MDMA and brain activity during neurocognitive performance: An overview of neuroimaging studies with abstinent ‘Ecstasy’ users

This systematic review (2018) examines the long-term effects of MDMA on neurocognitive performance amongst abstinent ecstasy users and found evidence of hemodynamic and electrophysiological changes in the prefrontal brain regions that is reflective of increased cognitive effort to maintain performance levels during executive functions.

Abstract

“Introduction: MDMA/Ecstasy has had a resurgence in popularity, with recent supplies comprising higher strength MDMA, potentially leading to increased drug-related harm. Neurocognitive problems have been widely reported in ecstasy users, equally some studies report null findings, and it remains unclear which factors underlie the development of neurocognitive impairments.

Methods: This review covers the empirical research into brain activity during neurocognitive performance, using fMRI, fNIRS, and EEG.

Results: Our main conclusion is that chronic repeated use of recreational ecstasy can result in haemodynamic and electrophysiological changes that reflect recruitment of additional resources to perform cognitive tasks.

Discussion: Findings are consistent with serotonergic system changes, although whether this reflects neurotoxicity or neuroadaptation, cannot be answered from these data. There is a degree of heterogeneity in the methodologies and findings, limiting the strengths of current conclusions. Future research with functional neuroimaging paired with molecular imaging, genetics or pharmacological challenges of the serotonin system may help to decipher the link between serotonergic and cognitive changes in ecstasy users.”

Authors: Carl A. Roberts, Boris B. Quednow, Catharine Montgomery & Andrew C. Parrott

Summary

MDMA/Ecstasy use has increased in popularity, potentially leading to increased drug-related harm. Neurocognitive problems have been reported in ecstasy users, but the cause remains unclear.

Recreational ecstasy use has recently undergone a resurgence in popularity, and poses a serious public health concern. Harm reduction strategies are thus urged to target novice users who are consuming high strength MDMA without being aware of the related psychological and psychobiological harm.

MDMA is a stimulant and empathogen drug, which can generate powerful feelings of euphoria and closeness to others. It has been shown to cause serotonin neurotoxicity in rats, monkeys, and other animal species, and lower indices of serotonin activity in humans.

MDMA use leads to chronic reductions in neocortical serotonin signalling. This is likely due to distal axotomy, the loss of synaptic terminals from the long-fine serotonin axons terminating in the higher brain regions, or other changes such as neuroplasticity.

In the following sections, studies are reviewed that investigated the link between brain functions and cognitive performance in human MDMA users using molecular imaging, functional neuroimaging, electroencephalography, and near-infrared spectroscopy.

2. Molecular imaging studies with cognitive performance measures

Reneman et al. (2000) investigated whether MDMA use produced alterations to post-synaptic 5-HT2A receptors and memory function. They found that MDMA users had higher binding ratios of 5-HT2A receptors and lower performance on a verbal memory test.

Current MDMA users had lower serotonin transporter densities than controls, but no significant differences were observed between former users and controls. Memory function was also poorer in both ecstasy user groups relative to controls.

McCann et al. (2008) conducted PET using [11C]DASB to investigate serotonin receptor (SERT) binding, alongside [11C]WIN 35,428 to investigate dopamine transporter (DAT) binding. They found that SERT binding was significantly reduced in multiple brain regions for MDMA users relative to controls, and that memory performance was also correlated with SERT binding.

Kish et al. (2010) found significant SERT binding reductions in the cerebral cortex and hippocampus of moderate Ecstasy users, compared to 50 nonuser controls. The reductions were not related to structural brain changes, polydrug use, blood testosterone or estrodial levels, gender, psyvholoical health or SERT gene polymorphism.

An imaging study in 19 male MDMA users and 19 male drug-nave controls revealed that MDMA users showed significantly decreased regional cerebral brain glucose metabolism, and that memory deficits related to MDMA use arise from a combined fronto-parieto-mediotemporal dysfunction.

Several studies have reported neurocognitive performance changes that are in parallel with serotonergic and metabolic adaptations following repeated use of MDMA. These studies have used PET and SPECT imaging to detect neuronal adaptation prior to functional deficits manifesting themselves.

3. fMRI studies and neurocognitive performance (Table 1)

In a functional imaging experiment with ecstasy users, Daumann et al. (2003a) found no differences in activation between groups at any level of the task, and no correlation between extent of previous drug use and BOLD signal changes.

In a similar fMRI/n-back study, Daumann et al. (2003b) found that pure MDMA users showed lower activation than both ecstasy polydrug users and healthy controls in the angular gyrus, suggesting that MDMA-induced neurotoxicity is associated with altered fMRI patterns.

A longitudinal study from the same research group found that ecstasy users showed increased activation in two clusters in the parietal cortex during the most difficult level of the n-back task, compared to baseline, at time 2. This suggests a role for higher nightly doses in neuronal damage. This longitudinal study of 30 participants found that continued use of amphetamines can lead to further neuronal changes, despite equivalent task performance between time 1 and time 2.

Moeller et al. (2004) studied activation in 15 MDMA users and 19 controls, and found that MDMA users displayed significantly greater BOLD activation in the left medial and superior frontal gyri, the left thalamus and right hippocampal gyrus. MDMA users had greater activation in the hippocampus than control subjects, despite equivalent performance in an n-back working memory task. Ecstasy users had restricted activation in the hippocampus relative to controls, despite performing at an equivalent level in an episodic memory retrieval task. A prospective study assessed hippocampal function in 40 ecstasy users who had minimal exposure to ecstasy and amphetamine at time 1, and 17 participants who continued ecstasy but had limited amphetamine use 12 months later.

In a study by Jager et al. (2008), 71 participants were assessed for concomitant use of other drugs. Ecstasy use did not predict cognitive performance in any of the 3 domains being investigated, but did predict lower activation in the left DLPFC and higher activation in the right middle occipital gyrus.

Raj et al. (2010) assessed BOLD signal change in 12 ecstasy polydrug users during a semantic recognition task. They found that lifetime episodes of MDMA use and lifetime dose were inversely correlated with BOLD signal change at BA 9, 18 and 21/22, though no such correlations were observed for the encoding phase.

Watkins et al. (2013) found that ecstasy users had a decreased efficiency for semantic memory, with peak activation in the right superior parietal lobe correlated with lifetime dose of ecstasy.

Ecstasy users showed greater activity in the right middle and inferior frontal gyri, right middle frontal gyrus and right inferior parietal lobule, during successful response inhibitions (STOPS) on a Go/NoGo task, compared to controls. Ecstasy users also showed greater error activation in the right middle and inferior temporal gyri.

These data suggest that fMRI can be used as a sensitive measure of neuronal changes prior to the appearance of performance indicators of cognitive deficits. However, gaining concrete conclusions from the literature is problematic due to small sample sizes and lack of understanding of the direction of task performance.

4. fNIRS studies and neurocognitive performance (Table 2)

Functional NIRS is a novel functional imaging technique that uses near-infrared light to calculate amounts of circulating oxy and deoxy-Hb in the PFC. It has been used to assess neurocognition in ecstasy user populations. During an inhibitory control task, ecstasy users displayed increased oxy-Hb in several voxels compared to controls, and ecstasy use was a significant predictor of oxy-Hb increase in several voxels after controlling for alcohol and cannabis use indices.

5. Electroencephalograpy and sensory evoked potential stuides

In two similar studies, currently abstinent, long-term MDMA users showed a stronger gradient of their EEG response to increasing loudness of auditory stimuli compared to regular cannabis users as well as drug-naive controls. In a subsequent study, the loudness dependence of auditory evoked potentials (LDAEP) was assessed in 18 MDMA users without ascertaining a control group. The results were consistent with a serotonergic change/neurotoxicity of MDMA. In a subsequent study, Wan et al. (2009) found that MDMA-experienced polydrug users showed a stronger tangential dipole source activity with increasing loudness of the acoustic stimuli compared to non-MDMA drug users. Moreover, aggression scores were correlated with intensity stimulus dependence of the source activity.

Casco et al. (2005) investigated the amplitude and latency of visual evoked potentials (VEP) in small groups of heavy MDMA users, moderate MDMA users, and 18 drug-free control participants. They concluded that cortical activity associated with low levels of cognitive processing is altered after prolonged exposure to ecstasy.

6. Electroencephalography and event-related potential studies (Table 3)

Gamma et al. (2005) assessed event-related potentials in 16 current polydrug MDMA users and 17 MDMA-naive controls. They found that MDMA users showed diminished amplitudes of the P300 component above central midline structures across both conditions, higher P300 NoGo amplitudes over the right posterior cortex, and less anterior location of P300 peaks in the NoGo condition.

Meijas et al. (2005) found that MDMA users showed slower responses to rare (fearful) stimuli and generally decreased N170 amplitudes during face presentation in general. They also found that MDMA users showed delayed P3b latencies for the detection of rare stimuli.

A study of 14 abstinent MDMA users, 13 cannabis users, and 22 non-using controls found that long-term MDMA use is associated with mild cognitive deficits but not with changes of the attention-related P300 wave.

Burgess et al. (2011) studied recognition memory in 15 MDMA polydrug users, 14 cannabis users, and 13 illicit-drug-naive healthy controls. They found that MDMA polydrug users showed lower ERP amplitudes during word recognition compared to cannabis users and drug-naive controls.

In a memory ERP study, MDMA users, polydrug users, and non-drug users performed equally well in verbal working memory, but MDMA users did not display an increased P3b component in the forward compared to the backward condition.

In three experiments, 20 MDMA polydrug users, 20 non-MDMA polydrug users, and 20 drug naive controls performed similarly on three different tasks. However, higher MDMA use intensity predicted worse performance in the set switching tasks. MDMA polydrug users showed a higher mean amplitude of the P200 component at the frontal midline electrodes, a larger negativity of the N2 wave at occipito-parietal electrodes, and a reduction in positivity of the P300 component at parieto-occipital electrodes in comparison to drug-nave controls. MDMA users have deficits in executive functions, but no performance deficits have been revealed. This is explained by compensatory mechanisms.

Ecstasy related atypicalities may reflect serotonergic changes, but EEG research is limited by small sample sizes, heterogeneous drug user groups and open to author interpretation.

7. Conclusions

Ecstasy use is associated with alterations of the serotonin system and neurocognitive performance deficits, with frontal, parietal and temporal regions being especially vulnerable to MDMA neuroadaptation.

fNIRS studies consistently note increases in oxy-Hb in areas of the PFC associated with executive performance, while fMRI studies have observed increases in BOLD activity in prefrontal areas during cognitive inhibition, face recognition and immediate and delayed recall.

Ecstasy users have been reported to have reduced BOLD activation in frontal regions, despite equivalent performance on updating tasks, however the direction of the BOLD response (increased or decreased) suggests a reasonable amount of inconsistency in the results.

The results of ERP studies with ecstasy polydrug users are often interpreted in terms of atypical/aberrant processing that reflects changes to the serotonin system. However, there are several inconsistencies with the methodology and results that make drawing firm conclusions difficult.

The literature on executive function in ecstasy users relative to controls has shown to be inconsistent due to many executive tasks relying on multiple cognitive abilities. It has been suggested that there may be a differential pattern of performance deficits based on function type and drug use.

Future studies should focus on cognitive functions that are impaired in MDMA users and pair neuroimaging techniques with molecular imaging, genetics or pharmacological challenges of the serotonin system to decipher the link between serotonin and cognitive changes in MDMA users.