Purpose: Neuropsychological, neuroendocrine: to investigate whether neuroendocrine response to the dopamine D2 receptor agonist bromocryptine was altered in ecstasy users as compared with non-drug using controls.

Design: Retrospective (non-experimental) between-group design, with drug use (ecstasy users versus non-drug user control), and with all participants undergoing a challenge with 5 mg bromocryptine administered p.o.

Subjects: 12 male ecstasy users and 12 male non-drug user controls probably residing in or near Parma (Italy), with ecstasy user participant recruited through contacting the local Drug Addiction Service, either seeking information or treatment from this organization. Non-drug user controls were recruited from hospital staff and local high school students. Matching - Groups were matched on gender, age and demographics.

Criteria for Inclusion - Ecstasy Users - Reported having used ecstasy at least once and perhaps a minimum of 20 times (not stated in text, but suggested by range of lifetime doses), no history of prolonged consumption or dependence on other psychoactive drugs, no past or current excessive alcohol intake, abstinence from ecstasy for three weeks prior to study day, with abstinence verified via urinary analysis 3 times each week. Non-drug user controls - Reported never having used any illicit psychoactive drug, and no past or current alcoholism, similar in age and demographics to ecstasy user sample. Both Groups - Male, healthy, as established via medical and psychiatric examination and laboratory analyses.

Drug Use Parameters - Average total (lifetime) number of ecstasy tablets taken was 53.2 +/- 33 tablets (range = 22-86). Average dose per use is not stated, but authors sought people who took 1 to 2 tablets per occasion. Average duration of use, in months, was 18.8 +/- 8 months (range = 8-30 months), and average frequency of use was 5.7 +/- 3.7 times per month (range = 8-30 times per month). Time since last use of ecstasy, in days, was reported as at least 27 days prior to study day, with abstinence verified through urinary analyses performed three times each week. Other drugs - Cannabis was detected in urine in 5/12 participants on admittance and in 4/12 of urinary samples taken after admittance. Heroin was detected in 2/12 urine samples on study admittance and in 1/12 sample after study admittance, and cocaine was found in urine of 1/12 study participant on study admittance and again in 1/12 study participant after study admittance.

Group Demographics and Matched Variables - The authors matched groups on gender, age, weight, height, education and demographics. Gender, as M/F ratio - Ecstasy users, 12/0, Non-drug user controls, 12/0. Age - Average age of ecstasy users was 22.7 +/- 2.8 years, and average age of non-drug user controls was 24.3 +/- 5.6 years. Weight and height - Average weight of ecstasy users was 67.9 +/- 9.6 kg, and average height was 173.6 +/- 10.3 cm. Average weight of non-drug user controls was 74.5 +/- 10.8 kg and average height was 175.4 +/- 13.4 cm. Education - 7/12 of the ecstasy users were students (does not distinguish between high school and university), 3/12 were working and 2/12 were unemployed. Information is not provided on education or employment of non-drug using controls; all were either high school students or hospital staff.

Measures: Neuroendocrine Measures - Prolactin was measured via radioimmunoassay (RIA) and growth hormone (GH) was measured via chemiluminescence assay. Both hormones measured from blood drawn at 0, 15, 30, 60, 90 and 120 min (2 h) post-drug.

Personality Measures - Participants completed the MMPI, the Tridimensional Personality Questionnaire (TPQ) (containing novelty seeking, harm avoidance and reward dependence scales), and an Italian version of the Buss-Durkee Hostility Inventory (BDHI).

Mental Disorders - All participants were assessed via structured interview for personality disorders (SDIP). Depression was measured via Hamilton Rating Scale (HRS-D).

Analyses: Neuroendocrine Measures - Area under curve (AUC) was calculated for prolactin and GH for each subject. A one-way analysis of variance (ANOVA) was used to examine prolactin and GH values across group, with drug use (ecstasy user or non-drug user) serving as a between-subjects factor. Differences in prolactin and GH values over time and across groups were examined via two-way repeated measures repeated measures ANOVA, with time of collection (0, 15, 30, 60, 90 or 120 min post-drug) serving as repeated measure (within subjects factor) and drug use (ecstasy use versus no drug use) serving as a between-subjects factor.

Personality Measures - Scores on personality measures (TPQ, BDHI and MMPI scales in ecstasy users and controls were compared via student's t tests.

Mental Disorders - Student's t test was used to compare scores on the HDRS scale in ecstasy users with control scores. No formal analyses were reported for rates of diagnoses from the SDIP.

Personality Measures, Mental Disorders and Neuroendocrine Measures - Scores on personality measures were also correlated with AUCs for prolactin and growth hormone.

Neuroendocrine Responses and Drug Use Parameters - AUCs for prolactin and growth hormone were correlated with overall (lifetime) uses of ecstasy.

Results - Significant Differences Found: Neuroendocrine Response - Bromocryptine significantly increased prolactin release in ecstasy users and controls. Bromocryptine significantly released growth hormone in controls, but only a trend for higher growth hormone after bromocryptine was seen in ecstasy users. Ecstasy users had significantly lower growth hormone AUCs compared to non-drug using controls (ecstasy users < controls). At 120 min post-drug, GH was much higher than baseline in non-drug using controls, whereas it was significantly lower at this point in time in ecstasy users.

Personality Measures - Ecstasy users had significantly higher scores than non-drug user controls on the MMPI D (depression) scale and on the HDRS. Ecstasy users had higher TPQ Novelty Seeking scores than did non-user controls. BDHI "guilt," and "direct aggressiveness" scale scores were both significantly higher in ecstasy users when compared with controls (ecstasy users > controls). Mental Disorders - Out of 12 ecstasy users, 3 were diagnosed with borderline personality disorder and 1 with avoidant personality disorder. Symptoms of avoidant personality disorder were seen in 2 / 12 ecstasy users without full diagnosis, and partial symptoms of antisocial personality disorder seen in 1/12 ecstasy user. None of the non-drug user controls were diagnosed with personality disorders.

Personality and Neuroendocrine Response - Prolactin AUC obtained after bromocryptine challenge was inversely correlated with novelty seeking in both ecstasy users and controls, with higher prolactin AUC associated with lower novelty seeking scores. Growth hormone AUCs obtained after bromocryptine were associated with novelty seeking in non-drug users, but not in ecstasy users.

Neuroendocrine Response and Drug Use Parameters - Growth hormone AUCs after bromocryptine challenge were inversely associated with total (lifetime) number of ecstasy uses, with attenuated GH release seen with increasing number of total number of ecstasy exposures.

Results - No Significant Differences: Neuroendocrine Response - Basal prolactin and growth hormone levels in ecstasy users were not significantly different from levels in non-drug user controls. Ecstasy users and non-drug users had similar prolactin AUCs, and ecstasy users and non-drug users did not significantly differ in the time course of their prolactin response to bromocryptine.

Personality measures - Ecstasy users and non-drug user controls did not differ on any other MMPI scale. Ecstasy users and non-drug user controls did not have any other significantly different scale scores on the BDHI (e.g. indirect aggression, hostility). TPQ "harm avoidance" and "reward dependence" were similar in ecstasy users and non-drug controls.

Personality and Neuroendocrine Response - Neither prolactin nor growth hormone AUCs were significantly associated with MMPI, HDRS, BDHI or other TPQ scores in ecstasy users or in non-drug user controls.

Neuroendocrine response and Drug Use Parameters - Prolactin AUCs after bromocryptine were neither positively nor negatively associated with lifetime number of ecstasy exposures.

Overall Effects: Male ecstasy users and non-drug users both exhibited an increase in prolactin release after bromocryptine challenge, but only non-drug user controls exhibited a significant increase in growth hormone post-challenge. There was only a trend for increased growth hormone after bromocryptine challenge in ecstasy users. Ecstasy users scored higher on the TPQ Novelty Seeking scale, HDRS depression rating scale and MMPI D (depression) scale than non-drug users, and they also had higher scores on some (but not other) BDHI scale scores. A greater number of ecstasy users were diagnosed with personality disorders than were non-user controls, including borderline, avoidant and (partial diagnosis) anti-social disorder. While higher prolactin AUC after bromocryptine was associated with lower novelty seeking in members of both groups, higher growth hormone AUCs were associated with greater novelty seeking only in non-drug users. Lower growth hormone AUCs were associated with a higher total (lifetime) number of exposures to ecstasy, an indication that blunted growth hormone response to the D2 agonist bromocryptine was associated with greater use of ecstasy. The authors contend that blunted growth hormone response without blunted prolactin response has precedence in studies of people with other conditions.

Comments: To date, this is the first comparison of ecstasy users with non-drug using controls on bromocryptine challenge. As with most reports from the same team (Gerra et al. 2000; Gerra et al. 2001), this paper is notable for employing continual urinary monitoring of drug intake, and offering a stronger verification of abstinence from drug use than reports relying on self-reports or urinary analysis conducted on the study day only. The authors interpret their findings as reflecting a direct effect of MDMA on dopamine function, but acknowledge that changes in 5HT2A receptors or pre-existing differences in the dopamine system might also account for different responses to bromocryptine challenge. Others (Meltzer and Reynolds 1999) have questioned the usefulness of neuroendocrine challenge studies in reflecting brain function, since changes in neuroendocrine response to a test drug is multiply determined. Greater frequency of personality disorders in ecstasy users suggests that at least some participants in this conditions suffered from pre-existing conditions, and it is not impossible for pre-existing conditions to be associated with changes in neuroendocrine function. Study limitations include small sample size, retrospective study design, unusually self-selected participants in the ecstasy user group (individuals seeking information or treatment for substance abuse), and restriction of study participation to men. Since time since last use of ecstasy was reported at three weeks before the study day, it is possible that changes in neuroendocrine response to bromocryptine reflect a transient phenomenon, possibly related to reduced number of 5HT2A receptors. As noted in a study by Reneman et al. (2002), MDMA-associated reductions in 5HT2A receptors increase again after a period of abstinence.