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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Arch Gen Psychiatry. Author manuscript; available in PMC 2013 April 1.
Published in final edited form as:
PMCID: PMC3538835
NIHMSID: NIHMS425397

Evidence for chronically altered cortical serotonin function in human female recreational ecstasy (MDMA) polydrug users

Abstract

Context

MDMA (ecstasy) is a popular recreational drug that produces loss of serotonin (5-HT) axons in animal models. Whether MDMA produces chronic reductions in 5-HT signaling in humans remains controversial.

Objective

To determine if MDMA use is associated with chronic reductions in serotonin signaling in female human cerebral cortex as reflected by increased 5-HT2A receptors.

Design

Cross sectional case-control study comparing 5-HT2A receptor levels in abstinent female MDMA polydrug users to MDMA-naive females; within-group design assessing the association of lifetime MDMA use and 5-HT2A receptors. Subjects had at least 90 days abstinence from MDMA use as verified by hair sampling. Cortical 5-HT2A receptor levels were assayed with the 5HT2A-specific Positron Emission Tomography (PET) radioligand [18F]setoperone.

Setting

Academic Medical Center Research Laboratory.

Participants

Volunteer female MDMA users (N=14) and MDMA-naive controls (N=10). Main exclusion criteria were non-drug-related DSM-IV axis I psychiatric disorders and general medical illness.

Main Outcome Measure

Cortical 5-HT2A receptor non-displaceable binding potential (5-HT2ABPND).

Results

MDMA users had increased 5-HT2ABPND in occipital-parietal (19.7%), temporal (20.5%), occipito-temporal-parietal (18.3%), frontal (16.6%), and fronto-parietal (18.5%) regions (p<0.05; corrected). Lifetime MDMA use associated positively with 5-HT2ABPND in fronto-parietal (β=0.665;p=0.007), occipito-temporal (β=0.798;p=0.002), fronto-limbic (β=0.634;p=0.024), and frontal (β=0.691;p=0.008) 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 5-HT2ABPND.

Conclusions

Human recreational MDMA use is associated with long-lasting increases in 5-HT2A receptor density. 5-HT2A receptor levels correlate positively with lifetime MDMA use and do not decrease with abstinence. These results suggest that MDMA produces chronic 5-HT neurotoxicity in humans. Given the broad role of 5-HT 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.

Introduction

3,4-methylenedioxymethamphetamine (MDMA; sold under the street name of Ecstasy) is a widely-used drug that is linked to neuropsychiatric impairment and neurophysiological alterations in human users.1;2 MDMA acutely increases synaptic concentrations of serotonin (5-HT) and other monoamines3 producing mood changes4 accounting for its recreational popularity. U.S. surveys indicate that 6% of high school seniors and 5% of the general population report lifetime MDMA exposure.5 Across the E.U., average lifetime MDMA use is 5.6% in young adults with highest rates in the United Kingdom (15.4%) and Denmark (10.5%).6 Neurotoxic regimens of MDMA (e.g.--5 mg/kg subcutaneously twice/day for 4 days in nonhuman primates7 or 40 mg/kg orally twice/day for 4 days in rodents8)—produce loss of 5-HT axons9 that is greater for fine diameter cortical 5-HT axons most distal to the cell bodies of origin. In animals, MDMA spares the cell bodies of brainstem 5-HT neurons.9 Whether dose regimens that more closely mimic human use lead to loss of 5-HT axons is unknown.

While the ability of some MDMA dosing regimens to produce chronic 5-HT axon loss is clear,9 the evidence for MDMA-induced chronic reductions in 5-HT signaling in humans remains equivocal.1;2 Recent studies suggesting that MDMA enhances psychotherapy10 and that some MDMA users have minimal impairments in neurocognition11 have potentially enhanced the perception that MDMA is safe for human use. However, there is little evidence for the use of MDMA as a psychotherapeutic agent and a great deal of evidence to support neurocognitive deficits in recreational MDMA users.12;13 Given its widespread use, efforts to find therapeutic indications, and the critical role of 5-HT in brain function, it is essential to determine whether human MDMA use is associated with long-term changes in 5-HT function.

Consistent evidence for chronic reductions in 5-HT signaling in human recreational MDMA users derives from nuclear imaging measures of the pre-synaptic axonal 5-HT transporter as a surrogate marker for 5-HT axon integrity.1418;1822 The bulk of these studies have found lasting reductions in 5-HT transporter binding in MDMA users that is prominent in cerebral cortex.1;2 While reductions in 5-HT transporter are consistent with 5-HT axon loss, there is evidence that transporter levels show some recovery with sustained abstinence,17;23 suggesting that partial recovery from initial axon injury may be possible.

In contrast to the pre-synaptic 5-HT transporter, the post-synaptic 5-HT2A receptor may have advantages as an assay of ongoing 5-HT signaling because 5-HT2A receptors reflect pre-synaptic agonist signaling. 5-HT2A receptor levels decrease in the face of increased agonist stimulation 24,25 and MDMA-induced 5-HT release acutely decreases 5-HT2A levels in rats in some brain regions.25;26 MDMA administration producing reductions of 20–30% in 5-HT markers was associated with reduced 5-HT2A binding in cortical and subcortical regions in rats at 3 months post-administration, whereas MDMA dosing regimens causing 5-HT depletions of around 80% produced chronic increases in 5-HT2A binding in rat frontal cortex.26 A preliminary study using single photon emission computed tomography (SPECT) in ongoing MDMA users found reduced 5-HT2A levels in all brain regions while abstinent MDMA users had increased 5-HT2A receptor binding only in occipital cortex.26 Erritzoe and colleagues27 examined both 5-HT2A receptor binding and 5-HT transporter binding in humans with recent use of both MDMA and hallucinogens (characterized as MDMA-preferring or hallucinogen-preferring users). Overall, there was a slight tendency for lower 5-HT2A receptors in the hallucinogen and MDMA user groups when compared to controls but no differences in 5-HT2A binding were seen between the two drug-using groups, despite widespread reductions in the 5-HT transporter that were restricted to the MDMA-preferring users.

In addition to the need to determine whether MDMA use is associated with chronic 5-HT loss in humans, more evidence is needed regarding the effects of MDMA in females. Sex has been shown to influence toxicity to drugs of abuse.28 Female MDMA users metabolize MDMA differently than males29 and report more pronounced subjective effects, such as hallucinogen-like effects, than males.30 While most studies do not report an association between sex and 5-HT transporter levels in MDMA users, a minority of studies reported greater reductions in the 5-HT transporter19;23 in females. Female MDMA users also had lower 5-hydroxyindoleacetic acid, a 5-HT metabolite, than males.31 Additionally, 5-HT2A receptor binding has also been associated with sex differences with females having reduced 5-HT2A binding compared to males.32;33 We therefore focused on recruiting female MDMA users.

The evidence to date suggests that human recreational MDMA use may lead to chronic alterations in cortical 5-HT function. To determine if MDMA use is associated with chronic changes in 5-HT signaling as reflected by 5-HT2A receptor levels, we used [18F]setoperone34 positron emission tomography (PET) to assay cerebral cortical 5-HT2A receptors in long-abstinent female MDMA polydrug users and controls. We estimated receptor levels as the non-displaceable binding potential (BPND), which reflects receptors available to bind [18F]setoperone. In line with the observations of Reneman and colleagues,26 we hypothesized that long-abstinent MDMA users would have increased 5-HT2A receptor levels in cortex and that greater lifetime MDMA exposure would predict greater 5-HT2A receptor levels.

Methods

Participants

Fifteen female MDMA users and ten female non-MDMA exposed controls, ages 18–25, completed [18F]setoperone PET scans to assay cortical 5-HT2A receptor status. Data from one female MDMA user was excluded for recent cocaine use confirmed by hair sampling (described below).

We recruited control subjects in parallel with MDMA users with advertisements in local media, flyers, and by word of mouth requesting participants who had used ecstasy, marijuana, or other recreational drugs. Participants were compensated for their participation. The study was approved by the Vanderbilt University Institutional Review Board and conformed to the World Medical Association’s Declaration of Helsinki. Participants were screened by phone for inclusion/exclusion criteria and those meeting provisional enrollment criteria were additionally screened in-person.

Inclusion criteria

Caucasian females ages 18–25 who did not use drugs of abuse within 2 weeks of enrollment were eligible for inclusion. Participants were required to have regular menstrual cycles or use oral hormonal contraceptives. Control group participants were MDMA naïve while MDMA users reported MDMA use on at least 5 occasions (a minimum exposure based on our prior fMRI studies3538). For all participants their last cocaine, LSD, and other amphetamines exposures were at least 90 days prior to enrollment in the study. These use and abstinence criteria were chosen based upon our earlier fMRI studies and on the literature reviewed below regarding the time frame of 5-HT2A receptor changes following MDMA exposure.

Exclusion criteria

Exclusions were: general medical conditions or endocrine abnormalities; contraindications to PET or MRI scanning; lifetime history of Axis-I psychiatric diagnoses except for drug-induced mood disorder (one MDMA user met criteria for a history of substance-induced hypomania); current or past substance dependence (other than nicotine and caffeine); positive urine drug screen within two weeks of the PET scan, alcohol use within 72 hours of the PET scan; use of psychoactive or vasoactive medications within 6 weeks of enrollment; and lifetime head injury with loss of consciousness greater than 20 minutes.

Screening

Participants were screened with the Mini-International Neuropsychiatric Interview (M.I.N.I) ,39 North American Adult Reading Test (NAART—to assess verbal intelligence [IQ] quotient), urine drug testing (Triage Drugs of Abuse Panel, Biosite Diagnostics, San Diego, CA), urinary cotinine testing (Cotinine Test Device, Innovacon Inc., San Diego, CA), and urine pregnancy (Sure-Vue Urine hCG, Fisher HealthCare, Houston, TX). Participants were screened for drug use, cotinine, and pregnancy twice a week for at least two weeks and until completing the PET scan. Participants with positive drug or pregnancy screens were removed from the study. Participants provided their drug use history through a self-report Drug Use Questionnaire35;37;38 using a time-line follow-back method.40 Lifetime units of each reported drug were calculated as the product of the lifetime episodes of a drug (defined as use within a single 24-hour period) and the average use per episode. Since the MDMA content of ecstasy pills was unknown, lifetime MDMA exposure was estimated as the amount of ecstasy consumed. Subjects also completed personality and psychiatric symptom inventories for exploratory analyses for co-morbid conditions potentially increased in ecstasy users—including assessments for depression (Beck Depression Inventory41;42 and Hamilton D-1743), anxiety (Hamilton Anxiety Scale44), impulsiveness (Barratt Impulsivity Scale, BIS-11)45 and Temperament and Character Inventory,46 Impulsiveness/NS2), and novelty seeking (Temperament and Character Inventory/NS total47).

Twenty-four hours prior to PET scanning, we assayed serum estrogen levels. Urine drug and cotinine tests were performed prior to the PET scan for all participants to reconfirm drug abstinence and self-reported nicotine exposure. An alcohol breathalyzer (Intoximeters, St. Louis, MO) was used to confirm recent abstinence from alcohol. A hair sample was taken to perform a drug screen analysis of prolonged abstinence (up to 90 days) (United States Drug Testing Laboratories, Des Plaines, IL). Hair sampling measures of MDMA correlate well with self-report.48 Results from the hair screen lead to the removal of one participant who tested positive for cocaine. All other participants tested negative for drug use within the 90 day exposure window.

PET Scanning

[18F]Setoperone has been used by a number of investigators to study cortical 5-HT2A receptor levels in depression,49;50 schizophrenia,51;52 and Alzheimer’s disease,53 and to measure the effects of antipsychotic and antidepressant medications54;55 on 5-HT2A receptor levels. [18F]setoperone binding to 5-HT2 receptors in cortex largely reflects 5-HT2A receptors, having an affinity for 5-HT2A versus 5-HT2C receptors of 100:1.13 [18F]setoperone has subnanomolar affinity for the 5-HT2 receptor (K=0.37 nM, KD=0.7 nM), and moderate affinity for the D2 (IC50=56 nM, D2/5-HT2 K1 ratio of 70) and alpha1 receptor (IC50=38 nM, alpha1/5-HT2 K1 ratio of 35).56;57 In humans specific cortical uptake is due to binding to 5-HT2A receptors while striatal uptake is due to binding at both 5-HT2A and D2 receptors.34 [18F]Setoperone has polar radiolabeled metabolites in humans that do not appear to cross the blood barrier unlike another 5-HT2 ligand, [18F]altanserin.58;59

[18F]Setoperone was synthesized using a single-mode microwave accelerator and modified commercial fluorination module(GE-TRACERlab©FX-FN).60 PET scans were acquired with a GE Discovery LS Scanner using a 3D emission acquisition (reconstructed resolution of 5.0–5.5mm). Serial scans of increasing lengths were started immediately after the intravenous injection of 7.0mCi of [18F]setoperone (specific activity greater than 1,000 Ci/mmol) over a 20 second period and were obtained for 70 minutes. Eight 15 second scans, six 30 second scans, five 1 minute scans, two 2.5 minute scans, three 5 minute scans, and four 10 minute scans were obtained.

Image and Data Analysis

PET images were pre-processed as previously reported.6164 The dynamic PET scans were co-registered using an independent implementation of a rigid body mutual information algorithm. This algorithm registers images by computing a transformation that maximizes the mutual information between the images.65;66 We used a multiresolution alogorithm couple with a resampling strategy to avoid local extrema problems reported by Pluim and colleagues67 when registering images with the same voxel dimensions. This algorithm is fully automatic and does not require any type of manual preprocessing.

Regional 5-HT2A binding potentials (BPND) and parametric images of BPND were calculated using the full reference region method.68 We bilaterally sampled the cerebellum using automated processes to create the reference region. The very low levels of 5-HT2A receptors in the cerebellum do not invalidate the use of cerebellum as a reference region for estimating 5-HT2 receptor levels in cortex. Petit-Taboue34;69 has demonstrated that neocortical:cerebellar ratios of [18F]setoperone uptake at 30–60 minutes demonstrate correlation coefficients of 0.97 – 0.99 with modeled estimates using either Logan graphical analysis or compartmental modeling. Using the cerebellum as a reference region, correlation of estimates of 5-HT2A receptor levels obtained with a 4 compartment (3-tissue compartments plus plasma) model with least squares fitting and the reference region approach have shown an r2 = 0.95 with a zero intercept.70

Data were analyzed using SPM5 (Wellcome Department of Cognitive Neuroscience, London, UK). 5-HT2ABPND maps were coregistered to each individual’s magnetic resonance high resolution 3-D anatomical T1-weighted image acquired by a Philips 3T Intera Achieva MRI scanner (Phillips Medical Systems, Andover, MA, USA). Images were spatially normalized into MNI space using the SPM5 avg152T1 template. Normalized BPND images were smoothed with an 8mm full-width-half-maximum (FWHM) Gaussian kernel. Final voxel resolution was 2×2×2 mm.

Prior reports indicate that birth control, estrogen,71 and age72 affect 5-HT2A receptor expression. We used multivariable regression within SPM5 to test for the effects of confounding factors (birth control, estrogen, and age) on 5-HT2ABPND. Birth control and estrogen were significantly positively associated with 5-HT2ABPND and age was significantly negatively associated with 5-HT2ABPND (p<0.01, corrected).Therefore, subsequent between and within group analyses were adjusted for birth control, estrogen, and age.

Because [18F]setoperone is not specific to 5-HT2A binding outside of the cortex,34 we used the Wake Forest University Pickatlas tool (v2.4) in SPM to apply a cortical mask to exclude subcortical regions. Because we had no firm a priori hypotheses regarding which cortical regions would be most strongly affected by MDMA we chose to perform a whole cortex regression analysis as opposed to a region of interest (ROI) analysis. This approach was chosen also to avoid potential partial volume effects inherent in an ROI analysis if the effect of interest is confined to a portion of the ROI. To adjust for multiple comparisons in the search volume, we used Monte Carlo simulations implemented in AlphaSim (AFNI, NIMH) to generate a family-wise error corrected p value =0.05. This corrected p corresponded to a voxel level p-value of 0.05 and cluster size of 910 voxels.

Between-groups Analysis

Non-parametric Mann-Whitney-U testing was used to examine drug use differences between groups for drugs used by over 10 participants (nicotine, alcohol, cannabis, amphetamine, cocaine, sedatives/hypnotics, LSD, psilocybin). General linear modeling analysis was performed within SPM5 to assess between-group differences in 5-HT2ABPND between MDMA users and controls while controlling for birth control, estrogen, and age. A MATLAB script was employed to extract mean 5-HT2ABPND in clusters showing significant between group differences for subsequent analysis using SPSS (SPSS for Windows version 18.0; SPSS Inc., Chicago, IL, USA). As within SPM5, data were adjusted for birth control, estrogen, and age. This two-step approach, to first identify areas differing between groups in 5-HT2A binding within SPM and then to extract that data for further analysis was used to ensure that the association of MDMA use with greater 5-HT2A binding potential was not explained by other drug use or other factors, such as the duration of drug abstinence.

Within-group Analysis

Animal administration studies9;7377 reveal a dose-dependent effect of MDMA on 5-HT axon loss and human functional magnetic resonance imaging (fMRI) studies3537 reveal dose-dependent effects of MDMA on brain activation. As such, these studies predict that increasing MDMA exposure would be associated with higher levels of 5-HT2ABPND if the 5-HT2A receptor reflects the same processes associated with MDMA toxicity in animals and with the altered neurophysiology seen in fMRI studies. Therefore, we used multivariable regression analysis to assess the relationship of lifetime MDMA use in units (as ecstasy mg) and receptor levels within the MDMA user group. We controlled for confounding factors (age, birth control, and estrogen levels). Once regions displaying a main effect of lifetime MDMA exposure were identified, BPND values from clusters with significant associations (significant associations were defined as those having a Family Wise Error (FWE) corrected p<0.05, which was achieved using a voxel level p=0.05 and a cluster extent threshold of 910 voxels) with lifetime MDMA use were extracted and further analyses were performed in SPSS as for the between groups results.

Results

Participant demographics and lifetime drug use are summarized in Table 1. Due to the skewed distributions of the drug use variables, those distributions are described by the median and 25th75th interquartile ranges representing the middle 50% of the observed values, and minimum and maximum. No statistically significant differences between the groups were observed for age, IQ score, depression, anxiety, impulsivity, or novelty ratings (p>0.05). Psilocybin was the only drug found to have a significant between-groups difference (p=0.001).

Table 1
Demographics and Drug Use

Between-groups analysis

MDMA users had increased 5-HT2ABPND in five cortical clusters (Figure 1; Table 2) that were mainly localized to occipito-parietal, temporal, occipito-temporal-parietal, frontal, and fronto-parietal regions but which also included limbic areas. The greatest between-groups difference in 5-HT2ABPND was found in the temporal cluster (Table 3), where 5-HT2A receptor availability was 20.5% higher in the MDMA users. The other regions showed increases in 5-HT2ABPND of 19.7% (occipito-parietal), 18.3% (occipito-temporal-parietal), 16.6% (frontal) and 18.5% (fronto-parietal) in MDMA users. Regions having increased 5-HT2A binding potential involved more brain regions in the right hemisphere than in the left. This was notable for the right frontal regions (Table 2). In contrast to the widespread increases in 5-HT2ABPND in MDMA users, there were no regions in which 5-HT2ABPND was lower in MDMA users than in controls (p>0.05, corrected).

Figure 1
Panels a. and b. depict right hemisphere and bilateral superior regions, respectively, in which 5-HT2ABPND was greater in ecstasy (MDMA) users than in controls (Table 2). Panels c.-f. show representative clusters from a. and b. with Brodmann Area labels ...
Table 2
Between-Groups Analysis (all subjects)
Table 3
Adjusted Mean 5-HT2ABPND from between-groups analysis

Within-group analysis of MDMA/ecstasy dose effects

Lifetime MDMA use (as ecstasy mg) was positively associated with receptor binding in four cortical clusters located mainly in fronto-parietal (β=0.665, p=0.007), occipito-temporal (β=0.798, p=0.002), fronto-limbic (β=0.634, p= 0.024), and frontal regions (β=0.691, p=0.008) (Figure 2; Table 4). In contrast, there were no regions in which lifetime MDMA use was statistically significantly associated with lower 5-HT2A receptor availability. While 5-HT2ABPND levels were non-significantly positively associated with the duration of MDMA abstinence, abstinence duration was not statistically significantly associated with 5-HT2ABPND in any region (fronto-parietal cluster [β=0.462, p=0.336]; occipito-temporal [β=0.200, p=0.971]; fronto-limbic [β=0.331, p=0.527]; and frontal [β=0.450, p=0.372] clusters; p>0.05, uncorrected) in the model adjusting for covariates but excluding the predictor variable of lifetime MDMA use. When we included the duration of MDMA abstinence in the regression model, the association of lifetime MDMA use remained significant in all regions (p<0.05). This result suggested that the association between lifetime MDMA use and increased 5-HT2ABPND does not weaken with extended abstinence.

Figure 2
Panels a. and b. depict right hemisphere and bilateral superior regions, respectively, in which lifetime ecstasy use correlates positively with 5-HT2ABPND in the ecstasy (MDMA) user group after adjusting for birth control, estrogen, and age (Table 4). ...
Table 4
Within-Group Regression Analysis (MDMA/ecstasy users only)

Within-group analysis of polydrug use effects

To ensure that the observed association of lifetime MDMA use with 5-HT2ABPND was not driven by exposure to other drugs of abuse, we conducted analyses examining the association of regional 5-HT2ABPND with other drug use, including nicotine. There were no statistically significant associations (p>0.05, uncorrected) of lifetime units of other drugs with 5-HT2ABPND in any cluster (fronto-parietal, occipito-temporal, fronto-limbic, and frontal).

Comment

The current findings reveal that female MDMA users have chronic changes in cortical 5-HT function that consist of greater 5-HT2A receptor levels in MDMA users and increasing 5-HT2A receptor levels with increasing MDMA use. We hypothesized that MDMA users would have increased cortical 5-HT2ABPND--a finding consistent with MDMA-induced chronic reductions in cortical 5-HT synaptic neurotransmission leading to compensatory upregulation of the 5-HT2A receptors. While the results support our hypothesis, the interpretation of these findings must remain speculative since we did not measure brain 5-HT levels and since factors other than MDMA-induced 5-HT axon loss may account for the current findings.

While the current observations are consistent with chronically reduced cortical 5-HT, this interpretation is limited by the fact that the 5-HT2A receptor has not been sufficiently validated as a measure of 5-HT denervation and it is also possible that chronic reductions in cortical 5-HT neurotransmission might occur in the absence of 5-HT axon loss. Increased 5-HT2ABPND could theoretically be due to a combination of compensatory receptor upregulation or reduced competition for synaptic 5-HT with [18F]setoperone. However, acute tryptophan depletion has been associated with decreased 5-HT2A receptor binding in humans in broad regions of cortex using [18F]setoperone78 and in frontal cortex using the highly selective 5-HT2A ligand [11C]MDL100907.79 Studies examining the effects of chronically reduced 5-HT on the 5-HT2A receptor have produced mixed results; for example, three weeks of chronic tryptophan depletion leads to increased 5-HT2A levels in rat cortex80 and 5-HT2A receptors were increased in rat prefrontal cortex 20 days after 5,7-dihydroxytryptamine (5,7-DHT) lesions of the dorsal raphe81 but were decreased in cortex three weeks after 5,7-DHT lesions to rat dorsal and median raphe82 and unchanged in rat frontal cortex two weeks after intracisternal 5,7-DHT.83 Rats given neurotoxic regimens of MDMA had decreased 5-HT2A binding in frontal, parietal, and occipital cortices at 6 hours after MDMA administration, but at 3 days, receptors were decreased only in occipital cortex.26 Animals studied at 30 days after MDMA receipt had significant increases in 5-HT2A receptor binding only in frontal regions, despite a 90% average reduction in cortical 5-HT and 5-HIAA content.26 The strong relationship between increased MDMA exposure and greater 5-HT2ABPND observed in the current study is in line with animal studies of graded increases in toxicity with increasing exposure to MDMA9;74 and is also consistent with results indicating that lifetime MDMA exposure is positively correlated with task-evoked brain activation.3537 MDMA use is also associated with altered functional connectivity84 that is suggestive of reduced 5-HT function.32 This suggests the possibility that both 5-HT2A receptor levels and increased task-evoked activation reflect reduced cortical 5-HT signaling.

Reneman and colleagues26 reported that MDMA users abstinent from MDMA for an average of 3.3 weeks had reduced 5-HT2A receptor levels in frontal, parietal, and occipital cortices (as measured by [123I]R91150 SPECT), whereas those abstinent for an average of 19.6 weeks had significantly increased 5-HT2A binding in occipital regions, but not the remainder of cortex. Our current findings are consistent with their results26 regarding increased 5-HT2A receptors in occipital cortex of abstinent MDMA users but extend those findings in a cohort of females to multiple cortical regions, demonstrate a lack of recovery with extended abstinence, and strengthen the argument for specificity to MDMA exposure by demonstrating a dose-response effect. Several factors, including a homogenous female cohort, verified abstinence, improved kinetic properties and tracer kinetic modeling, as well as possible increases in resolution (although partially offset by the degree of smoothing) afforded by PET may have permitted us to detect broader effects. A recent report used [18F]altanserin to examinine the 5-HT2A receptor and [11C]DASB to examine the 5-HT transporter in MDMA-preferring and hallucinogen-preferring drug users and controls. Because both hallucinogens and MDMA have 5-HT2A agonist effects, Erritzoe and colleagues27 predicted that the 5-HT2A receptor would be lower in recent hallucinogen and MDMA users than in controls. However, use of MDMA or hallucinogens was not clearly associated with lower 5-HT2A receptor binding, despite reductions in the 5-HT transporter binding in the MDMA-preferring group. In a subset analysis of users with longer MDMA abstinence periods that more closely paralleled those of Reneman and colleagues26 Erritzoe and colleagues were unable to detect chronic increases in 5-HT2A binding, which they considered potentially due to opposing effects of hallucinogen use on receptor regulation or due to reduced 5-HT transporter binding and associated changes in 5-HT transmission. Concern for the possibility of residual acute effects of recent MDMA use led to our choice of a minimum 90-day abstinence period from MDMA and other drugs potentially influencing the 5-HT2A receptor as a requirement for enrollment. Although we did not find evidence to suggest that receptor levels decrease with increasing abstinence from MDMA, it is possible that 5-HT2A levels might have normalized in our cohort with a greater period of abstinence.

Increased 5-HT2ABPND in association with MDMA use was not found in all cortical regions and involved more regions in the right hemisphere. The basis for the pattern of findings is unclear. It is possible that 5-HT axons in some brain regions are more vulnerable to MDMA effects or that regional differences in 5-HT2A receptors account for the findings. There was considerable overlap between regions having increased 5-HT2A in MDMA users and regions showing a positive association of 5-HT2ABPND and lifetime ecstasy use, suggesting that MDMA exposure may account for the findings in both analyses.

While we did not detect differences in depression or anxiety,85;86 impulsivity, or novelty seeking between MDMA users and controls, a cross sectional study method as used here cannot rule out the possibility that pre-existing differences in brain function, personality, or behavior87;88 might predispose to MDMA use and might also be associated with altered serotonin function. Some evidence suggests that memory impairment persists in abstinent MDMA users despite the potential for recovery of the 5-HT transporter.89 This suggests that the persistent changes in the 5-HT receptor may be related to chronic memory impairments. However, the relationship between memory, the 5-HT2A receptor and the 5-HT transporter may prove complex as McCann and colleagues90 reported that verbal memory correlated more strongly with 5-HT transporter levels in controls than in MDMA users and preliminary data suggested that verbal memory was negatively correlated with 5-HT2A receptors in MDMA users.15 The significance of altered 5-HT signaling in the absence of detected negative consequences of MDMA exposure remains uncertain but one possibility is that MDMA users may have compensated for partial reductions in brain 5-HT signaling. Since MDMA users have been reported to have impairments in neurocognition,12 sleep,91 and altered pain processing,92 as well as increased sleep apnea,93 studies assessing the relationship of 5-HT function to these conditions are warranted.

We applied strict inclusion criteria to our cohort and restricted our study to females to maximize cohort homogeneity and to isolate the effects of MDMA on 5-HT2A receptors. We controlled for factors associated with receptor binding in our cohort (estrogen, birth control, and age), but the number of variables that we adjusted for was large relative to our sample size. Therefore, we may not have fully accounted for the influence of these variables in the overall model. Since we studied healthy females, we cannot generalize these findings to males or to those with anxiety or depression. However, we consider it likely that similar processes operate in males and that the association of MDMA use with 5-HT2A levels is likely to be equally evident, if not more so, in those more vulnerable to psychiatric disorders. Given the major role of 5-HT in anxiety and mood disorders, coupled with evidence from some studies that MDMA users have higher rates of anxiety and depression,85;86 additional studies that examine 5-HT2A receptor status in broader cohorts are warranted. Although we did not find strong evidence that drug use was higher in the MDMA users, this is likely in part due to sample size limitations. However, we did not detect a significant association of other drug use and 5-HT2A receptor levels and it therefore seems unlikely that other drug exposure accounts for the current findings. We did not assess MDMA users to determine why they stopped using MDMA, creating the possibility that we recruited a group of subjects who stopped MDMA due to negative effects and who potentially were more vulnerable to toxicity. While we excluded subjects who had been diagnosed and treated for psychiatric conditions such as depression, it is possible that some subjects had prior exposure to non-recreational drugs that could potentially affect the 5-HT2A receptor. While we interpret our findings as consistent with reduced cortical 5-HT signaling, we did not obtain additional measures of cortical 5-HT signaling, such as cerebrospinal fluid 5-HT metabolite levels.31;94

MDMA is a fascinating drug that acutely affects psychological processes and social behaviors. Acute MDMA use produces a sense of improved mood and well-being95 and enhances sociability.4;96 However, MDMA may also prove to be neurotoxic when taken in large or in multiple dosages,97 or when combined with activities (such as dancing) that raise body temperature. Human MDMA plasma concentrations increase greatly when multiple dosages are taken within a narrow time window97 and animal studies have demonstrated that MDMA’s 5-HT toxicity is dose and hyperthermia dependent.9 If MDMA is approved as a treatment for psychiatric conditions, studies determining the dose and conditions that are therapeutic versus neurotoxic will be essential.

In conclusion, our findings indicate that human MDMA use is associated with long-lasting changes in 5-HT2A receptor availability that do not decrease with drug abstinence. The current results suggest that MDMA produces chronic alterations in cortical 5-HT signaling that is possibly reflective of MDMA-induced neurotoxicity in humans. Given the broad role of 5-HT in human brain function, the possibility for therapeutic MDMA use, and the widespread recreational popularity of this drug, our results have critical implications for human MDMA users.

Acknowledgments

This work was supported by NIDA/NIH (R01 DA015137 and R21 DA020149 to RLC-design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript), NIMH/NIH (K01 MH083052 to JUB)-preparation, review, or approval of the manuscript, NIMH/NIH (R21 MH087803-02 to RMS)-preparation, review, or approval of the manuscript, NIDA/NIH (K12 DA00357 to MB)-preparation, review, or approval of the manuscript, and NCRR/NIH (Vanderbilt CTSA Grant UL1 RR024975).

Contributor Information

Christina R Di Iorio, Vanderbilt University School of Medicine, Vanderbilt University Psychiatric Neuroimaging Program, Vanderbilt University Addiction Center, 1601 23rd Avenue S, Suite 3057, Nashville, TN 37212.

Tristan J Watkins, Vanderbilt University School of Medicine, Vanderbilt University Psychiatric Neuroimaging Program, Vanderbilt University Addiction Center, 1601 23rd Avenue S, Suite 3057, Nashville, TN 37212.

Mary S Dietrich, Vanderbilt University School of Medicine, Vanderbilt University School of Nursing, Vanderbilt University Psychiatric Neuroimaging Program, Vanderbilt University Addiction Center, 410 Godchaux Hall, 461 21st Avenue S, Nashville, TN 37240.

Aize Cao, Vanderbilt University Institute of Imaging Science, Vanderbilt University Psychiatric Neuroimaging Program, Vanderbilt University Addiction Center, 1161 21st Avenue S, AA-1105 MCN, Nashville, TN 37232-2310.

Jennifer U Blackford, Vanderbilt University School of Medicine, Vanderbilt University Psychiatric Neuroimaging Program, Vanderbilt University Addiction Center, 1601 23rd Avenue S, Suite 3057, Nashville, TN 37212.

Baxter Rogers, Vanderbilt University Institute of Imaging Science, 1161 21st Avenue S, AA-1105 MCN, Nashville, TN 37232-2310.

Mohammed S Ansari, Vanderbilt University School of Medicine, 1161 21st Avenue S, CCC 1121 MCN, Nashville, TN 37232-2675.

Ronald M Baldwin, Institute for Neurodegenerative Disorders, 60 Temple St, Suite 8A, New Haven, CT 06510.

Rui Li, Vanderbilt University School of Medicine, 1161 21st Avenue S, CCC 1121 MCN, Nashville, TN 37232-2675.

Robert M Kessler, Vanderbilt University School of Medicine, 1161 21st Avenue S, CCC 1121 MCN, Nashville, TN 37232-2675.

Ronald M Salomon, Vanderbilt University School of Medicine, 3rd Floor Clinic, 1601 23rd Avenue S, Nashville, TN 37212.

Margaret Benningfield, Vanderbilt University School of Medicine, 1601 23rd Avenue S, Suite 3011, Nashville, TN 37212.

Ronald L Cowan, Vanderbilt University School of Medicine, Vanderbilt University Psychiatric Neuroimaging Program, Vanderbilt University Addiction Center, 1601 23rd Avenue S, Suite 3057, Nashville, TN 37212.

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