Editing MDMA (section)

===Long-term===
{{As of|2015}}, the long-term effects of MDMA on human brain structure and function have not been fully determined.<ref name="Abstinent MDMA fMRI review">{{cite journal | vauthors = Garg A, Kapoor S, Goel M, Chopra S, Chopra M, Kapoor A, McCann UD, Behera C | title = Functional Magnetic Resonance Imaging in Abstinent MDMA Users: A Review | journal = Current Drug Abuse Reviews | volume = 8 | issue = 1 | pages = 15–25 | date = 2015 | pmid = 25731754 | doi = 10.2174/1874473708666150303115833 }}</ref> However, there is consistent evidence of structural and functional deficits in MDMA users with high lifetime exposure.<ref name="Abstinent MDMA fMRI review" /> These structural or functional changes appear to be dose dependent and may be less prominent in MDMA users with only a moderate (typically <50 doses used and <100 tablets consumed) lifetime exposure. Nonetheless, moderate MDMA use may still be [[Neurotoxicity|neurotoxic]] and what constitutes moderate use is not clearly established.<ref name="mueller2015">{{cite journal | vauthors = Mueller F, Lenz C, Steiner M, Dolder PC, Walter M, Lang UE, Liechti ME, Borgwardt S | title = Neuroimaging in moderate MDMA use: A systematic review | journal = Neuroscience and Biobehavioral Reviews | volume = 62 | pages = 21–34 | date = March 2016 | pmid = 26746590 | doi = 10.1016/j.neubiorev.2015.12.010 | doi-access = free }}</ref>

Furthermore, it is not clear yet whether "typical" recreational users of MDMA (1 to 2 pills of 75 to 125{{nbsp}}mg MDMA or analogue every 1 to 4 weeks) will develop neurotoxic brain lesions.<ref>{{cite journal | vauthors = Gouzoulis-Mayfrank E, Daumann J | title = Neurotoxicity of drugs of abuse--the case of methylenedioxyamphetamines (MDMA, ecstasy), and amphetamines | journal = Dialogues in Clinical Neuroscience | volume = 11 | issue = 3 | pages = 305–17 | date = 2009 | doi = 10.31887/DCNS.2009.11.3/egmayfrank | pmid = 19877498 | pmc = 3181923 }}</ref> Long-term exposure to MDMA in humans has been shown to produce marked [[neurodegeneration]] in [[striatal]], [[hippocampal]], [[prefrontal cortex|prefrontal]], and [[occipital cortex|occipital]] serotonergic [[axon terminal]]s.<ref name="Abstinent MDMA fMRI review" /><ref name="Meth MDMA NTox">{{cite journal | vauthors = Halpin LE, Collins SA, Yamamoto BK | title = Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine | journal = Life Sciences | volume = 97 | issue = 1 | pages = 37–44 | date = February 2014 | pmid = 23892199 | pmc = 3870191 | doi = 10.1016/j.lfs.2013.07.014 | quote = In contrast, MDMA produces damage to serotonergic, but not dopaminergic axon terminals in the striatum, hippocampus, and prefrontal cortex (Battaglia et al., 1987, O'Hearn et al., 1988). The damage associated with Meth and MDMA has been shown to persist for at least 2 years in rodents, non-human primates and humans (Seiden et al., 1988, Woolverton et al., 1989, McCann et al., 1998, Volkow et al., 2001a, McCann et al., 2005) }}</ref> Neurotoxic damage to serotonergic axon terminals has been shown to persist for more than two years.<ref name="Meth MDMA NTox" /> Elevations in brain temperature from MDMA use are positively correlated with MDMA-induced neurotoxicity.<ref name="pmid22392347" /><ref name="Abstinent MDMA fMRI review" /><ref name="mueller2015" /> However, most studies on MDMA and serotonergic neurotoxicity in humans focus more on heavy users who consume as much as seven times or more the amount that most users report taking. The evidence for the presence of serotonergic neurotoxicity in casual users who take lower doses less frequently is not conclusive.<ref>{{cite journal | vauthors = Szigeti B, Winstock AR, Erritzoe D, Maier LJ | title = Are ecstasy induced serotonergic alterations overestimated for the majority of users? | journal = Journal of Psychopharmacology | volume = 32 | issue = 7 | pages = 741–748 | date = July 2018 | pmid = 29733742 | doi = 10.1177/0269881118767646 | s2cid = 13660975 | quote = Given the dose-response relationship between MDMA exposure and SERT reductions and the statistically non-significant SERT binding differences for users with use levels similar to the majority of real-life users, it can be speculated that SERT levels may not be significantly affected for most recreational ecstasy users. }}</ref>

However, adverse [[neuroplastic]] changes to brain [[microvasculature]] and [[white matter]] have been observed to occur in humans using low doses of MDMA.<ref name="pmid22392347" /><ref name="Abstinent MDMA fMRI review" /> Reduced [[gray matter]] density in certain brain structures has also been noted in human MDMA users.<ref name="pmid22392347" /><ref name="Abstinent MDMA fMRI review" /> Global reductions in gray matter volume, thinning of the parietal and orbitofrontal cortices, and decreased hippocampal activity have been observed in long term users.<ref name="Betzler2017" /> The effects established so far for recreational use of ecstasy lie in the range of moderate to severe effects for [[serotonin transporter]] reduction.<ref>{{cite journal | vauthors = Roberts CA, Jones A, Montgomery C | title = Meta-analysis of molecular imaging of serotonin transporters in ecstasy/polydrug users | journal = Neuroscience and Biobehavioral Reviews | volume = 63 | pages = 158–67 | date = April 2016 | pmid = 26855234 | doi = 10.1016/j.neubiorev.2016.02.003 | doi-access = free }}</ref>

Impairments in multiple aspects of cognition, including attention, learning, memory, [[Role of serotonin in visual orientation processing#MDMA and Visual Orientation Processing|visual processing]], and sleep, have been found in regular MDMA users.<ref name=Betzler2017/><ref name=Current2013 /><ref name=Pharm2014>{{cite journal | vauthors = Parrott AC | title = The potential dangers of using MDMA for psychotherapy | journal = Journal of Psychoactive Drugs | volume = 46 | issue = 1 | pages = 37–43 | year = 2014 | pmid = 24830184 | doi = 10.1080/02791072.2014.873690 | s2cid = 23485480 | url = https://www.researchgate.net/publication/262381558 }}</ref><ref name="Abstinent MDMA fMRI review" /> The magnitude of these impairments is correlated with lifetime MDMA usage<ref name=Current2013 /><ref name=Pharm2014 /><ref name="Abstinent MDMA fMRI review" /> and are partially reversible with abstinence.<ref name=Betzler2017/> Several forms of memory are impaired by chronic ecstasy use;<ref name=Current2013 /><ref name=Pharm2014 /> however, the effects for memory impairments in ecstasy users are generally small overall.<ref>{{cite journal|vauthors=Rogers G, Elston J, Garside R, Roome C, Taylor R, Younger P, Zawada A, Somerville M|date=January 2009|title=The harmful health effects of recreational ecstasy: a systematic review of observational evidence|journal=[[Health Technology Assessment (journal)|Health Technology Assessment]]|volume=13|issue=6|pages=iii–iv, ix–xii, 1–315|doi=10.3310/hta13050|pmid=19195429|doi-access=free|hdl=10871/11534|hdl-access=free}}</ref><ref name="Meta analysis - MDMA memory impairment">{{cite journal | vauthors = Kuypers KP, Theunissen EL, van Wel JH, de Sousa Fernandes Perna EB, Linssen A, Sambeth A, Schultz BG, Ramaekers JG | title = Verbal Memory Impairment in Polydrug Ecstasy Users: A Clinical Perspective | journal = PLOS ONE | volume = 11 | issue = 2 | pages = e0149438 | year = 2016 | pmid = 26907605 | pmc = 4764468 | doi = 10.1371/journal.pone.0149438 | bibcode = 2016PLoSO..1149438K | doi-access = free }}</ref> MDMA use is also associated with increased impulsivity and depression.<ref name=Betzler2017/>

Serotonin depletion following MDMA use can cause depression in subsequent days. In some cases, depressive symptoms persist for longer periods.<ref name=Betzler2017/> Some studies indicate repeated recreational use of ecstasy is associated with depression and anxiety, even after quitting the drug.<ref>{{cite journal | vauthors = Laws KR, Kokkalis J | title = Ecstasy (MDMA) and memory function: a meta-analytic update | journal = Human Psychopharmacology | volume = 22 | issue = 6 | pages = 381–8 | date = August 2007 | pmid = 17621368 | doi = 10.1002/hup.857 | s2cid = 25353240 }}</ref> Depression is one of the main reasons for cessation of use.<ref name=Betzler2017/>

At high doses, MDMA induces a [[neuroimmune system|neuroimmune response]] that, through several mechanisms, increases the permeability of the [[blood–brain barrier]], thereby making the brain more susceptible to environmental toxins and [[pathogen]]s.<ref name="MDMA BBB">{{cite journal | vauthors = Kousik SM, Napier TC, Carvey PM | title = The effects of psychostimulant drugs on blood brain barrier function and neuroinflammation | journal = Frontiers in Pharmacology | volume = 3 | pages = 121 | year = 2012 | pmid = 22754527 | pmc = 3386512 | doi = 10.3389/fphar.2012.00121 | doi-access = free }}</ref><ref>{{cite book| vauthors = McMillan B, Starr C |title=Human biology |date=2014 |publisher=Brooks/Cole Cengage Learning |location=Belmont, CA |isbn=978-1-133-59916-6 |edition=10th }}</ref>{{Page needed|date=September 2015}} In addition, MDMA has [[immunosuppressive]] effects in the [[peripheral nervous system]] and pro-inflammatory effects in the [[central nervous system]].<ref>{{cite journal | vauthors = Boyle NT, Connor TJ | title = Methylenedioxymethamphetamine ('Ecstasy')-induced immunosuppression: a cause for concern? | journal = British Journal of Pharmacology | volume = 161 | issue = 1 | pages = 17–32 | date = September 2010 | pmid = 20718737 | pmc = 2962814 | doi = 10.1111/J.1476-5381.2010.00899.X }}</ref>

MDMA may increase the risk of [[cardiac valvulopathy]] in heavy or long-term users due to activation of serotonin [[5-HT2B receptor|5-HT<sub>2B</sub> receptor]]s.<ref name="pmid24361689">{{cite journal | vauthors = Cavero I, Guillon JM | title = Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy | journal = Journal of Pharmacological and Toxicological Methods | volume = 69 | issue = 2 | pages = 150–161 | date = 2014 | pmid = 24361689 | doi = 10.1016/j.vascn.2013.12.004 }}</ref><ref name="pmid28676029">{{cite journal | vauthors = Padhariya K, Bhandare R, Canney D, Velingkar V | title = Cardiovascular Concern of 5-HT2B Receptor and Recent Vistas in the Development of Its Antagonists | journal = Cardiovascular & Hematological Disorders Drug Targets | volume = 17 | issue = 2 | pages = 86–104 | date = 2017 | pmid = 28676029 | doi = 10.2174/1871529X17666170703115111 }}</ref> MDMA induces cardiac [[epigenetics|epigenetic changes]] in [[DNA methylation]], particularly hypermethylation changes.<ref>{{cite journal | vauthors = Koczor CA, Ludlow I, Hight RS, Jiao Z, Fields E, Ludaway T, Russ R, Torres RA, Lewis W | title = Ecstasy (MDMA) Alters Cardiac Gene Expression and DNA Methylation: Implications for Circadian Rhythm Dysfunction in the Heart | journal = Toxicological Sciences | volume = 148 | issue = 1 | pages = 183–191 | date = November 2015 | pmid = 26251327 | pmc = 4731408 | doi = 10.1093/toxsci/kfv170 }}</ref>