Elsevier

Biological Psychiatry

Volume 47, Issue 2, 15 January 2000, Pages 127-136
Biological Psychiatry

Original Articles
Long-lasting effects of (±)3,4-methylene-dioxymethamphetamine (Ecstasy) on serotonin system function in humans

https://doi.org/10.1016/S0006-3223(99)00180-8Get rights and content

Abstract

Background: Fifteen (±)3,4-Methylenedioxymethamphetamine (MDMA) users, who did not show other drug dependencies or prolonged alcohol abuse, and 15 control subjects were included in the study.

Methods: Prolactin (PRL) and cortisol (CORT) responses to the serotonergic agonist d-fenfluramine (D-fen), clinical psychobehavioral changes, and psychometric measures were evaluated 3 weeks and then 12 months after MDMA discontinuation.

Results: MDMA users showed significantly reduced PRL and CORT responses in comparison with control subjects at 3 weeks (respectively, p < .001; p < .005). The responses of PRL to D-fen were unmodified at 12 months after prolonged abstinence and were significantly reduced in comparison with controls (p < .001). In contrast, CORT responses in MDMA users were restored after 12 months of abstinence, with significantly higher responses to D-fen, in comparison with 3-week responses (p < .05). MDMA users’ high scores on the Novelty Seeking (NS) scale on the Tridimensional Personality Questionnaire (TPQ) appeared unchanged by long-term abstinence. In contrast, Buss Durkee Hostility Inventory (BDHI) (Buss and Durkee 1957) direct and guilt scores decreased significantly after 12 months of abstinence. PRL AUCs at 12 months were inversely correlated with the measures of MDMA exposure (r = −.538).

Conclusions: Our data indicate long-lasting 5-HT system impairment in abstinent MDMA users although the hypothesis of serotonergic changes attributable to a premorbid condition cannot be excluded. CORT restored responses to D-fen at 12 months, and the correlation of neuroendocrine changes with MDMA exposure suggest that the neuroendocrine impairment may be due to a partially reversible neurotoxic action of MDMA on the human brain.

Introduction

The substance (±)3,4-methylenedioxymethamphetamine (MDMA or “Ecstasy”) seems to be able to induce serotonin (5-HT) neuron impairment in experimental animals at doses that closely approximate those used by humans. MDMA affects serotonergic neuron function (Schuldiner et al 1993), particularly at the synaptic level Insel et al 1989, O’Hearn et al 1988, Rudnick and Wall 1992, Rudnick and Wall 1993, with significant changes in the reuptake system of brain monoamines (De Souza et al 1990). Serotonergic neurotoxicity after MDMA and denervation has been suggested by a variety of studies Ricaurte et al 1992, Robinson et al 1993 with contrasting findings concerning the possible reversibility of brain damage.

Animals treated with MDMA develop persistent losses in various markers of 5-HT axons, including 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), tryptophan hydroxylase, and the 5-HT transporter Commins et al 1987, Insel et al 1989, Molliver et al 1990, O’Hearn et al 1988, Ricaurte et al 1988, Schmidt 1987, Slikker et al 1988, which suggests a distal axotomy of central 5-HT neurons (McCann et al 1998). In primates, the loss of 5-HT axonal markers is long lasting Insel et al 1989, Ricaurte et al 1988 and may, in some brain regions, be permanent Fischer et al 1995, Ricaurte et al 1992.

Few data are available in the literature concerning MDMA effects on the human brain. Cerebro-spinal fluid (CSF) findings in humans, suggesting that 5-HT neurotoxicity may be a complication of MDMA use, have been reported by McCann et al (1994). More recently, our neuroendocrine study demonstrated the impairment of the serotonergic system in MDMA users who were abstinent for a few weeks, as well as the inverse correlation of serotonin function measures with aggressiveness and novelty seeking scores in these patients (Gerra et al 1998).

Increased evidence of amphetamine-derived neurotoxicity in humans has been found utilizing PET with the radioligand carbon-11-labeled McN-5652, which selectively labels the 5-HT transporter. Abstinent MDMA users showed decreased global and regional brain 5-HT transporter binding compared with control subjects. Decreases of this structural component of brain 5-HT neurons positively correlated with the extent of previous MDMA use (McCann et al 1998).

In agreement with the biological findings, many of the adverse neuropsychiatric consequences noted after MDMA involve behavioral domains that are putatively influenced by brain serotonin (e.g., mood, cognition, and anxiety) (Steele et al 1994). A few hours after the last use of MDMA, for example, users have reported feeling significantly more depressed, abnormal, unsociable, unpleasant, and ill-tempered than control subjects. Cognitive performance was significantly reduced in MDMA-exposed subjects. Memory recall was also significantly impaired in drug-free MDMA users, with regular MDMA users displaying the worst memory scores at every test session (Parrott and Lasky 1998). In another study reporting similar results, the extent of memory impairment correlated with the degree of MDMA exposure and the reduction in brain 5-HT, as indexed by CSF 5-HIAA (Bolla et al 1998).

Some cases of depersonalization, dysphoria, and depression with suicidal thoughts and mental anorexia were observed after chronic MDMA use Greer and Tolbert 1986, Nichols 1986, Wodarz and Boning 1993, in accord with the hypothesis of possible serotonin system dysfunction in these subjects. MDMA users also were found to exhibit elevated impulsivity; those who had taken the most MDMA had the most elevated trait impulsiveness scores. These findings are consistent with previous evidence that elevated levels of impulsivity in humans are associated with reduced levels of serotonergic function (Morgan et al 1998). At the moment, several findings obtained in humans suggest that MDMA use can lead to persistent changes in CNS structures (Allen et al 1993), but the data concerning the possible reversibility of MDMA-induced brain dysfunction are very scarce. Furthermore, the relationships between long-lasting neuroendocrine changes and premorbid conditions, with their biological correlates, were not studied extensively.

The aim of the present study was to investigate in MDMA users the possible reversibility (after 12 months of abstinence) of changes in serotonergic system function as evidenced during the early phase after MDMA discontinuation (Gerra et al 1998). Subjects were administered a d-fenfluramine challenge (a specific serotonergic stimulus) (Preziosi et al 1983) 3 weeks and again 12 months after they stopped MDMA use, in comparison with healthy control participants. All participants underwent extensive clinical psychiatric diagnosis and psychometric measures during the first month and again after 12 months of abstinence from MDMA. The results were correlated with the biological measures, their variations, and time and number of MDMA exposures.

Section snippets

Study participants

Fifteen male MDMA users, aged 18–26 years (M±SD = 21.8 ± 3.3 years), with a history of at least 25 occasions of drug use (M±SD = 69.3 ± 38.0; range 25–95) prior to drug interruption entered the study. All the participants gave informed consent. The participants included in the study used MDMA only on weekend nights, 1–2 pills each use. In the Italian illicit market, the variability of MDMA concentration is from 25 mg to 125 mg (Bellomo 1995). The duration of MDMA use was from 8 to 25 months

Results

Psychological data (mean score ± SE) obtained by the MMPI II, BDHI, HDRS, and TPQ at 3 weeks and 12 months of abstinence are reported in Table 2. MDMA users showed significantly higher scores than control subjects at MMPI subscale D both at 3 weeks (df = 1;28; F = 18.628; p < .001) (Bonferroni correction: p = .0002) and at 12 months after drug discontinuation (df = 1;28; F = 5.9; p < .05) (Bonferroni correction: p = .032). No other significant differences between MDMA users and control

Discussion

The present findings increase the evidence regarding long-lasting impairment of brain 5-HT function in MDMA users. Blunted PRL responses to the serotonergic agonist in MDMA users were demonstrated both in participants who had abstained from use of MDMA for 3 weeks before the study, which accords with our previous data (Gerra et al 1998), and in the same sample studied after 12 months of MDMA abstinence.

Although the lack of serotonergic responses evident in our experiment was related to the

Acknowledgements

The research was supported by a grant of the Drug Addiction Bureau, Addiction Service of the Emilia Romagna Region.

References (49)

  • G Battaglia et al.

    3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brainQuantification of neurodegeneration by measurement of [3H]paroxetine-labelled serotonin uptake sites

    J Pharmacol Exp Ther

    (1987)
  • Bellomo RD (1995): Aspetti di polizia scientifica. In: Atti del Seminario Studi sui Derivati Amfetaminici. Rome:...
  • D.W Black et al.

    Personality disorder in obsessive-compulsive volunteers, well comparsion subjects, and their first-degree relatives

    Am J Psychiatry

    (1993)
  • K.I Bolla et al.

    Memory impairment in abstinent MDMA (“Ecstasy”) users

    Neurology

    (1998)
  • A.H Buss et al.

    An inventory for assessing different kinds of hostility

    J Consult Psychol

    (1957)
  • P Castrogiovanni et al.

    Aggressive behaviour and hostility in depressionClinical aspects

  • W Chappell et al.

    Extrapolation of toxicological and pharmacological data from animals to humans

  • C.R Cloninger

    A systematic method for clinical description and classification of personality variants

    Arch Gen Psychiatry

    (1987)
  • E.F Coccaro et al.

    Serotonin in Major Psychiatric Disorders

    (1990)
  • D.L Commins et al.

    Biochemical and histological evidence that methylenedioxymethamphetamine (MDMA) is toxic to neurons in the rat brain

    J Pharmacol Exp Ther

    (1987)
  • E.B De Souza et al.

    Neurotoxic effect of MDMA on brain serotonin neuronsEvidence from neurochemical and radioligand binding studies

    Ann N Y Acad Sci

    (1990)
  • Fava M, Guaraldi GB, Mazzi F, Rigatelli M (1993): Intervista Clinica Strutturata per il DSM-III-R, Florence:...
  • C.A Fischer et al.

    Reorganization of ascending serotonin axon projections in animals previously exposed to the recreational drug 3,4-methylenedioxymethamphetamine

    J Neurosci

    (1995)
  • G Gerra et al.

    Serotonergic function after (±)3, 4-methylene-dioxy-methamphetamine (MDMA, “Ecstasy”) in humans

    Int Clin Psychopharmacol

    (1998)
  • Cited by (130)

    • Increased cortisol levels in hair of recent Ecstasy/MDMA users

      2014, European Neuropsychopharmacology
      Citation Excerpt :

      Yet cortisol is a labile and reactive hormone, and its release is also stimulated by physical and psychological stressors. Gerra et al.'s (2000, 2003) earlier cortisol findings are consistent with deficits in reactive homoeostasis. This could help explain why abstinent Ecstasy/MDMA users reported feeling more stressed and less calm, than non-user controls (Scholey et al., 2011; Wetherell et al., 2012).

    • The Neuropathology of Drug Abuse

      2013, The Effects of Drug Abuse on the Human Nervous System
    • MDMA, serotonergic neurotoxicity, and the diverse functional deficits of recreational 'Ecstasy' users

      2013, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      Schifano et al. (1998) provided psychiatric assistance for Ecstasy-related problems, to 150 young recreational users attending a drug addiction centre. Gerra et al. (2000) provided ‘a long term psychosocial rehabilitation programme’, for problematic Ecstasy/MDMA users referred to another Italian drug treatment clinic. An important difference between MDMA and the other recreational stimulants, such as amphetamine, methamphetamine, or cocaine, is that Ecstasy/MDMA users typically quit on their own.

    • MDMA: Interactions with other psychoactive drugs

      2011, Pharmacology Biochemistry and Behavior
    View all citing articles on Scopus
    View full text