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Brain serotonin transporter binding in former users of MDMA (‘ecstasy’)

  • Sudhakar Selvaraj (a1), Rosa Hoshi (a2), Zubin Bhagwagar (a3), Naga Venkatesha Murthy (a4), Rainer Hinz (a5), Philip Cowen (a6), H. Valerie Curran (a2) and Paul Grasby (a7)...
Abstract
Background

Animal experimental studies have prompted concerns that widespread use of 3,4-methylenedioxymethamphetamine (MDMA; ‘ecstasy’) by young people may pose a major public health problem in terms of persistent serotonin neurotoxicity.

Aims

To determine the status of brain serotonin neurons in a group of abstinent MDMA users.

Method

We assessed the integrity of brain serotonin neurons by measuring serotonin transporter (SERT) binding using positron emission tomography (PET) and [11C]DASB in 12 former MDMA users, 9 polydrug users who had never taken MDMA and 19 controls who reported no history of illicit drug use.

Results

There was no significant difference in the binding potential of [11C]DASB between the groups in any of the brain regions examined.

Conclusions

To the extent that [11C]DASB binding provides an index of the integrity of serotonin neurons, our findings suggest that MDMA use may not result in long-term damage to serotonin neurons when used recreationally in humans.

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Copyright
Corresponding author
Correspondence: Paul Grasby, PET Psychiatry, Cyclotron Building, MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital, London W12 0NN, UK. Email: paul.grasby@csc.mrc.ac.uk
Footnotes
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Declaration of interest

P.G. has received occasional consultancy for GlaxoSmithKline (GSK), MERCK, Pfizer and GE Healthcare. P.C. is an MRC Clinical Scientist. N.V.M. is a GSK employee and holds GSK shares. Z.B. has served on the speakers' panel of BMS, AstraZenaca and Janssen.

Footnotes
References
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Brain serotonin transporter binding in former users of MDMA (‘ecstasy’)

  • Sudhakar Selvaraj (a1), Rosa Hoshi (a2), Zubin Bhagwagar (a3), Naga Venkatesha Murthy (a4), Rainer Hinz (a5), Philip Cowen (a6), H. Valerie Curran (a2) and Paul Grasby (a7)...
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eLetters

Lack of long-term effect of �ecstasy� use on serotonin binding fits with known risk profile of MDMA

Teri S. Krebs, Research fellow
07 April 2009

Selvaraj et al. found no evidence of effects on serotonin transporter binding in the brains of former heavy users of ecstasy (an unregulated street-drug version of (+/-)-3,4-methylenedioxymethamphetamine; MDMA), with lifetime use between 60 and 864 tablets and abstinence between 390 and 1825 days.

These findings fit well with a recent prospective study that found no changes in serotonin transporter binding after initial use of ecstasy (1). A recent report by the UK Academic Council on Misuse of Drugs (ACMD) concluded that any effect of MDMA on human serotonin functioning appears small and temporary (2).

A few days of exposure to ethanol is known to kill brain cells in laboratory animals. In contrast, low doses of MDMA have few long-term effects in animals, and even high or repeated doses of MDMA do not typically destroy neurons but rather may induce temporary or prolonged changes in various measures of serotonin functioning (3). Serotonin transporters are regulated by many feedback loops, and serotonin functioning is known to fluctuate in response to anti-depressants, time of year, and other factors. Thus, any differences in serotonin functioning in ecstasy users should not be assumed to represent neuronal damage but may be pre-existing or due to adaptive plasticity (3).

The ACMD report also notes the low incidence of serious adverse effects among ecstasy users, with approximately one death per two million ecstasy tablets consumed in the UK, and most ecstasy-related deaths also involved alcohol or other dangerous drugs (2). According to the ACMD, overall risks from illicit ecstasy are similar to amphetamine, but with less potential for compulsive use, or for risky and aggressive behavior, or for psychiatric and cognitive problems (2). Retrospective surveys have found small, clinically-insignificant associations between ecstasy use and depression and memory deficits (2). These non-randomized surveys mostly ignored potential confounders that may explain both repeated ecstasy use and mood and cognitive problems, such as childhood anxiety and depression (4).

Research priorities are guided by a public health perspective. Exposure to industrial chemicals, some prescription drugs, alcohol, and childhood poverty and neglect are all likely far more significant causes of brain damage than exposure to ecstasy.

Taken together, the Selvaraj et al. study and the ACMD report are reassuring to the millions of people who have taken moderate amounts of ecstasy. These findings add to the many clinical and preclinical studies that indicate, in the judgment of health authorities in the UK and elsewhere, a favorable risk-benefit profile of a few doses of pharmaceutical MDMA, administered in scientific research, with appropriate medical screening and supervision, as seen in numerous completed and on-going trials of MDMA in healthy volunteers and anxiety patients. Future neuroimaging studies could explore the biological basis of the noteworthy, and potentially medically useful, effects of MDMA on affiliation and emotional regulation (5).

References

1. de Win MM, Jager G, Booij J, Reneman L, Schilt T, Lavini C, Olabarriaga SD, den Heeten GJ, van den Brink W. Sustained effects of ecstasy on the human brain: a prospective neuroimaging study in novel users. Brain 2008; 131:2936-45. [Pubmed 18842607]2. Advisory Council on the Misuse of Drugs. MDMA (ecstasy): a review of its harms and classification under the Misuse of Drugs Act 1971. Home Office, 2009. http://drugs.homeoffice.gov.uk/publication-search/acmd/mdma-report3. Baumann MH, Wang X, Rothman RB. 3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings. Psychopharmacology (Berl) 2007; 189:407-24. [Pubmed 16541247]4. Huizink AC, Ferdinand RF, van der Ende J, Verhulst FC. Symptoms of anxiety and depression in childhood and use of MDMA: prospective, population based study. BMJ 2006; 332:825-8. [Pubmed 16500927]5. Johansen P, Krebs T. How could MDMA (ecstasy) help anxiety disorders? A neurobiological rationale. J Psychopharmacol 2009 (in press). [Pubmed 19273493]Declaration of interest

TS Krebs has previously received funding support from the US nonprofit Multidisciplinary Association of Psychedelic Studies (www.maps.org), sponsor of clinical research on MDMA. PØ Johansen is director of Evidence Knowledge Exchange (www.evidence.no), a Norwegian nonprofit offering continuing education courses.

Teri S. Krebs, Dept of Neuroscience, and Pål-Ørjan Johansen, Dept of Psychology, Norwegian University of Science and Technology (NTNU)
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Conflict of interest: None Declared

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