypogonadal men: a double-blind controlled study. Clin Endocrinol. 1981;1449- 61
Link to Article
O'Carroll  RBancroft  J Testosterone therapy for low sexual interest and erectile dysfunction in men: a controlled study. Br J Psychiatry. 1984;145146- 151
Link to Article
Su  T-PPagliaro  MSchmidt  PJPickar  DWolkowitz  OMRubinow  DR Neuropsychiatric effects of anabolic steroids in male normal volunteers. JAMA. 1993;2692760- 2764
Link to Article
Yates  WRPerry  PMacindoe  JHolman  TEllingrad  V Psychosexual effects of three doses of testosterone cycling in normal men. Biol Psychiatry. 1999;45254- 260
Link to Article
Bhasin  SStorer  TWBerman  N  et al.  The effect of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996;3351- 7
Link to Article
Tricker  RCasaburi  RStorer  TW  et al.  The effect of supraphysiological doses of testosterone on angry behavior in healthy eugonadal men. J Clin Endocrinol Metab. 1996;813754- 3758
Spitzer  RLWilliams  JBWGibbon  M Structured Clinical Interview for DSM-III-R (SCID).  New York, NY New York State Psychiatric Institute1989;
Jackson  ASPollock  ML Generalized equations for predicting body density of man. Br J Nutr. 1978;40497- 504
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.  Washington, DC American Psychiatric Association1987;
Young  RCBiggs  JTZiegler  VEMeyer  DA A rating scale for mania: reliability, validity, and sensitivity. Br J Psychiatry. 1978;133429- 435
Link to Article
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;2356- 62
Link to Article
Buss  AHPerry  M The Aggression Questionnaire. J Pers Soc Psychol. 1992;63452- 459
Link to Article
Derogatis  LR Symptom Checklist-90-R: Administration, Scoring, and Procedures Manual.  Minneapolis, Minn National Computer Systems Inc1994;
Catlin  DHKammerer  RCHatton  CKSekera  MHMerdink  JM Analytical chemistry at the Games of the XXIIIrd Olympiad in Los Angeles, 1984. Clin Chem. 1987;33319- 327
Aguilera  RBecchi  MCasabianca  H  et al.  Improved method of detection of testosterone abuse by gas chromatography/combusion/isotope ratio mass spectrometry analysis of urinary steroids. J Mass Spectrom. 1996;31169- 176
Link to Article
Cherek  DRSchnapp  WMoeller  FGDoughterty  DM Laboratory measures of aggressive responding in male parolees with violent and nonviolent histories. Aggr Behav. 1996;2227- 36
Link to Article
Kouri  EMLukas  SEPope  HG  JrOliva  PS Increased aggressive responding in male volunteers following the administration of gradually increasing doses of testosterone cypionate. Drug Alcohol Depend. 1995;4073- 79[published correction appears in Drug Alcohol Depend. 1998;50:255].
Link to Article
Senn  S The AB/BA crossover: past, present and future? Stat Methods Med Res. 1994;3303- 324
Link to Article
Freeman  PR The performance of the two-stage analysis of two-treatment, two-period crossover trials. Stat Med. 1989;81421- 1432
Link to Article
Schulte-Beerbuhl  MNieschlag  E Comparison of testosterone, dihydrotestosterone, luteinizing hormone, and follicle-stimulating hormone in serum after ingestion of testosterone enanthate or testosterone cypionate. Fertil Steril. 1980;33201- 203
Nankin  HR Hormone kinetics after intramuscular testosterone cypionate. Fertil Steril. 1987;471004- 1009
SAS Institute Inc, SAS/GIS Software [computer program]: release 6.12.  Cary, NC SAS Institute Inc1997;
Kouri  EMPope  HG  JrKatz  DLOliva  PS Fat-free mass index in users and non-users of anabolic-androgenic steroids. Clin J Sports Med. 1995;5223- 228
Link to Article
Kouri  EMPope  HG  JrOliva  PS Changes in lipoprotein-lipid levels in normal men following increasing doses of testosterone cypionate. Clin J Sports Med. 1996;6152- 157
Link to Article
Allen  TJDougherty  DMRhoades  HMCherek  DR A study of male and female aggressive responding under conditions providing an escape response. Psychol Rec. 1996;46651- 664

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