Neurological and cognitive alterations induced by MDMA in humans

This preprint review (2021) surveys the literature on cognition and neuroimaging studies that have investigated functional and structural changes associated with MDMA use. It concludes that the neurocognitive/neurophysiological changes that occur with repeated MDMA use are potentially reversible over time.

Abstract

“3,4 Methylenedioxymethamphetamine generally referred to as MDMA or ‘ecstasy’ is a ring-substituted phenethylamine stimulant which produces powerful empathogenic effects. Use of MDMA remains popular despite prohibition, and potential long-term negative consequences of repeated use. MDMA produces its acute subjective effects primarily by stimulating the release of serotonin via action at the serotonin transporter (SERT). There is evidence that MDMA administration may lead to long lasting neurotoxic effects on serotonin neurons in primates, and reductions in markers of central serotonin axons, and axon terminals in animals. In humans, demonstration of serotonergic neurotoxicity is much more difficult to identify, and much of the research is complicated by confounding issues of polysubstance use, genetic and environmental factors and reliance on self-reports of previous drug use. We do not review the mechanisms for neurotoxicity in detail as they are covered elsewhere in this special issue. There is a large body of literature, however, which has investigated potential cognitive and neurocognitive consequences of repeated MDMA use. Here we review the literature on cognition, and neuroimaging studies that have investigated structural and functional brain changes associated with ecstasy use.”

Authors: Catherine Montgomery & Carl A. Roberts

Summary

MDMA, a ring-substituted phenethylamine stimulant, produces powerful empathogenic effects, and may have long-term negative consequences in humans. Here we review the literature on cognition and neuroimaging studies that have investigated structural and functional brain changes associated with ecstasy use.

Introduction

MDMA, originally patented by Merck in 1914, was resynthesised by Shulgin in 1965 and became a popular club drug from the 1980s onwards. It was estimated that there were 21.3 million MDMA users globally in 2019, representing 0.4% of adults aged 16-54. MDMA/ecstasy is administered orally and causes increased levels of serotonin in the synapse, which causes the majority of the MDMA-specific primary subjective effects. However, damage to the serotonin system could occur after repeated use causing a range of neurological and cognitive alterations.

Neurological alterations in human recreational users

Using a structural MRI analysis technique called voxel-based morphometry, Cowan et al. (2003) reported that ecstasy users had reduced grey matter volume in the frontal cortex, temporal cortex, and occipital lobe, but no between group differences were observed in brain activation during photic stimulation. Daumann and colleagues conducted fMRI studies to investigate brain activity during cognitive performance in MDMA users. They found no significant differences in brain activity between heavy MDMA users, moderate MDMA users and non-user controls. Ecstasy users showed greater activity in the left medial and superior frontal gyri, the left thalamus, caudate and putamen, and the right hippocampal formation during immediate and delayed recall performance, compared to non-users. However, the effect was no longer significant after controlling for cannabis use.

Adolescent MDMA users show lower activity in the left dorsolateral prefrontal cortex (DLPFC) during associative learning, and poorer performance on a selective and divided attention task. However, ecstasy users show greater activation in the right middle and inferior frontal gyri, right middle frontal gyrus and right inferior parietal lobule. Functional Near-Infrared Spectroscopy (fNIRS) is a newer neuroimaging modality that uses near-infrared light to measure changes in oxygenated and deoxygenated haemoglobin from baseline in the cerebral cortex. It has been used to assess prefrontal cortex activity in ecstasy user samples, and the data so far have been more consistent than the published fMRI data.

Ecstasy may cause hypoxia due to prolonged vasoconstriction, which has been observed not only acutely, but for prolonged periods of abstinence. In a study investigating inhibitory control in ecstasy users and non-users, increased blood oxygenation in the inferior right medial prefrontal cortex and bilateral DLPFC was observed. This suggests that increased oxygenation in these areas reflects recruitment of additional resources to maintain performance at a similar level to controls. The findings from fNIRS suggest neurobiological alterations in ecstasy users, but none of the studies assessed potential recovery of function following prolonged abstinence. Molecular imaging techniques have been used to assess the integrity of the serotonin system in ecstasy users, as the major concomitant drugs are not known to act on the serotonin system to a great extent.

In a meta-analysis of molecular imaging studies, current ecstasy users had reduced serotonin transporter availability in 11 out of 14 brain regions measured. However, there are studies that suggest that effects on SERT may recover following abstinence. Thomasius et al. (2006) observed that ecstasy related reductions in SERT were no longer present at follow up, following abstinence or significant reductions in use. However, McCann et al. (2008) observed that former ecstasy users showed no sign of improvement in verbal memory following 2.5 years of abstinence.

MDMA is a potent agonist of the monoamine neurotransmitters serotonin, dopamine and norepinephrine, which affect cognitive processes. The evidence base was limited to two studies assessing executive functioning and no studies assessing memory. Kuypers & Ramaekers (2005; 2007) found that 75mg MDMA impaired immediate and delayed recall, spatial memory, but not syntactic reasoning or the Digit Symbol Substitution Test. However, the impairments were not present during a 24-hour withdrawal period. Studies have found that MDMA impairs visual, verbal and spatial memory, though accuracy on the Sternberg memory test is improved in the MDMA condition. However, these studies were performed during the day time in a laboratory setting, and do not mirror the conditions under which individuals would usually use MDMA. MDMA has been shown to impair everyday aspects of memory, including prospective memory, deactivation in the inferior parietal lobules, and the encoding of positive and negative emotional information. Long-term effects of MDMA administration in laboratory animals have been assessed in various domains. There is little evidence for impairment in the majority of studies using doses larger than 3mg/kg, and confounding factors such as drug purity, environmental conditions and concomitant use of other substances could affect the results. Studies of human recreational MDMA users have found that they exhibit impairments in declarative memory, particularly in immediate and delayed recall of words and prose. While the underlying cause of such deficits is purported to be depleted 5HT, it is surprising that recall deficits are found acutely after MDMA administration, but not during withdrawal. It is also clear that level of MDMA use plays a role in the deficits. Ecstasy users have deficits in various aspects of prospective memory, including short-term habitual memory subscales of the Prospective Memory Questionnaire (PMQ) and the virtual week task. Ecstasy users have been found to have deficits in PM, but cocaine use is also correlated with PM deficits. Ecstasy users also have impairments in subjective and objective measures of PM, though these impairments improve with increasing abstinence period from MDMA.

Ecstasy users exhibit cognitive deficits in PM, but the concomitant use of other drugs, especially cannabis, needs to be controlled for. One possibility is that the prefrontal cortex is richly innervated with 5HT2A receptors, which could contribute to such deficits. Ecstasy use does not appear to affect inhibitory control using a range of paradigms, including the Stroop task, Random Letter Generation, and Go/NoGo paradigms. There is limited evidence that ecstasy use impairs task switching, but a recent meta-analysis observed that ecstasy users were significantly impaired compared to nonusers in set switching when the data was pooled. Ecstasy use also appeared to impair spatial working memory. A 2012 meta-analysis found that ecstasy users had deficits in visuospatial memory, though these deficits were not related to past ecstasy use.

Studies of ecstasy users have consistently reported poorer performance on memory updating tasks, with higher levels of use leading to worse performance. However, studies using less demanding updating tasks have reported no between group differences. Studies using simpler n-back tasks have not found evidence of ecstasy-related cognitive deficits, but ecstasy users do exhibit increased oxygen turnover during tasks compared to nonusers. Ecstasy users have deficits in the Chicago Word Fluency Task (CWFT) and Controlled Oral Word Association Task (COWAT), yet there is limited evidence of impairments using a simpler oral variant of the CWFT (COWA).

Ecstasy users perform worse than non-users on the COWA, Hanson and Luciana (2004) found that ecstasy users commit more rule breaking errors, and Raj et al. (2010) found that cannabis use is related to cognitive deficits. The prohibition of MDMA raises a number of methodological caveats for researchers studying the drug. One problem is that recreational doses of ecstasy contain varying amounts of MDMA, making it difficult to make direct comparisons between laboratory studies administering MDMA and field studies of ecstasy users. Polydrug use is common among recreational ecstasy users and may exacerbate the cognitive impairments caused by ecstasy use, with cocaine increasing the neurotoxic potential and cannabis decreasing it.

There are a number of factors which could exacerbate the toxic effects of MDMA, including individual differences in pharmacokinetics, genetic polymorphisms, environmental conditions, and physical activity. Longitudinal research may be able to detect genetic vulnerabilities to cognitive/neurological changes associated with MDMA use. Many studies have shown that ecstasy use can alter brain structure and function, but the interpretation of these results is often inconsistent. Molecular imaging studies are more robust in demonstrating neuroadaptation associated with repeated MDMA use, but the clinical significance remains speculative.

The consensus of the data suggests that repeated use of MDMA produces subtle neurocognitive/neurophysiological changes that are potentially reversible over time.