This systematic review (2016) examines the acute and long-term neurotoxicity of MDMA across neuroimaging studies that investigated deleterious effects on neurotransmission. MDMA does significantly not affect dopamine transmission, and its effects on the 5-HT2A system remain unclear. Although heavy long-term use was consistently shown to be associated with reduced serotonin binding affinity that may indicate serotonin depletion due to neurotoxicity, abstinence leads to significant recovery. Some studies showed that the use of MDMA is correlated with deficits in several cognitive functions; however, opinions remain divided on this topic.
Abstract
“Rationale: Ecstasy is a commonly used psychoactive drug with 3,4-methylenedioxymethamphetamine (MDMA) as the main content. Importantly, it has been suggested that use of MDMA may be neurotoxic particularly for serotonergic (5-hydroxytryptamine (5-HT)) neurons. In the past decades, several molecular imaging studies examined directly in vivo the effects of ecstasy/MDMA on neurotransmitter systems.
Objectives: The objective of the present study is to review the effects of ecstasy/MDMA on neurotransmitter systems as assessed by molecular imaging studies in small animals, non-human primates and humans.
Methods: A search in PubMed was performed. Eighty-eight articles were found on which inclusion and exclusion criteria were applied. Results: Thirty-three studies met the inclusion criteria; all were focused on the 5-HT or dopamine (DA) system. Importantly, 9 out of 11 of the animal studies that examined the effects of MDMA on 5-HT transporter (SERT) availability showed a significant loss of binding potential. In human studies, this was the case for 14 out of 16 studies, particularly in heavy users. In abstinent users, significant recovery of SERT binding was found over time. Most imaging studies in humans that focused on the DA system did not find any significant effect of ecstasy/MDMA use.
Conclusions: Preclinical and clinical molecular imaging studies on the effects of ecstasy/MDMA use/administration on neurotransmitter systems show quite consistent alterations of the 5-HT system. Particularly, in human studies, loss of SERT binding was observed in heavy ecstasy users, which might reflect 5-HT neurotoxicity, although alternative explanations (e.g. down-regulation of the SERT) cannot be excluded.”
Authors: Yosta Vegting, Liesbeth Reneman & Jan Booij
Summary
Abstract
Ecstasy, a commonly used psychoactive drug, may be neurotoxic to serotonergic neurons. Several molecular imaging studies have examined these effects.
Results Thirty-three studies met the inclusion criteria; all were focused on the 5-HTor dopamine (DA) system. MDMA use was found to decrease 5-HT transporter (SERT) availability in animals and humans.
Preclinical and clinical molecular imaging studies of ecstasy/MDMA use/administration show consistent alterations of the 5-HT system.
Introduction
Ecstasy is a common recreationally used psychoactive drug that induces euphoric feelings and the ability to socialize. It also induces entactogenic effects and a relatively small release of another monoaminergic neurotransmitter, namely dopamine.
Molecular neuroimaging techniques can be used to study neurotransmitter systems in the living brain. Results indicate that the 5-HT transporter (SERT) binding is decreased in different brain regions of frequent MDMA users. Experimental studies in rodents and primates indicate that administration of MDMA damages the structural and functional integrity of the 5-HT system. However, alternative explanations for the loss of SERT after MDMA administration have also been put forward.
The United Nations Office on Drugs and Crime estimates that 18.8 million people used ecstasy worldwide in 2013. However, the average amount of MDMA in an ecstasy tablet has increased over the years.
Although the average dosage of MDMA in ecstasy tablets has increased in the last 10 years, the long-term effects of MDMA/ecstasy use remain unclear, most likely because the conducted studies differ in their methodology.
Search and information source
A search was made in the online database PubMed using the PICO system and only search terms for the intervention with MDMA were included.
Selection of studies
We reviewed articles on in vivo imaging findings on neurotransmitter systems, and excluded articles that were case report studies, reviews, or re-evaluations of previously published data.
Data extraction
Data was extracted about the receptor/transporter studied, number of participated subjects and controls with key features, radiotracer used, amount of ecstasy use/administration, minimal time of MDMA/ecstasy abstinence and results of the particular study. We calculated effect sizes.
Inclusion of studies
Eighty-eight studies were found after the initial search in PubMed, and thirty-three studies were included after applying inclusion and exclusion criteria.
5-Hydroxytryptamine synthesis
In our search, only one human study on 5-HT synthesis was found and included. The results showed that 5-HT synthesis was decreased in a large brain area, and that 5-HT uptake was increased in the brainstem, raphe nuclei, and pre-central gyrus in MDMA polydrug users.
Serotonin transporter
Twenty-seven studies were included that studied SERT binding in vivo. Of these, 14 were performed in humans and 16 were performed in animals.
5-HT2A receptor
In five human studies, MDMA increased or decreased 5-HT2A receptor binding. Two studies showed a decrease in binding, and the other two showed no change.
5-HT1A receptor
In 5-HT-rich brain areas, such as the hypothalamus, vesicular monoamine transporter (VMAT) is expressed preferentially. Seven monkeys were studied, whereof four self-administered MDMA.
Dopamine D2/3 receptor and dopamine release
One study explored the effect of MDMA on striatal D2/3 receptors and endogenous DA release. Ex-MDMA users had lower D2/3 binding and endogenous DA release than controls, but these differences were not statistically significant.
Dopamine transporter
Three studies examined the DAT in ecstasy users, and one showed a significant increase of 13 % compared to controls.
Decarboxylase activity ([18F]dopa positron emission tomography)
Table 10 presents data of one study that indicated that decarboxylase activity was increased in the caudate nucleus, putamen and ventral striatum comparing ex-MDMA users to drug-naive controls.
Discussion
Results of molecular imaging studies showed that SERT binding is lower after use of ecstasy/MDMA, particularly after administration of high dosages, while studies on the 5-HT2A receptor showed inconsistent results.
5-Hydroxytryptamine synthesis
This review included one human study on 5-HT synthesis, which found increases in the brainstem and decreases in the prefrontal – orbital and parietal regions. The authors suggest that the increases could be explained by an up-regulation of synthesis to compensate for the loss of 5-HT neurons.
Serotonin transporter
Eleven animal studies looked at the effects of MDMA on SERT binding, and all of them showed lower SERT binding. The effects were statistically significant in ten of these studies.
In animal studies, MDMA was administered frequently and in high doses for four days in a row. This may explain the large ES observed in animals to humans. Researchers have calculated that a human can be neurotoxic at a dose of 1.28 mg/kg, based on differences in clearance and body mass/surface area between monkeys and humans. However, this dosage may be too high to compare with human studies. In 14 out of 16 studies, MDMA users showed significantly lower SERT binding, particularly in cortical brain areas. The decrease was most pronounced in the occipital cortex, and in 3 out of 4 studies, the decrease was corrected for multiple comparisons. Heavy MDMA users have verbal and visuo-spatial memory deficits, and SERT loss in the thalamus may contribute to these deficits.
Urban et al. (2012) found that SERT binding in the orbitofrontal and parietal cortex decreased by 100 %.
Different radiotracers with different binding characteristics were used in studies on the effects of MDMA use/administration on SERT, which may have influenced outcomes. Furthermore, the limited spatial resolution of PET scanners may have led to an underestimation of the binding potential in small volumes.
Pharmacological MRI was evaluated to assess 5-HT dysfunction in the past 10 years. However, more research is necessary to validate this technique.
5-HT2A receptor
Three out of five imaging studies showed increased 5-HT2A receptor binding in MDMA users, while two studies showed a loss of 5-HT2A receptor binding. Reneman et al. (2002c) showed that in recent MDMA users, 5-HT2A receptor binding was lower in all cortical areas studied, while 5-HT2A receptor densities were higher in the occipital cortex of ex-MDMA users. The time of abstinence was varied in the studies of Erritzoe et al. (2011 ), Di Iorio et al. (2012), and Urban et al. (2012), and no correlation between 5-HT2A receptor binding and time of abstinence was found.
Dopamine system (dopaminergic vesicular monoamine transporter, D2/3 receptor and dopamine release, dopamine transporter, decarboxylase activity)
Some experimental studies in animals suggested that MDMA/ecstasy affects not only the 5-HT system, but also the DA system. However, other research showed that MDMA has limited effect on the dopamine nerve endings in rats.
One animal study and five human imaging studies examined the influence of ecstasy on the central DA system and they showed consistently no significant effects of MDMA on the DA system. However, one study showed that use of amphetamines might induce loss of nigrostriatal DA neurons.
Only one study looked into decarboxylase activity in ex-MDMA users, and it found no significant effect. However, when comparing ex-MDMA users to polydrug using controls, there was no significant effect anymore.
Limitations
This review found that few imaging studies have been done on other neurotransmitter systems than the 5-HT or DA system that might be affected by MDMA. Moreover, most studies used a very small number of subjects and some used a minimal period of abstinence for ecstasy of only 1 week.
3,4-Methylenedioxymethamphetamine and additional drug use
MDMA users are likely to be polydrug users. Several studies have looked at the effects of MDMA by including polydrug using control groups, and some have also investigated the effects of other drugs in combination with MDMA.
The studies of de Win et al. (2008b) and Erritzoe et al. (2011a) showed that use of cannabis, cocaine and hallucinogens did not influence the effects of MDMA on the SERT significantly.
Age-of-first exposure
One study looked at the effects of age-of-first exposure on SERT binding in humans and rats. The results showed that the developing brain might be sensitive to the potential neurotoxic effects of MDMA use, but the effects were less pronounced in early-exposed rats and humans.
Gender differences
Reneman et al. (2001a) reported that gender may play a role in the neurotoxic effects of MDMA use. However, Buchert et al. (2004) found no association between sex and reduction of SERT availability.
Alteration in receptor binding and neurotoxicity
Imaging research shows decreased receptor/transporter binding, but the cause of the alteration remains unclear. Further research is needed to distinguish between causes of lower receptor/transporter binding, e.g. down-regulation of the receptor/transporter, neuronal damage resulting in loss of receptors/transporters, decreased expression of protein levels of the receptor and endogenous neurotransmitter release.
More translational research is necessary to examine in which conditions lower SERT binding may reflect neurotoxicity, since several techniques have been developed to measure 5-HT neurotoxicity. Immunocytochemistry, immunohistochemistry and silver staining can be used to assess the structural and functional integrity of the assessed neurotransmitter system. However, there are several limitations of these techniques, and a lowered receptor/ transporter binding as assessed by PET/SPECT studies in humans is still a matter of interpretation. MDMA is not only used recreationally, but also in psychotherapy for PTSD patients, which highlights the need to assess its neurotoxicity.
Recovery
MDMA/ecstasy effects on receptor/transporter binding are important to be further explored. In baboons, midbrain and hypothalamus, SERT binding is increased from 40 days to 9 months after MDMA administration, whereas it remains decreased in cortical regions. After one year of abstinence, former ecstasy users showed no difference in SERT binding between them and drug-naive controls. Moreover, Erritzoe et al. (2011 ) suggested that recovery of SERT binding takes 200 days.
Ex-MDMA users demonstrated similar deficits on the RAVLT memory test as current MDMA users, suggesting that recovery of SERT binding may reflect sprouting of 5-HT neurons or reduced endogenous neurotransmitter release after 5-HT toxicity has occurred.
A study found little evidence in ecstasy users for cognitive impairments, but a recovery in SERT binding may simply reflect normalization of the adaptation (e.g. down-regulation), which may occur initially after MDMA use.
Implications for practice
Selection criteria for the inclusion of subjects are very important for the quality of a given study. Polydrug-using controls should be used to rule out the effects of other drugs.
MDMA self-administration may best reflect the human situation, as the effects on SERT binding are less pronounced compared to studies using passive administration. However, the number of animals used in these studies is relatively small.
Concluding remarks
In the present review, we examined the effects of ecstasy/MDMA use/administration on neurotransmitter systems in human and animal brains through imaging studies. The results revealed that ecstasy/MDMA use/administration decreases SERT binding, but after a certain period of time, SERT binding recovers.
MDMA use is able to induce detectable changes in 5-HT synthesis, but a decline in SERT binding may reflect neurotoxicity. Further research is recommended to investigate the cause of SERT binding recovery.
Results suggest that age-at-first ecstasy use is inversely related to [123 I]-CIT binding ratios in the midbrain. However, more research is needed to draw valid conclusions.