Are Ecstasy Induced Serotonergic Alterations Overestimated For The Majority Of Users?

This study compared survey data (Global Drug Survey, >11.000 participants who used ecstasy) to that of those included in brain imaging studies and found that the latter group fell within the top 5-10% of users of ecstasy, possibly overestimating use and serotonergic (transporter levels) effects/disturbance for the average user.

Abstract

Background: Neuroimaging studies imply that the regular use of ±3,4-methylenedioxymethamphetamine (MDMA), the major constituent of ecstasy pills, alters the brain’s serotonergic system in a dose-dependent manner. However, the relevance of these findings remains unclear due to limited knowledge about the ecstasy/MDMA use pattern of real-life users.

Aims: We examined the representativeness of ecstasy users enrolled in neuroimaging studies by comparing their ecstasy use habits with the use patterns of a large, international sample.

Methods: A systematic literature search revealed 10 imaging studies that compare serotonin transporter levels in recreational ecstasy users to matched controls. To characterize the ecstasy use patterns we relied on the Global Drug Survey, the world’s largest self-report database on drug use. The basis of the dose comparison were the Usual Amount (pills/session), Use Frequency (sessions/month) and Dose Intensity (pills/year) variables.

Results: Both the average Usual Amount (pills/session) and Use Frequency (sessions/month) of neuroimaging study participants corresponded to the top 5–10% of the Global Drug Survey sample and imaging participants, on average, consumed 720% more pills over a year than the Global Drug Survey participants.

Conclusions: Our findings suggest that the serotonin brain imaging literature has focused on unusually heavy ecstasy use and therefore the conclusions from these studies are likely to overestimate the extent of serotonergic alterations experienced by the majority of people who use ecstays.”

Authors: Balázs Szigeti, Adam R Winstock, David Erritzoe & Larissa J. Maier

Summary

Introduction

MDMA is an empathogenic stimulant that is the major constituent of ecstasy pills. A number of clinical studies have demonstrated the efficacy of MDMA-assisted psychotherapy for the treatment of post-traumatic stress disorder.

MDMA increases serotonergic neurotransmission, inhibits presynaptic reuptake of serotonin, increases levels of serotonin and its metabolite, and increases cortisol, oxytocin, vasopressin and dopamine. Ecstasy use is associated with decreased SERT levels, which suggests that MDMA plays a causal role.

The long-term impacts of MDMA use on the brain have been heavily reliant on SERT imaging studies. However, how representative are these studies of the wider ecstasy user population?

Neuroimaging studies suggest that MDMA alters the brain’s serotonergic system in a dose-dependent manner.

We compared the ecstasy use patterns of real-life users with a large, international sample.

We used the Global Drug Survey to compare serotonin transporter levels in recreational ecstasy users to matched controls. Ecstasy users consumed 720% more pills over a year than matched controls.

Conclusions: The findings suggest that the serotonin brain imaging literature has focused on unusually heavy ecstasy use.

Studies suggest that ecstays may alter serotonergic function.

This paper compares the ecstasy use of SERT imaging study participants with the use parameters reported by respondents to the Global Drug Survey.

Global Drug Survey

The Global Drug Survey (GDS) is a large quantitative anonymous web survey that aims to identify emerging trends in legal and illicit drug use as well as associated harms. It was conducted in November and December 2014 and recruited a non-probability sample.

This study included 11,168 GDS participants who reported at least one occasion of ecstasy pill use in the previous year. The participants were asked about their Usual Amount and Use Frequency, and people who have experimented with the drug more than a year ago are counted as non-users.

Search strategy and inclusion criteria for neuroimaging studies

We included studies that reported participant data on the Usual Amount (pills/session) and Use Frequency (sessions/month) of MDMA/ecstasy users versus non-using controls. The Use Frequency was estimated from the Usual Amount, Lifetime Exposure (pills) and Time of Use (months).

In total, 292 publications were retrieved, 23 were further examined after abstract screening, and 18 relevant SERT imaging studies were identified. A total of 10 SERT imaging studies were included in the dose comparison.

Characterization of ecstasy use patterns

The GDS records the Usual Amount (pills/session) and the Use Frequency (sessions/month) of ecstasy used, and the SERT imaging studies consistently described Lifetime Exposure (pills) and Time of Use (months) along with the Usual Amount.

We constructed a new variable, the Dose Intensity, which is calculated by multiplying the mean Use Frequency and mean Usual Amount.

Dose IntensityU» 12 sual Amount UseFrequency

We defined the Intensity ratio as the proportion of ecstasy pills used throughout a year by SERT imaging study participants relative to the GDS sample.

Intensity ratio = DI neuroimaginggroup / DI GDS

In GDS 2015, Use Frequency was a categorical variable. To numerically analyze the data, the categorical data were converted to numeric values and the mean value was carried into the calculations.

SERT imaging studies have often examined the possibility of SERT recovery, therefore people with recent use of ecstasy were included in the sample.

MDMA content of ecstasy pills

All three agencies have a laboratory with several analysis instruments that allow for quantitative analyses of drugs submitted by users. The data presented here are based on pills that contained a quantifiable amount of MDMA.

SERT imaging studies of ecstasy users

We performed a systematic literature search to identify SERT imaging studies of ecstasy users and included 10 studies. The participants’ drug history was reported for each study.

Comparison of ecstasy use patterns

The ecstasy use habits of the neuroimaging study participants were compared with those of 11,168 recreational ecstasy users who participated in the GDS.

In the GDS sample, average Usual Amount and Use Frequency were 1.5 pills/session and 0.67 sessions/month, resulting in an estimated Dose Intensity of 12.2 pills/year. In contrast, average Usual Amount and Use Frequency of neuroimaging study participants were 2.7 pills/session and 2.6 sessions/month, resulting in an estimated Dose Intensity of 87.3 pills/year.

Variable MDMA content of ecstasy pills

Ecstasy pills have variable MDMA content, and the mean amount of MDMA in ecstasy pills has increased steadily since 2009 (when the GDS data were collected). This increase is consistent with a recent report by the European Monitoring Centre for Drugs and Drug Addiction.

Discussion

The novel contribution of this paper is twofold: first, we have presented ecstasy use pattern data for the GDS sample, and second, we have used this data to compare the ecstasy use habits of the GDS sample with those of ecstasy users in PET/SPECT imaging studies.

The dose-response relationship between MDMA exposure and SERT reductions suggests that people with a history of low and moderate ecstasy use are less affected than heavy users, but further investigation is needed with ecstasy/MDMA users representative of the real-world user population.

Most studies administer 125 mg of MDMA during 2 – 4 separate sessions, so chronic serotonergic alterations are unlikely.

PET studies report decreased SERT binding levels. The exact cause of this decrease is uncertain, but it may be caused by adaptive internalization of SERT as opposed to neuronal damage.

Most people who use ecstasy/MDMA also use other drugs that may be interacting with the serotonin system. Furthermore, ambient temperature and possibly other environmental variables also modulate the drug’s effect on the serotonin system.

The increase in MDMA content of ecstasy pills is only a fraction of the observed 720% difference in the average Dose Intensity, and thus the difference between the GDS and neuroimaging groups is unlikely to be explained by the large amount of MDMA in modern pills.

The GDS sample has a mean Use Frequency of 8 use/year, with 45% of users using ecstasy only 1 – 2 times annually. The likely causes of this use pattern are the quick development of tolerance and the long time it takes to recover after use.

Our investigation suffers from a number of limitations, including the fact that the GDS is a non-random, self-selected sample, and that there is no forensic evidence that the GDS participants’ ecstasy pills have contained MDMA and/or other substance(s).

The dose comparison was based on measures of intensity of ongoing ecstasy use, but not duration. The high Usual Amount for the neuroimaging participants likely reflects a building up of tolerance.

Researchers have shown that ecstasy use can decrease SERT and cause memory related and other cognitive deficits, but participants are generally normal in behaviour and have normal or close to normal cognitive performance.

We concluded that serotonin brain imaging studies have focused on unusually heavy ecstasy use and that further neuroimaging studies should be undertaken with more representative ecstasy/MDMA users.

Study details

Compounds studied
MDMA

Topics studied
Safety

Study characteristics
Literature Review

Authors

Authors associated with this publication with profiles on Blossom

Balazs Szigeti
Balazs Szigeti is involved in the Imperial College London-Beckley self-blinding microdosing study that at this moment hasn't found significant effects of microdosing.

David Erritzoe
David Erritzoe is the clinical director of the Centre for Psychedelic Research at Imperial College London. His work focuses on brain imaging (PET/(f)MRI).