MAPS Neuroimaging in moderate MDMA use: A systematic review

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Neuroimaging in moderate MDMA use: A systematic review
F. Muellera, C. Lenza, M. Steinera, P.C. Dolderb, M. Waltera, U.E. Langa, M.E. Liechtib, S. Borgwardta

Received 2 October 2015, Revised 11 November 2015, Accepted 19 December 2015, Available online 30 December 2015

Highlights

• Systematic neuroimaging review of moderate MDMA use in humans
• No effect of moderate MDMA use on brain structure and function
• High methodological heterogeneity and small sample sizes

Abstract

MDMA (“ecstasy”) is widely used as a recreational drug, although there has been some debate about its neurotoxic effects in humans. However, most studies have investigated subjects with heavy use patterns, and the effects of transient MDMA use are unclear. In this review, we therefore focus on subjects with moderate use patterns, in order to assess the evidence for harmful effects. We searched for studies applying neuroimaging techniques in man. Studies were included if they provided at least one group with an average of < 50 lifetime episodes of ecstasy use or an average lifetime consumption of < 100 ecstasy tablets. All studies published before July 2015 were included. Of the 250 studies identified in the database search, 19 were included.

There is no convincing evidence that moderate MDMA use is associated with structural or functional brain alterations in neuroimaging measures. The lack of significant results was associated with high methodological heterogeneity in terms of dosages and co-consumption of other drugs, low quality of studies and small sample sizes.

Keywords
MDMA; ecstasy; 3,4-methylenedioxymethamphetamine; neuroimaging; MRI; chronic effects; adverse effects; neurotoxicity; moderate use


1. Introduction

MDMA (3,4-methylenedioxymethamphetamine) is the most common psychoactive component of illicit drugs sold as “ecstasy”. Like other amphetamines, MDMA influences the dopamine and norepinephrine systems, but also shows strong serotonergic effects (Liechti and Vollenweider, 2001). Because of this serotonergic component, MDMA exhibits some mental effects that differ qualitatively from other amphetamine-type stimulants (Schmid et al., 2014) and for this reason MDMA has been classified as an “entactogen” (Nichols, 1986). This term can be translated as “producing a touch within”, which describes a state of consciousness characterised by increased openness, positive mood and calmness (Dumont and Verkes, 2006). MDMA was first mentioned in a patent of the German pharmaceutical company Merck in 1912, but was not widely known until its rise as a recreational drug in the 1980s. Today, MDMA is one of the most commonly used illicit drugs, especially in Oceania, North America and Europe, where prevalences of between 0.5 and 2.9% have been reported (UNODC, 2014). MDMA is currently often sold as crystals of relatively high purity (EMCDDA, 2015).

For over 20 years, there has been an ongoing debate about possible neurocognitive alterations in MDMA users and concerns that MDMA may be neurotoxic - especially to serotonergic neurons (Parrott, 2013). Many neuroimaging studies in MDMA consumers have been published. Most of these studies investigated samples with heavy use patterns, reflected in cumulative lifetime doses of hundreds or even thousands of consumed units and typically co-use of many other substances. However, use of MDMA is an incidental and transient phenomenon for most consumers and these studies therefore do not describe this large cohort appropriately (von Sydow et al., 2002 and Webb et al., 1996). Only 15% of all MDMA users show considerable or heavy use patterns and approximately 80% of occasional users stop their use of MDMA and related drugs in their twenties (von Sydow et al., 2002). Moreover, there is increasing evidence that MDMA may be useful in psychotherapy, especially in the treatment of posttraumatic stress disorder (Mithoefer et al., 2011 and Oehen et al., 2013). In this approach, MDMA is used as an additive in a psychotherapeutic setting and its administration is restricted to a few, typically 2-5, therapeutic sessions. Given the controversial debates surrounding MDMA, this approach, unsurprisingly, has been questioned (Parrott, 2014). Therefore, results on moderate MDMA use might also be informative for this debate.

In the present study, we systematically reviewed structural, functional and neurochemical brain imaging studies in moderate MDMA users, as defined by an average cumulative lifetime use of <50 lifetime episodes of ecstasy use or a lifetime consumption of <100 ecstasy tablets.


2. Methods

To ensure high quality reporting, we adhered to the recommendation for systematic reviews of the PRISMA statement (Moher et al., 2015).


2.1. Search strategy

Electronic search was performed using the PubMed database. The following search term was used: (mdma OR ecstasy OR 3,4-methylenedioxymethamphetamine) AND (mri OR fmri OR pet OR spect OR imaging OR neuroimaging). All studies published before July 2015 were included, without any language restriction. Additionally, the reference lists of all included studies identified in the database search were manually screened for relevant studies.


2.2. Selection criteria and study selection

Inclusion criteria were 1) original publication in a peer-reviewed journal, 2) observational or interventional study design, 3) application of structural, functional or neurochemical neuroimaging techniques, 4) investigation of non-acute effects of MDMA on the human brain, 5) inclusion of at least one group with an average of <50 lifetime episodes of ecstasy use or an average lifetime consumption of <100 ecstasy tablets. After inspection for duplicates, the titles and abstracts of all records were reviewed. Publications that clearly did not meet inclusion criteria were excluded. The decision for inclusion or exclusion of the publications was made on the basis of a review of the full texts. The whole process was conducted by two reviewers (FM, MS) independently. In case of disagreement, reviewers discussed their reasons for initial inclusion and exclusion. If consensus was not reached, a third reviewer (CL) was included.


2.3. Recorded variables, data extraction and analysis

The recorded variables for each article included in the review were: centre where the study was performed, authors and year of publication, study design, imaging method, number of subjects, number of subjects overlapping with other included studies, age, gender distribution, cumulative lifetime exposure to ecstasy (tablets, episodes, dosage in mg), usual MDMA dose per occasion, maximum MDMA dose per occasion, age at onset of MDMA use, time since last MDMA use, duration of MDMA use, control group matched for use of other drugs, required abstinence from alcohol, nicotine, cannabis and other (illicit) drugs, domains tested, regions analysed, statistical thresholds and principle findings (user group vs. controls and within-group results). When data were missing but computation based on the original publication was possible, the missing values were calculated and included in the review. If necessary, units were transformed. If overlaps between subjects were suspected but the original publications did not contain information on that topic, we contacted the authors and included the obtained data in the review.


2.4. Standardisation of data on lifetime ecstasy use

The data on lifetime ecstasy use provided in the included studies were heterogeneous (tablets, episodes, dosage in mg). In order to obtain comparable results, we performed an additional search for articles providing information about the content of MDMA in ecstasy tablets. Additionally, we calculated the mean number of tablets consumed per episode, on the basis of the data provided in the studies included in this review.

Three studies, with a total sample of 1149 tablets, were identified between 1991 and 2006 (Table 1). Tablets sold as ecstasy had a weighted mean of 76 mg per tablet.

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