Is MDMA Neurotoxic?
This page will quote heavily from the MAPS MDMA brochure. This is the best source on evidence backed information on MDMA.
MAPS MDMA Brochure Key Excerpts
What is MAPS?
"Founded in 1986, the Multidisciplinary Association for Psychedelic Studies (MAPS) is a 501(c)(3) non-profit research and educational organization that develops medical, legal, and cultural contexts for people to benefit from the careful uses of psychedelics and marijuana."
Why do they summarize MDMA research?
MAPS is the main sponsor behind the recent FDA Phase 3 trial approval for MDMA.
As part of their work on MDMA for PTSD, MAPS has spent lots of money and time doing literature reviews on MDMA. MAPS is the best source for literature overviews on most MDMA related topics.
Why is there so much confusion and false information surrounding MDMA?
This letter by Rick Doblin should be informative regarding why there is so much propaganda. This letter was written back in 2004, and sadly it is still relevant in 2017.
4.0 Nonclinical Studies
Repeated very high doses of MDMA in animals reduce total serotonin levels in the brain, impair transport of serotonin, and cause psychobehavioral changes such as increased anxiety [124, 226, 391-393]. In combination with other drugs or in high dose binge administration studies, MDMA may provoke serotonin syndrome. For example, rodents respond to high doses of MDMA by exhibiting flat body posture, forepaw treading and an erect tail (“Straub tail”) . These behaviors are considered indicators of serotonin syndrome. Doses used in most preclinical studies of neurotoxicity are at least five times the amount used in clinical trials or nonmedical settings, and can be as high as 20 times that amount. Studies in rodents and primates suggest that repeated high doses of MDMA could reduce regional serotonin, damage serotonin axons and cause neurotoxicity [124, 135, 394-397] and promote apoptosis in the hippocampus after 5 or 10 mg/kg MDMA given daily for 1 week . However, the majority of these studies employed large doses of MDMA that overestimated human-equivalent doses, with findings now clearly indicating that doses used in nearly all rat and most primate studies are inappropriately high for comparison to use in clinical settings and are more pertinent toxicological effects of MDMA [78, 114, 119]. Most studies suggested that heavy but not moderate Ecstasy users had impaired verbal memory and lower numbers of estimated SERT sites, assessed via imaging with radioactively labeled ligands in positron emission tomography (PET) or single photon emission tomography (SPECT), with heavy use often defined as 50 or more times or tablets. Taken together, findings from these studies suggest there is some risk of long-term effects in heavy Ecstasy users with respect to number of estimated SERT sites in specific brain areas and performance on measures of memory. However, interpreting findings of changes in serotonin receptors or cognitive function after repeated Ecstasy use are complicated by the possible impact of polydrug use and other potential pre-existing factors in retrospective reports, and the findings are not readily transferrable to use of MDMA in a therapeutic or research context.
Many investigations have examined cognitive function in Ecstasy users with the goal of demonstrating long-term effects of purported neurotoxicity of Ecstasy. Rogers and colleagues performed a meta-analysis on a large number of retrospective studies of Ecstasy users and various cognitive functions. Given methodological flaws in this type of analysis, the investigators cautiously concluded that there might be a significant effect of Ecstasy use on verbal memory, and a lesser effect on visual memory . Retrospective designs and inappropriately matched samples continue to appear in the literature [398-400], even when using multiple control groups. Two meta-analyses of memory in Ecstasy users arrived at somewhat contradictory conclusions [401, 402]. Both detected an association between Ecstasy use and impaired performance on at least some measures of memory. However, one reported that this association had a medium to large effect size with no effect of Ecstasy dose , while the other reported that the association had a small to medium effect size with an Ecstasy dose effect, and that polydrug use itself contributed to impaired cognitive function . A meta-analysis comparing current Ecstasy users and drug-using controls on visuospatial skills reported that current users performed less well on measures of visual recall, recognition and item production than controls , but found no significant relationship between lifetime Ecstasy use and visuospatial task performance. A longitudinal study comparing people who continued to use Ecstasy with those who did not do so detected lower performance on immediate and delayed visual memory . In a second follow- up in the same sample reported lower scores in visual memory, at marginal significance and no further impairment . An examination of the relationship between elements of Ecstasy use history and verbal memory reported that use in the past year, especially in men, was associated with impaired verbal memory . The authors suggest that gender differences in polydrug use may be involved. A study comparing performance on a test of verbal memory in 65 ecstasy users enrolled in clinical trials of MDMA and an equal number of age and gender matched non-drug using controls from other trials failed to detect significant differences between the two groups . This study employed a pre-determined measure of clinical significance, 1.5 times the average standard deviation of the healthy controls, and used a Bayesian statistical test suited for assessing a null hypothesis. It is notable that none of the subjects were enrolled in studies designed to compare cognitive function in ecstasy users, which may have reduced anxiety and potential risk of “stereotype threat” that may be faced by substance users completing assessments of cognitive function, which was done to reduce expectancy in the study .
The nature and strength of the association between regular Ecstasy use and any impairments in executive function remains inconclusive, with studies reporting conflicting results [5, 258, 259, 409, 410]. Findings from a study published in 2014 did not find differences in multitasking . A meta-analysis comparing executive function in Ecstasy users and non-Ecstasy using controls found a significant effect of Ecstasy use on one component of executive function (updating), no effect on another (shifting) and mixed results when looking at other components (response inhibition and access to long-term memory) . Polydrug use likely contributes to findings of impaired executive function seen in Ecstasy users [292, 412]. Current research has not settled the question.
Psychiatric problems after uncontrolled, non-medical Ecstasy use were reported in 22.1% of 199 case reports from the early 1990s to 2001, and are the most common reason for appearance at an emergency department [52, 55]. Psychiatric symptoms included affective responses, such as dysphoria, anxiety, panic, and psychotic response, as well as cases with mixed psychotic and affective features. The most common problem reported included panic, restlessness and psychotic response, as seen a systematic review and several epidemiological case series [53, 413]. The mechanisms behind Ecstasy-associated psychiatric problems remain unclear, but are likely the result of an interaction between pharmacology and individual susceptibility. The difficulty of assessing the frequency of these events is increased given that pre-existing psychiatric problems occur in people who choose to use Ecstasy  and findings of an association between use of Ecstasy and other drugs and self-reported symptoms of anxiety and depression. As described earlier, most cases of psychological distress after Ecstasy use resolved after supportive care [52, 55].
Anxiety responses associated with MDMA administration reported in controlled trials have resolved over time, usually either during the period of acute drug effect or with the waning of drug effects.
5.0 Effects in Humans in Clinical Settings
5.3.7 Neurobiological Effects
Ten Ecstasy user subjects receiving a minimum of two doses of 1 to 1.25 mg/kg or 2.25 to 2.5 mg/kg MDMA exhibited signal decreases in bilateral visual cortex, caudate, superior parietal, and dorsolateral frontal regions 10 to 21 days later, with increased rCBF measured in two subjects at a later time point. However, a comparison between heavy Ecstasy users and non-user controls failed to find differences in baseline rCBF , and a report assessing changes before and after initial Ecstasy use found increased rCBF in only one area of the prefrontal cortex , suggesting that the changes seen by Chang and colleagues are a transient effect.
22.214.171.124 Cognitive Function
In MP-1, no significant differences in cognitive function were detected at the 2-month follow-up between subjects who received two sessions with 125 mg of MDMA compared to subjects who received placebo, as measured by RBANS and PASAT . These findings suggest that MDMA did not impair cognitive function in this sample or that the effect was too small to attain statistical significance in this small pilot study. Two ongoing studies (MP-12 and MP-4) include these measures to assess reproducibility of this finding. Since both MP-4 and MP-12 were ongoing as of the data cut-off, available data pooled across studies are presented below by dose.
On average, RBANS scores trend towards improvement after treatment with placebo and 40 mg to 100 mg initial dose of MDMA, whereas scores stay the same after treatment with 125 mg initial dose of MDMA. The trend towards improvement could be a practice effect from repeated assessments, although stimuli were varied across these, or could possibly be correlated with PTSD symptom reduction. One to three additional treatments with open-label active dose MDMA do not appear to worsen cognitive function based on preliminary End of Stage 1 and End of Stage 2 results. The significance of these pooled findings is yet to be determined.On average, PASAT scores stay about the same after treatment with placebo and 100 mg initial dose of MDMA and trend towards improvement after treatment with 40 and 125 mg initial dose of MDMA. The trend towards improvement could be a practice effect from repeated assessments or could be correlated with PTSD symptom reduction. One to three additional treatments with open-label active dose MDMA do not appear to worsen cognitive function and continued to trend towards improvement on average based on preliminary End of Stage 1 and End of Stage 2 results. Cognitive function tests such as the PASAT are also known to be subject to individual variability, as they require basic proficiency with mathematical skills that are influenced by education level. The significance of these pooled findings is yet to be determined, but it does not appear that MDMA-assisted psychotherapy is negatively impacting cognitive function.
Matthew Baggott, MDMA researcher
"To the best of my understanding, doses around 1.5-1.7 mg/kg MDMA (roughly 100 to 125 mg MDMA) are unlikely to cause long-lasting serotonin changes. Studies by MAPS have looked for changes in mental abilities after people participated in their studies, with some participants receiving 125 mg followed by 62.5 mg, and have not found any changes. I looked for changes in mental abilities and mood in about the first 25 people I gave 1.5 mg/kg MDMA to and did not see any changes." Via.
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.
Moderate in this study refers to <50 lifetime MDMA sessions / <100 lifetime MDMA tablets