I’ve been writing a short book called “Open MDMA: An Evidence-Based Synthesis, Theory, and Manual for MDMA Therapy Based on Predictive Processing, Complex Systems, and the Defense Cascade,” available here: https://osf.io/preprints/psyarxiv/aps5g. I have a large section on all the different risks, but here is the bit about cognitive/serotonin-system effects, in case anyone is interested in another assessment of the issue:
Some observational human studies and controlled high-dose animal studies have found that MDMA use is associated with neurotoxcicity (oxidative stress in this case) or cognitive problems (The History of MDMA by Torsten Passie). However, these problems have not been found in controlled studies in humans (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053129/pdf/nihms-247953.pdf). The human observational studies that find problems usually fail to adequately control for multiple-drug use, a significant risk factor. Notably, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053129/pdf/nihms-247953.pdf ruled out high levels of long-term cognitive issues from recreational MDMA use in a population that had exceptionally low lifetime use of other psychoactive substances. Unfortunately the study didn’t have the statistical power to rule out low-moderate levels of cognitive issues. One small randomized study of MDMA therapy also did not find any significant cognitive effects (https://journals.sagepub.com/doi/10.1177/0269881110378371). The animal studies that found problems typically used extreme doses, extreme frequencies of use, or injected the medicine, a more potent method of administration than swallowing a pill (The History of MDMA by Torsten Passie). It’s also not clear that humans respond the same way as rats to an equivalent dose. It’s possible that replicating these conditions of extreme doses or frequency of use could cause harmful neural oxidative stress in humans. Some studies have found serotonin system changes in humans, but the studies use a poorly controlled cross-sectional observational design (https://onlinelibrary.wiley.com/doi/abs/10.1002/hup.2811). So it’s not clear that MDMA, rather than other drug use or population difference, causes these changes, that the changes are bad, or that the changes are even clinically significant. The changes appear to decrease with abstinence. Fear and misinformation about MDMA is widespread due to the War on Drugs, sensationalized of poor quality research, and misattribution of MDMA-related deaths as an inherent risk of MDMA instead of its interactions with certain medications and health conditions, and the risks of heat illness or hyponatremia at raves (The History of MDMA by Torsten Passie). See chapter “The Toxicity Debate” in The History of MDMA by Torsten Passie for a comprehensive review of the topic.
High doses of certain antioxidants, including alpha-lipoic acid, ascorbic acid, and acetyl-L-carnitine, administered shortly before and during the session, prevent oxidative stress in rats (10.1097/00001756-199911260-00039, https://onlinelibrary.wiley.com/doi/abs/10.1002/1098-2396%28200104%2940%3A1%3C55%3A%3AAID-SYN1026%3E3.0.CO%3B2-O, 10.1016/j.neuroscience.2008.10.041). Some companies bundle these antioxidants together in commercially available products, but we are not aware of them having been rigorously tested for usefulness in humans (Rollkit).
For the sake of comprehensiveness here is MDMA researcher Matthew Baggott’s somewhat-disagreeing take:
I’m not sure if this is in the category of things you’re looking for, but I’ve spent a couple years writing “Open MDMA: An Evidence-Based Synthesis, Theory, and Manual for MDMA Therapy Based on Predictive Processing, Complex Systems, and the Defense Cascade” as my own way to scale up healing and secure attachment. https://osf.io/preprints/psyarxiv/aps5g
I think the circle model is oversimplified and that reality is some unfathomable complex system with a ton of known and unknown nonlinear factors pushing in different directions. But that’s not much practical use :P.