Evidence for Chronically Altered Serotonin Function in the Cerebral Cortex of Female 3,4-Methylenedioxymethamphetamine Polydrug Users

Department of Psychiatry, School of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37212, USA.
Archives of general psychiatry (Impact Factor: 14.48). 12/2011; 69(4):399-409. DOI: 10.1001/archgenpsychiatry.2011.156
Source: PubMed


MDMA (3,4-methylenedioxymethamphetamine, also popularly known as "ecstasy") is a popular recreational drug that produces loss of serotonin axons in animal models. Whether MDMA produces chronic reductions in serotonin signaling in humans remains controversial.
To determine whether MDMA use is associated with chronic reductions in serotonin signaling in the cerebral cortex of women as reflected by increased serotonin(2A) receptor levels.
Cross-sectional case-control study comparing serotonin(2A) receptor levels in abstinent female MDMA polydrug users with those in women who did not use MDMA (within-group design assessing the association of lifetime MDMA use and serotonin(2A) receptors). Case participants were abstinent from MDMA use for at least 90 days as verified by analysis of hair samples. The serotonin(2A) receptor levels in the cerebral cortex were determined using serotonin(2A)-specific positron emission tomography with radioligand fluorine 18-labeled setoperone as the tracer.
Academic medical center research laboratory.
A total of 14 female MDMA users and 10 women who did not use MDMA (controls). The main exclusion criteria were nondrug-related DSM-IV Axis I psychiatric disorders and general medical illness.
Cortical serotonin(2A) receptor nondisplaceable binding potential (serotonin(2A)BP(ND)).
MDMA users had increased serotonin(2A)BP(ND) in occipital-parietal (19.7%), temporal (20.5%), occipitotemporal-parietal (18.3%), frontal (16.6%), and frontoparietal (18.5%) regions (corrected P < .05). Lifetime MDMA use was positively associated with serotonin(2A)BP(ND) in frontoparietal (β = 0.665; P = .007), occipitotemporal (β = 0.798; P = .002), frontolimbic (β = 0.634; P = .02), and frontal (β = 0.691; P = .008) regions. In contrast, there were no regions in which MDMA use was inversely associated with receptor levels. There were no statistically significant effects of the duration of MDMA abstinence on serotonin(2A)BP(ND).
The recreational use of MDMA is associated with long-lasting increases in serotonin(2A) receptor density. Serotonin(2A) receptor levels correlate positively with lifetime MDMA use and do not decrease with abstinence. These results suggest that MDMA use produces chronic serotonin neurotoxicity in humans. Given the broad role of serotonin in human brain function, the possibility for therapeutic MDMA use, and the widespread recreational popularity of this drug, these results have critical public health implications.

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Available from: Margaret M Benningfield, Oct 05, 2015
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    • "Parrott (2009) noted that many of the functions affected by cortisol were also impaired in recreational ecstasy/MDMA users (see Table 2 in Parrott, 2009); hence, any chronic changes in cortisol may well contribute to some of these psychobiological deficits. In theoretical terms, most explanatory models have focused on the contributory role of serotonin, more specifically serotonergic neurotoxicity (McCann et al., 2008; Kish et al., 2010; Biesonski and Meyer, 2011; Di Iorio et al., 2012; Benningfield and Cowan, 2013; Parrott, 2013b). However, the actions of serotonin and cortisol are closely interlinked (Chaouloff, 2000); hence, any explanatory model should debate their cofunctions and interrelationships . "
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    ABSTRACT: Stress develops when an organism requires additional metabolic resources to cope with demanding situations. This review will debate how recreational 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') can increase some aspects of acute and chronic stress in humans. Laboratory studies on the acute effects of MDMA on cortisol release and neurohormone levels in drug-free regular ecstasy/MDMA users have been reviewed, and the role of the hypothalamic-pituitary-adrenal (HPA) axis in chronic changes in anxiety, stress, and cognitive coping is debated. In the laboratory, acute ecstasy/MDMA use can increase cortisol levels by 100-200%, whereas ecstasy/MDMA-using dance clubbers experience an 800% increase in cortisol levels, because of the combined effects of the stimulant drug and dancing. Three-month hair samples of abstinent users revealed cortisol levels 400% higher than those in controls. Chronic users show heightened cortisol release in stressful environments and deficits in complex neurocognitive tasks. Event-related evoked response potential studies show altered patterns of brain activation, suggestive of increased mental effort, during basic information processing. Chronic mood deficits include more daily stress and higher depression in susceptible individuals. We conclude that ecstasy/MDMA increases cortisol levels acutely and subchronically and that changes in the HPA axis may explain why recreational ecstasy/MDMA users show various aspects of neuropsychobiological stress.
    Behavioural Pharmacology 07/2014; 25(5-6). DOI:10.1097/FBP.0000000000000060 · 2.15 Impact Factor
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    • "Positron emission tomography (PET) studies of MDMA users found evidence of altered in vivo binding in cortical and/or subcortical areas, relative to controls, for tracers labeling brain SERT sites (see Capela et al. 2009 for review). A recent PET study also reported that the recreational use of MDMA was associated with longlasting increases in 5-HT 2A receptor density (Di Iorio et al. 2012). Whether 5-HT alterations in MDMA users are preexisting , because of MDMA or the other drugs used by MDMA users, or a combination of these, remain unknown. "
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    ABSTRACT: 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) use may have long-term neurotoxic effects. In the present study, positron emission tomography with the tracer alpha-[11C]Methyl-L-Tryptophan (11C-AMT) was used to compare human brain serotonin (5-HT) synthesis capacity in 17 currently drug-free MDMA polydrug users with that in 18 healthy matched controls. Gender differences and associations between regional 11C-AMT trapping and characteristics of MDMA use were also examined.MDMA polydrug users exhibited lower normalized 11C-AMT trapping in pre-frontal, orbitofrontal and parietal regions, relative to controls. These differences were more widespread in males than in females. Increased normalized 11C-AMT trapping in MDMA users was also observed, mainly in the brain stem and in frontal and temporal areas. Normalized 11C-AMT trapping in the brain stem and (pre)frontal regions correlated positively and negatively, respectively, with greater lifetime accumulated MDMA use, longer durations of MDMA use, and shorter time elapsed since the last MDMA use.Although the possibility of pre-existing 5-HT alterations predisposing people to use MDMA cannot be ruled out, regionally decreased 5-HT synthesis capacity in the forebrain could be interpreted as neurotoxicity of MDMA on distal (frontal) brain regions. On the other hand, increased 5-HT synthesis capacity in the raphe and adjacent areas could be due to compensatory mechanisms.This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 07/2014; 131(5). DOI:10.1111/jnc.12826 · 4.28 Impact Factor
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    • "A second common finding concerns changes in cortical 5-HT2 receptor binding by PET or SPECT imaging. Binding was typically found to be significantly upregulated in ecstasy users,106,107,109,111,112 although a few studies found a downregulation instead.106–109 Considering the typical regulation of G protein-coupled receptors (like the 5-HT2A receptor) found in animal studies, it is possible that initial ecstasy use causes a receptor downregulation due to excessive 5-HT release, whereas the 5-HT depletion thought to occur with chronic heavy ecstasy use leads to a compensatory receptor upregulation. "
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    ABSTRACT: Ecstasy is a widely used recreational drug that usually consists primarily of 3,4-methylenedioxymethamphetamine (MDMA). Most ecstasy users consume other substances as well, which complicates the interpretation of research in this field. The positively rated effects of MDMA consumption include euphoria, arousal, enhanced mood, increased sociability, and heightened perceptions; some common adverse reactions are nausea, headache, tachycardia, bruxism, and trismus. Lowering of mood is an aftereffect that is sometimes reported from 2 to 5 days after a session of ecstasy use. The acute effects of MDMA in ecstasy users have been attributed primarily to increased release and inhibited reuptake of serotonin (5-HT) and norepinephrine, along with possible release of the neuropeptide oxytocin. Repeated or high-dose MDMA/ecstasy use has been associated with tolerance, depressive symptomatology, and persisting cognitive deficits, particularly in memory tests. Animal studies have demonstrated that high doses of MDMA can lead to long-term decreases in forebrain 5-HT concentrations, tryptophan hydroxylase activity, serotonin transporter (SERT) expression, and visualization of axons immunoreactive for 5-HT or SERT. These neurotoxic effects may reflect either a drug-induced degeneration of serotonergic fibers or a long-lasting downregulation in 5-HT and SERT biosynthesis. Possible neurotoxicity in heavy ecstasy users has been revealed by neuroimaging studies showing reduced SERT binding and increased 5-HT2A receptor binding in several cortical and/or subcortical areas. MDMA overdose or use with certain other drugs can also cause severe morbidity and even death. Repeated use of MDMA may lead to dose escalation and the development of dependence, although such dependence is usually not as profound as is seen with many other drugs of abuse. MDMA/ecstasy-dependent patients are treated with standard addiction programs, since there are no specific programs for this substance and no proven medications. Finally, even though MDMA is listed as a Schedule I compound by the Drug Enforcement Agency, MDMA-assisted psychotherapy for patients with chronic, treatment-resistant posttraumatic stress disorder is currently under investigation. Initial results show efficacy for this treatment approach, although considerably more research must be performed to confirm such efficacy and to ensure that the benefits of MDMA-assisted therapy outweigh the risks to the patients.
    11/2013; 4:83-99. DOI:10.2147/SAR.S37258
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