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Human psychobiology of MDMA or 'Ecstasy': An overview of 25 years of empirical research
Abstract
This paper aimed to review how scientific knowledge about the human psychobiology of MDMA has developed over time.
In this paper, the empirical findings from earlier and later studies will be reviewed.
When MDMA was a 'novel psychoactive substance', it was not seen as a drug of abuse, as it displayed loss of efficacy. However, recreational users display a unique pattern of increasing doses, deteriorating cost-benefit ratios, and voluntary cessation. MDMA increases body temperature and thermal stress, with cortisol levels increased by 800% in dance clubbers. It can be extremely euphoric, although negative moods are also intensified. MDMA causes apoptosis (programmed cell death) and has been investigated for cancer therapy because of its anti-lymphoma properties. Recreational users show deficits in retrospective memory, prospective memory, higher cognition, problem solving, and social intelligence. Basic cognitive skills remain intact. Neuroimaging studies show reduced serotonin transporter levels across the cerebral cortex, which are associated with neurocognitive impairments. Deficits also occur in sleep architecture, sleep apnoea, complex vision, pain, neurohormones, and psychiatric status. Ecstasy/MDMA use during pregnancy leads to psychomotor impairments in the children.
The damaging effects of Ecstasy/MDMA are far more widespread than was realized a few years ago, with new neuropsychobiological deficits still emerging. Copyright © 2013 John Wiley & Sons, Ltd.
Supplementary resource (1)
... We conducted a structured literature search to retrieve publications from January 2000 to February 2020 using Embase, PubMed, and Google Scholar. We decided that it was not relevant to perform a systematic review, because several biomedical issues have already been covered by (systematic) reviews and metaanalyses, and a considerable part of the required information was only available from non-peer-reviewed (internet) sources (Dunlap et al., 2018;Liechti, 2014;Michael White, 2014;M€ uller et al., 2019;Murphy et al., 2012;Parrott, 2013;Rogers et al., 2009;Simmler & Liechti, 2018). The aim of this review is, therefore, to bring together the information on a broad range of ecstasy-related aspects, including and international review about (1) applications of MDMA, and (2) pharmacological profile of MDMA, and a review on the situation in the Netherlands regarding (3) use and user characteristics, (4) market characteristics, (5) harm to the user, (6) harm to the population, and (7) crime related to ecstasy. ...
... Ecstasy rarely leads to acquisitive crime or violent behavior in the public domain (van Amsterdam et al., 2019). In contrast, considering its empathogenic effects (Parrott, 2013), ecstasy facilitates altruism and social behavior. Indeed, it was demonstrated that ecstasy use was not associated with an increase in violent behavior (Parrott, 2013). ...
... In contrast, considering its empathogenic effects (Parrott, 2013), ecstasy facilitates altruism and social behavior. Indeed, it was demonstrated that ecstasy use was not associated with an increase in violent behavior (Parrott, 2013). However, in another study, after controlling for confounders (family history of antisocial behavior, lifetime psychiatric, and substance use disorders), ecstasy users in the USA were more often engaged in violent and nonviolent crime than non-ecstasy users, but this may be related to the concomitant use of other substances, notably alcohol (Vaughn et al., 2015). ...
Introduction
Ecstasy (MDMA) is a popular recreational drug, but its illegal production and trade in the Netherlands have developed into a serious public order and ecological problem which endanger and question the harm reduction approach of the Dutch ecstasy policy.
Methods
The market characteristics, adverse health effects, risk profile, and link to criminal activity of ecstasy were reviewed.
Results
Ecstasy is often used in combination with other substances (i.e. polydrug use). Compared to several other illicit drugs and alcohol, ecstasy has a very low abuse and dependence liability and, as yet, there is little evidence of long-term harm. A potential health risk associated with ecstasy is acute hyperthermia, however this occurs at an unknown incidence rate and seems to be more prevalent when ecstasy is consumed in combination with heavy exercise at high ambient temperatures or when used in combination with other substances, including alcohol. Organized crime related to the production and trafficking of ecstasy in the Netherlands is a growing problem.
Conclusions
This review provides a science-based summary that can be used to assist the public and political debate surrounding future Dutch ecstasy policy to reduce ecstasy-related organized crime while maintaining the principle of harm reduction.
... associated with MDMA use, including neurocognitive deficits in areas such as concentration and memory, as well as negative mental health consequences such as depression and anxiety (Parrott, 2013). Understanding the potential negative long-term impact of MDMA is vital for understanding its risk profile, but some research seems to approach the user experience of drug effects from what has been referred to in health psychology as a 'deficit model' (Joffe, 2003). ...
... Participants were asked to indicate the extent to which 26 statements indicating possible long-term effects were true or not true for them, using a 0-100 sliding scale (0 = "Not at all true for me", 100 = "Completely true for me"). Long-term effects were based upon several sources, including reported longterm effects that might occur in therapy (Mithoefer et al., 2019;Wagner et al., 2017), longterm effects of classic psychedelic drugs (Elsey, 2017), extrapolations of acute effects (Bershad et al., 2016;Green et al., 2019;Kamilar-Britt and Bedi, 2015;Sumnall et al., 2006;Verheyden et al., 2003), long-term effects reported in previous studies of MDMA (Carhart-Harris and Nutt, 2010;Parrott, 2013;Verheyden et al., 2003), anecdotal reports, and psychological factors of general clinical relevance (e.g., several items may be recognized as tapping into aspects of Beck's 'cognitive triad', reflecting views of the self, the world, and the future -Beck, Rush, Shaw, & Emery, 1979). ...
... Negative impacts of MDMA on concentration and memory, as well as on feelings about one's life and the future, stand out as receiving slightly more endorsement than other negative items. These types of effects were some of the more consistently reported negative effects of MDMA in previous research (Parrott, 2013). Hence, our findings further highlight that concentration, memory, and mood may be areas of concern for MDMA users (balanced with an appreciation that a larger number of people reported positive effects on their view of their life/the future). ...
Background. Previous research has focused largely on risks associated with non-clinical (‘recreational’) MDMA use. Potential benefits produced through MDMA-assisted psychotherapy raise the question whether recreational users might report some positive long-term effects of MDMA use.
Aim. 1) To assess the perceptions of recreational MDMA users regarding a wide range of both positive and negative long-term effects of MDMA use. 2) To generate a large data set including other correlates of interest to highlight targets for future research.
Methods. Eight-hundred and eighty-six MDMA users gave valid responses to an online survey, covering perceived long-term effects, acute and subacute effects, use motivations, contexts of use, and polydrug use. We present descriptive results for motivations, acute, subacute, and long-term effects, and exploratory relationships between long-term effects and these variables.
Results. User perceptions of MDMA’s long-term effects were far more positive than negative, with a positive overarching perspective on having used MDMA and endorsement of several more specific effects. Negative/unpleasant acute and subacute effects of MDMA use were positively related to negative long-term effects. Positive/pleasant acute and subacute effects were positively related to positive long-term effects. User motivations were also significantly associated with perceived long-term effects. A minority of users reported negative effects (e.g., on concentration/memory and mood), which should not be ignored.
Conclusions. Factors beyond the anticipation of a short-term high likely play into many users’ decisions to use MDMA. A nuanced understanding of user perceptions can inform drug safety communication, our understanding of drug effects, and drug policy.
... The substance became available worldwide in the 1980s and has been used since as a recreational drug [12]. MDMA is an amphetamine analog that possesses both central nervous system stimulant and hallucinogenic properties and functions primarily by acting as a presynaptic releasing agent of serotonin, norepinephrine, and dopamine [13]. As a PS, MDMA enhances euphoria, every sense (especially smell and touch), emotional empathy, and prosocial behavior and is thus called a good mood drug [14,15]. ...
... As a PS, MDMA enhances euphoria, every sense (especially smell and touch), emotional empathy, and prosocial behavior and is thus called a good mood drug [14,15]. Although cases of excessive MDMA intake are rare, an overdose can cause several acute adverse health effects such as hypertension, faintness, seizures, and panic attacks [13], and regular intake causes sleep disturbance, depression, heart disease, and impulsive behavior. The illicit substance destroys nerve cells that produce serotonin and dopamine [16], and its chronic use can lead to a decrease in cognitive function [17]. ...
The widespread abuse of illicit psychoactive substances is one of the most serious public health and social problems. A suspicious airmail package was seized by Korean customs, and two psychoactive substances in the grayish-green pills in the package were detected by ultra-performance liquid chromatography. The structures of the two substances were elucidated by a combination of liquid chromatography quadrupole time-of-flight mass spectrometry, nuclear magnetic resonance spectroscopy, and comparison with reported or newly generated spectral data of the suggested structures. One of the psychoactive substances proved to be MDMA (commonly known as “Ecstasy”), and the other compound was an M-ALPHA analog bearing a hydroxyl group and an N-methylcarboxamide group. The new M-ALPHA analog was determined as 3-(benzo[d][1,3]dioxol-5-yl)-2-hydroxy-N,2-dimethyl-3-(methylamino)propanamide and named as M-ALPHA-HMCA, wherein HMCA denotes hydroxymethylcarboxamide. Although psychoactivity of this compound has not been assessed, M-ALPHA-HMCA should be considered a potential new psychoactive substance and/or a by-product of MDMA.
... Literature also suggests that harms arising from MDMA consumption are predominantly associated with acute adverse events (e.g. jaw clenching, increased heart rate, dizziness and hyperactivity) [9] that are relatively modest and transient in their impact [10]. Some of the more serious adverse effects, however, include tachycardia, hypertension, hyperthermia, serotonin syndrome, seizures, stroke, hyponatremia and cardiac arrest [9,11,12], as well as an elevated risk for traumatic injury and suicide [13]. ...
... jaw clenching, increased heart rate, dizziness and hyperactivity) [9] that are relatively modest and transient in their impact [10]. Some of the more serious adverse effects, however, include tachycardia, hypertension, hyperthermia, serotonin syndrome, seizures, stroke, hyponatremia and cardiac arrest [9,11,12], as well as an elevated risk for traumatic injury and suicide [13]. These risks can occur as a result of pharmacokinetic actions of MDMA as well as in response to environmental conditions [14], and in some instances can result in death [11,15]. ...
Aims:
To determine trends in 3,4 methylenedioxymethamphetamine (MDMA)-related death rates across Australia, Finland, Portugal and Turkey and to analyse causes of death across countries; and 3. analyse the toxicology of deaths across countries.
Design:
Analysis of MDMA-related deaths extracted from a national coronial database in Australia (2001-2019) and national forensic toxicology databases in Finland (2001-2017), Portugal (2008-2019) and Turkey (2007-2017). Presentation of MDMA use and seizure data (market indicators).
Setting:
Australia, Finland, Portugal and Turkey.
Cases:
All deaths in which MDMA was considered by the forensic pathologist to be contributory to death.
Measurements:
Information collected on cause and circumstances of death, demographics, and toxicology.
Findings:
1,400 MDMA-related deaths were identified in Turkey, 507 in Australia, 100 in Finland, and 45 in Portugal. The median age ranged from 24 to 27.5 years and males represented between 81 and 95% of the deaths across countries. Standardised mortality rates significantly increased across all four countries from 2011-2017, during a period of increased purity and availability of MDMA. The underlying cause of death was predominantly due to drug toxicity in Australia (n=309, 61%), Finland (n=70, 70%) and Turkey (n=840, 60%), and other causes in Portugal (n=25, 56%). Minorities of all deaths across the countries were due to MDMA toxicity alone (13-25%). These deaths had a significantly higher blood MDMA concentration than multiple drug toxicity deaths in Australia, Finland and Turkey. Drugs other than MDMA commonly detected were stimulants (including cocaine, amphetamine and methamphetamine) (Australia 52% and Finland 61%) and alcohol (Australia 46% and Portugal 49%). In addition to MDMA toxicity, benzodiazepines (81%) and opioids (64%) were commonly identified in these deaths in Finland. In comparison, synthetic cannabinoids (15%) and cannabis (14%) were present in a minority of deaths in Turkey.
Conclusions:
Deaths related to 3,4 methylenedioxymethamphetamine (MDMA) increased in Australia, Finland, Portugal and Turkey between 2011 and 2017. MDMA toxicity alone can be fatal but multiple drug toxicity remains more prevalent.
... OM MDMA MDMA er et sentralstimulerende rusmiddel som kanskje er saerlig kjent for gi en følelse av empati, og som i tillegg kan ha lette hallusinogene virkninger [53]. Etter THC er MDMA og kokain de mest brukte illegale stoffene i Norge [54]. ...
... MDMA gir en rus kjennetegnet av eufori, økt empati, forsterkede sanseopplevelser og følelser, økt mental og fysisk energi, og redusert behov for og evne til å sove. Siden MDMA kan forsterke følelser og påvirkes av den underforliggende sinnsstemningen, kan også negative følelser bli fremtredende under rus [53]. Noen personer opplever derfor angst, irritabilitet, panikk, humørsvingninger, paranoia og tap av personlig kontroll. ...
Publication in Norwegian. "Drug and violence statistics 2010-2019 - Findings in blood samples taken during police investigation of cases of violence in the period 2010-2019"
... Extensive literature search on the MDMA's mechanism of action (8)(9)(10)(11) has come to characterize it as a drug with multiple mechanisms, that involve altering the activity of neurotransmitter amines in the brain, i.e., serotonin, dopamine and norepinephrine, but the final consensus is that the distinctive entactogenic effects arise primarily from the release of neurotransmitter serotonin which likely contributes to the recreational use (12)(13)(14)(15). ...
... The acute environmental toxicities were computed as follows: a) for entactogens the TOX_FHM in the range from 2.65 (11) to 172.27 (13) mg L -1 , TOX_ATPP from -0.62 (18) Based on the predicted biodegradability as well as the obtained computed scores for TOX_FHM, TOX_ATTP, TOX_DM and TOX BCF for the set of entactogen molecules 1-25 and the set of their o-quinone metabolites (1-M1 to 25-M1), it can be concluded that o-quinone metabolites are more ecotoxic comparing to their parent entactogens. ...
The impact of the selected entactogens and their o -quinone metabolites on the environment was explored in QSAR studies by the use of predicted molecular descriptors, ADMET properties and environmental toxicity parameters, i.e. , acute toxicity in Tetrahymena pyriformis (TOX_ATTP) expressed as Th_pyr_pIGC50 /mmol L ⁻¹ , acute toxicity in Pimephales promelas , the fathead minnow (TOX_FHM) expressed as Minnow LC50 /mg L ⁻¹ , the acute toxicity in Daphnia magna (TOX_DM) expressed as Daphnia LC50 /mg L ⁻¹ and bioconcentration factor (BCF).
The formation of corresponding o -quinones via benzo-dioxo-lone ring, O -demethylenation was predicted as the main metabolic pathway for all entactogens except for 1-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl)propan-2-amine (DiFMDA). The least favourable ADMET profile was revealed for N -(1-(benzo[ d ][1,3]dioxol-5-yl)propan-2-yl)- O- methylhydroxylamine (MDMEO).
QSAR studies revealed significant linear correlations between MlogP of entactogens and MlogP of o -quinone metabolites ( R = 0.99), and Th_pyr_pIGC50 /mmol L ⁻¹ ( R = 0.94), also their MlogP s with Minnow_LC50 /mg L ⁻¹ ( R = 0.80 and R = 0.78), BCF ( R = 0.86 and R = 0.82) and percentage of o -quinones’ yields ( R = 0.73 and R = 0.80). Entactogens were predicted as non-biodegradable molecules, whereas the majority of their o -quinones were biodegradable.
... 5. 3,4-Methylenedioxymethamphetamine. The debate on the neurotoxicity of MDMA creates a longstanding divide (Mithoefer et al., 2003;Parrott, 2013Parrott, , 2014Doblin et al., 2014;Pantoni and Anagnostaras, 2019;Ricaurte et al., 2002 [retracted]). Most of the available early preclinical research is focused on the neurotoxic effects of MDMA, which may explain cognitive impairments and psychiatric sequelae in MDMA abusers (Parrott, 2001(Parrott, , 2013. ...
... The debate on the neurotoxicity of MDMA creates a longstanding divide (Mithoefer et al., 2003;Parrott, 2013Parrott, , 2014Doblin et al., 2014;Pantoni and Anagnostaras, 2019;Ricaurte et al., 2002 [retracted]). Most of the available early preclinical research is focused on the neurotoxic effects of MDMA, which may explain cognitive impairments and psychiatric sequelae in MDMA abusers (Parrott, 2001(Parrott, , 2013. To simulate binge abuse and the resulting neurotoxic effects, relatively high doses (often in a chronic-administration design) were administered in these studies, with considerable neurotoxicity (Pantoni and Anagnostaras, 2019). ...
Mounting evidence suggests safety and efficacy of psychedelic compounds as potential novel therapeutics in psychiatry. Ketamine has been approved by the Food and Drug Administration in a new class of antidepressants, and 3,4-methylenedioxymethamphetamine (MDMA) is undergoing phase III clinical trials for post-traumatic stress disorder. Psilocybin and lysergic acid diethylamide (LSD) are being investigated in several phase II and phase I clinical trials. Hence, the concept of psychedelics as therapeutics may be incorporated into modern society. Here, we discuss the main known neurobiological therapeutic mechanisms of psychedelics, which are thought to be mediated by the effects of these compounds on the serotonergic (via 5-HT2A and 5-HT1A receptors) and glutamatergic [via N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] systems. We focus on 1) neuroplasticity mediated by the modulation of mammalian target of rapamycin–, brain-derived neurotrophic factor–, and early growth response–related pathways; 2) immunomodulation via effects on the hypothalamic-pituitary-adrenal axis, nuclear factor ĸB, and cytokines such as tumor necrosis factor-α and interleukin 1, 6, and 10 production and release; and 3) modulation of serotonergic, dopaminergic, glutamatergic, GABAergic, and norepinephrinergic receptors, transporters, and turnover systems. We discuss arising concerns and ways to assess potential neurobiological changes, dependence, and immunosuppression. Although larger cohorts are required to corroborate preliminary findings, the results obtained so far are promising and represent a critical opportunity for improvement of pharmacotherapies in psychiatry, an area that has seen limited therapeutic advancement in the last 20 years. Studies are underway that are trying to decouple the psychedelic effects from the therapeutic effects of these compounds.
Significance Statement
Psychedelic compounds are emerging as potential novel therapeutics in psychiatry. However, understanding of molecular mechanisms mediating improvement remains limited. This paper reviews the available evidence concerning the effects of psychedelic compounds on pathways that modulate neuroplasticity, immunity, and neurotransmitter systems. This work aims to be a reference for psychiatrists who may soon be faced with the possibility of prescribing psychedelic compounds as medications, helping them assess which compound(s) and regimen could be most useful for decreasing specific psychiatric symptoms.
... MDMA induces rapid serotonin and dopamine release, and directly binds to serotonin 5HT2 receptors (Parrott, 2013a). Repeated MDMA exposure is neurotoxic, with evidence of loss of serotonin transporters over time in both animal models and humans (Parrott, 2013a,b). ...
... Repeated MDMA exposure is neurotoxic, with evidence of loss of serotonin transporters over time in both animal models and humans (Parrott, 2013a,b). MDMA has been described as a "mood intensifier" and enhances feelings of intimacy and empathy (Parrott, 2013a). ...
Insomnia related to substance abuse, or substance-induced sleep disorder, refers to significant sleep difficulty that is directly associated with active use of or abstinence from a substance. There are numerous prescription and illicit substances that, when abused, can lead to insomnia. This article discusses the substances most commonly implicated in sleep disturbance, including their mechanistic and physiologic effects on sleep, according to the most recent literature. It also highlights potential treatment options for patients with insomnia related to substance abuse.
... However, MDMA's capacity to facilitate fear memory extinction is abolished when brain-derived neurotrophic factor (BDNF) signaling is inhibited before extinction paradigms suggesting a BDNF-dependent mechanism (59,(86)(87)(88). Facilitating the fear-extinction process is widely cited as one of MDMA's potential therapeutic mechanisms (34,35,60,61,(89)(90)(91). Under careful medical supervision and with specialized psychotherapy, a few sessions that include MDMA pre-treatment appear to facilitate the recall of traumatic memories without the user feeling overwhelmed by the negative affect that usually accompanies such memories (22,51). ...
... In concert, the distinct pharmacological profile of MDMA (including its ability to boost serotonin, oxytocin, prolactin, and cortisol) contributes to the unique subjective effects of MDMA (22,91). Given their similar etiologies and frequent symptom overlap, it is not surprising that we observed a high degree of therapeutic response among PTSD participants with depression comorbidity. ...
BACKGROUND:
Posttraumatic stress disorder (PTSD) is a common psychiatric condition that can develop following a traumatic experience. PTSD is associated with significant disability, a large economic burden, and despite the range of therapies to treat PTSD, response to antidepressants is limited. A growing body of clinical research suggests the efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in individuals with treatment-refractory PTSD.
AIM:
To assess the effectiveness and safety of MDMA-assisted psychotherapy for reducing symptoms of PTSD, a systematic review and meta-analysis was undertaken.
METHODS:
Six online databases were searched from inception to December 2018. Reference lists of relevant articles were manually searched as well as electronic sources of ongoing trials and conference proceedings. Researchers active in the subject were also contacted. Eligible studies included randomized and quasi-randomized clinical trials using MDMA-assisted psychotherapy for PTSD in comparison with other medications, placebo or no medication (supportive care). We used standard methodological procedures expected by the Cochrane Collaboration. Two authors assessed studies for inclusion and extracted data. Using random-effects meta-analysis with Cochrane's Review Manager 5.3, we obtained standardized mean differences [SMD] and rate ratios [RR] for reduction in PTSD symptomatology.
RESULTS:
A total of 5 trials met inclusion criteria, totaling 106 participants (average age: 35-40 years, 70% female). Studies were rated as moderate in quality. MDMA-assisted psychotherapy demonstrated a high rate of clinical response (RR = 3.47, 95% CI: 1.70, 7.06), remission (RR = 2.63, 95% CI: 1.37, 5.02), with a large effect size at reducing the symptoms of PTSD (SMD = 1.30, 95% CI: 0.66, 1.94). Available evidence indicates that MDMA was well-tolerated, with few serious adverse events reported across studies.
CONCLUSIONS:
MDMA-assisted psychotherapy appears to be a potentially safe, effective, and durable treatment for individuals with chronic, treatment-refractory PTSD. However, future studies involving larger samples and longer durations of treatment and follow-up are warranted-and underway.
... However, MDMA's capacity to facilitate fear memory extinction is abolished when brain-derived neurotrophic factor (BDNF) signaling is inhibited before extinction paradigms suggesting a BDNF-dependent mechanism (Andero and Ressler, 2012;Mouri et al., 2017;Soleimani Asl et al., 2017;Vas et al., 2009). Facilitating the fear-extinction process is widely cited as one of MDMA's potential therapeutic mechanisms (Meyer, 2013;Feduccia and Mithoefer, 2018;Young et al., 2015;Young et al., 2017;Doblin, 2002;Parrott, 2007Parrott, , 2013. Under careful medical supervision and with specialized psychotherapy, a few sessions that include MDMA pre-treatment appear to facilitate the recall of traumatic memories without the user feeling overwhelmed by the negative affect that usually accompanies such memories (Sessa, 2017a;Sessa, 2017b). ...
... In concert, the distinct pharmacological profile of MDMA (including its ability to boost serotonin, oxytocin, prolactin, and cortisol) contributes to the unique subjective effects of MDMA (Sessa, 2017a;Parrott, 2013). Given their similar etiologies and frequent symptom overlap, it is not surprising that we observed a high degree of therapeutic response among PTSD participants with depression comorbidity. ...
MDMA (3,4-methylenedioxymethamphetamine) is a amphetamine-type recreational drug that has recently re-emerged in clinical settings as a potential treatment for those with refractory PTSD.
... The present study is part of the ALAMA nightlife study, including five European countries: the Netherlands, the UK, Belgium, Italy, and Sweden. In the period May to November 2017, an online survey was conducted among young adults (age [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] frequently visiting EDM events (at least six times during the past 12 months). In the present study, data from Sweden were analyzed. ...
... The most common mental health consequences were mood disturbances (e.g., dysphoria), anxiety, panic attacks, sleep disturbances, and memory loss. Previous studies have attributed such consequences to the use of cannabis, ecstasy, amphetamine, and cocaine [5,29,[33][34][35][36][62][63][64], which are also the drugs most frequently used by participants in the present study. A recent meta-analysis shows that ecstasy users display deficits in the serotonergic transporter in several brain areas. ...
Illicit drug use is prevalent in the nightlife scene, especially at electronic dance music (EDM) events. The aim of the present study was to investigate illicit drug use patterns and consequences of drug use among frequent visitors of EDM events. Young adults (18–34 years old) who had visited at least six EDM events in Sweden during the past year participated in a web-based survey on drug use patterns and its consequences. Fifty-nine percent of participants had used illicit drugs during the past year, most often cannabis followed by ecstasy, cocaine, and amphetamine. Nightlife venues were identified as the main setting for the use of central stimulants, while cannabis was mostly used at home. Frequent alcohol and tobacco use was associated with illicit drug use. The most prevalent negative consequences of drug use were related to mental health, such as impairments in mood, sleep, and memory problems, but physical manifestations were also reported, such as palpitations and collapsing. These findings confirm that drug use is prevalent and associated with negative health effects among EDM nightlife attendees. The nightlife scene is a setting with promising potential to reach a high-risk target group with illicit drug use prevention interventions.
... Based on promising safety and efficacy results from the previous studies (Mithoefer et al., 2011;2013), Phase 2 randomized, controlled, double-blind, doseresponse studies trials were granted approval in the United States; a critical stage in new drug legalization (Hutchison & Bressi, 2020). One such study compared groups that received three different doses of MDMA (Ot'alora G et al., 2018). ...
... Another common criticism of legalizing MDMA for any kind of therapeutic use is its abuse potential, with studies upholding this claim often drawing from | Revue YOUR Review 8 recreational Ecstasy users who reported to health professionals or other substance use disorder (SUD) programs (Cottler et al., 2001;Danforth et al., 2016;Parrott, 2013). Sampling from recreational users who reported substance abuse issues introduces several confounding variables, including varying and extreme dosages, multiple substance use or "stacking," and dangerous environmental conditions (Danforth et al, 2016). ...
3, 4–methylenedioxymethamphetamine, or MDMA as it is commonly known, is classified as a “Schedule 1” substance in Canada and the United States. For decades, the compound has been shrouded by the stigma of being a dangerous party drug thought to kill brain cells and be severely addictive. However, when it was originally discovered, it was experimentally used in clinical settings as an adjunct to therapy. This idea is now resurfacing as researchers are turning back to MDMA as an innovative way to treat trauma-related mental health disorders like post-traumatic stress disorder. Considering the limitations of existing treatments for trauma-related disorders, MDMA’s pharmacological and psychological effects, and the growing body of methodologically sound research on MDMA-assisted psychotherapy, legalizing this type of therapy could provide much-needed relief to people struggling with the severe, painful, lifelong effects of trauma and related psychological disorders.
... An increased incidence of foetal cardiac and musculoskeletal anomalies and of psychomotor impairments in children has been reported in maternal users. 15 A component of the hallucination is increased libido, which can lead to unsafe sex. Because it causes impotence (affecting up to 19% of ecstasy users), it also leads to increased use of sildenafil. 1 ...
Recreational use of drugs may be viewed by those who indulge as a relatively victimless pursuit. However, as the author discusses in this article, that is far from the truth and those who engage in such activity should be made aware of the potential harms of their action, not least to the genitourinary system.
... MDMA strengthened action-outcome memory, blocking cocaine-induced habit biases, potentially suggesting that MDMA could be used as an adjunct to behavioral therapy for individual struggling with cocaine abuse. Although there is some concern regarding the use of MDMA as a therapeutic compound [58], it apparently has clinical efficacy in treating PTSD [59,60], and acute administration does not induce obvious harmful effects or trigger recreational usage [60]. Importantly, overexpression of a truncated form of trkB (TrkB.t1) ...
Cocaine use during adolescence decreases the likelihood that individuals will seek treatment for recurrent drug use. In rodents, developmental cocaine exposure weakens action-consequence decision-making, causing a deferral to familiar, habit-like behavioral response strategies. Here, we aimed to improve action-outcome decision-making. We found that acute pharmacological stimulation of the tyrosine/tropomyosin receptor kinase B (trkB) via 7,8-dihydroxyflavone (7,8-DHF) or 3,4-methylenedioxymethamphetamine (MDMA) blocked cocaine-induced habit biases by strengthening memory for action-outcome associations. We believe that MDMA acts by stimulating neurotrophin/trkB systems in the orbitofrontal cortex (OFC), a region involved in prospectively evaluating the consequences of one’s action, because 1) MDMA also increased brain-derived neurotrophic factor (BDNF) in the OFC, 2) MDMA corrected habit biases due to Bdnf loss in the OFC, and 3) overexpression of a truncated isoform of trkB occluded the memory-enhancing effects of MDMA. Thus, selecting actions based on their consequences requires BDNF-trkB in the OFC, the stimulation of which may improve goal attainment in both drug-naïve and cocaine-exposed individuals.
Significance Statement
Cocaine use during adolescence decreases the likelihood that individuals will seek treatment for recurrent drug use, even as adults. Understanding how early-life cocaine exposure impacts goal-oriented action and prospective decision-making in adulthood is thus important. One key aspect of goal-directed decision-making is anticipating the consequences of one’s actions, a process that likely involves the orbitofrontal cortex (OFC). In rodents, developmental cocaine exposure weakens action-consequence decision-making, causing a deferral to familiar, habit-like behavioral response strategies. Here, we report that we can improve memory for action-consequence relationships by stimulating neurotrophic factors, which support cell survival, development, and plasticity in the brain. With strengthened action-consequence associations, cocaine-exposed mice regain the ability to optimally select actions based on their likely outcomes. Brain region-selective manipulations reveal that neurotrophin systems in the OFC are necessary for stable memory of action-consequence relationships.
... The use of MDMA is highly alarming and, therefore, there is an urgent need to deeply understand the consequences of MDMA consumption. Neurotoxicity is one of them and evaluations of MDMA effects on human psychobiology have, consequently, been the focus of several studies [2][3][4][5][6]. Since studies on humans have ethical barriers, investigation on MDMA neurotoxicity in Immunohistochemical results showed no significant differences in NOX2 expression between CTRL and rats sacrificed after the three different time points from MDMA administration, as well as within the MDMA-exposed group ( Figure 1A-D). ...
Several mechanisms underlying 3,4-Methylenedioxy-N-methylamphetamine (MDMA) neurotoxicity have been proposed, including neurochemical alterations and excitotoxicity mediated by reactive oxygen species (ROS), nitric oxide (NO), and reactive nitrogen species (RNS). However, ROS, NO, and RNS sources in the brain are not fully known. We aimed to investigate possible alterations in the expression of the ROS producer NOX enzymes (NOX2, NOX1, and NOX4), NO generators (iNOS, eNOS, and nNOS), markers of oxidative (8-hydroxy-2′-deoxyguanosine, 8OHdG), and nitrosative (3-nitrotyrosine, NT) stress, as well as the colocalization between cells positive for the dopamine transporter (DT1) and cells expressing the neuronal nuclei (NeuN) marker, in the frontal cortex of rats receiving saline or MDMA, sacrificed 6 h, 16 h, or 24 h after its administration. MDMA did not affect NOX2, NOX1, and NOX4 immunoreactivity, whereas iNOS expression was enhanced. The number of NT-positive cells was increased in MDMA-exposed animals, whereas no differences were detected in 8OHdG expression among experimental groups. MDMA and NT markers colocalized with DT1 positive cells. DT1 immunostaining was found in NeuN-positive stained cells. Virtually no colocalization was observed with microglia and astrocytes. Moreover, MDMA immunostaining was not found in NOX2-positive cells. Our results suggest that iNOS-derived nitrosative stress, but not NOX enzymes, may have a crucial role in the pathogenesis of MDMA-induced neurotoxicity, highlighting the specificity of different enzymatic systems in the development of neuropathological alterations induced by the abuse of this psychoactive compound.
... While MDMA use is associated with its own unique dangers (Parrott, 2013), synthetic cathinones, commonly referred to as "bath salts" in the US, appear to be some of the most common adulterants or replacements for drugs sold as ecstasy/Molly (Oliver et al., 2018). Although drug-testing studies are lacking in the US, such studies throughout Europe have often detected "bath salts" such as methylone, mephedrone, 4-MEC, and ethylone in drugs sold as ecstasy (Brunt et al., 2016;Brunt, Poortman, Niesink, & van Den Brink, 2011;Hondebrink, Nugteren-van Lonkhuyzen, Van Der Gouwe, & Brunt, 2015;Vidal Gine et al., 2016). ...
Background: Ecstasy (3,4-methylenedioxymethamphetamine [MDMA]), commonly referred to as Molly in the US, is commonly adulterated with drugs potentially more dangerous than MDMA. Synthetic cathinones (“bath salts”) are common adulterants, and use of these compounds tends to be stigmatized. We investigated whether presenting information on the extent of ecstasy being adulterated with “bath salts” affects intentions to use.
Methods: A total of 1,025 adults entering electronic dance music parties were surveyed in 2018. Using an experimental posttest-only design with random assignment, half were randomly assigned to view a published Vice headline about ecstasy/Molly commonly being adulterated with “bath salts.”
Results: Overall, 30.5% of the sample reported past-year ecstasy use, and before viewing the headline, 16.4% agreed that ecstasy/Molly commonly contains “bath salts.” While controlling for pre-test knowledge of “bath salt” adulteration, viewing the headline reduced the odds of intention to use ecstasy/Molly only among non-past-year ecstasy users (Odd ratio [OR] = 0.54; p = .048). Viewing the headline increased the odds (OR = 1.81, p = .030) of past-year ecstasy users’ intention to test their ecstasy for adulterants.
Conclusions: Knowledge that ecstasy is commonly adulterated may help reduce the risk for future use among non-recent users and increase the willingness of users to test their ecstasy. This information can be used to target those at risk for ecstasy/Molly use.
... Decades of research has associated the consumption of pure MDMA with a range of health harms dependent on dose and context (potentiated by dancing in hot, crowded environments), including thermal stress and overheating, impaired thermoregulatory control and serotonin syndrome (15). But over and above the management of symptoms attributable to recreational consumption of pure MDMA, people who consume adulterated MDMA may experience psychoactive effects that are discrepant with their expectations. ...
Introduction and Aims
Ecstasy users in the electronic dance music scene are at high risk for using ecstasy adulterated with new psychoactive substances and/or methamphetamine. We examined self‐reported testing of ecstasy among users in this scene.
Design and Methods
We surveyed individuals (aged 18–40 years) entering electronic dance music parties in New York City in 2017. Past‐year ecstasy users (n = 351) were asked if they had tested their ecstasy in the past year. We estimated prevalence and correlates of having tested one's ecstasy.
Results
23.1% reported having tested their ecstasy in the past year. Those with some college (adjusted prevalence ratio [aPR] = 0.49, P = 0.014) or a college degree (aPR = 0.41, P = 0.025) were less likely to test their ecstasy than those with a high school diploma or less. Using ecstasy pills (aPR = 1.89, P = 0.036) or crystals (aPR = 1.90, P = 0.006) ≥3 times in the past year was associated with increased likelihood of testing one's ecstasy, and purchasing from an unknown or untrustworthy dealer was associated with decreased likelihood (aPR = 0.63, P = 0.034) of testing one's ecstasy. Half (51.1%) of ecstasy users reported finding out or suspecting their ecstasy had contained a drug other than MDMA. Of these, 49.2% reported finding out their ecstasy contained methamphetamine or speed/amphetamine. Most ecstasy users reported that they would be less likely to use again upon learning their ecstasy contained ‘bath salts’ (54.8%) or methamphetamine (54.3%).
Discussion and Conclusions
Drug testing appears to help ecstasy users detect adulterants and results can help inform harm reduction efforts. Less frequent users in particular may require education about adulteration and drug‐testing.
... Even 12 weeks later, a higher dose of MDMA was required to produce the prosocial effects previously elicited by MDMA in these subjects. This kind of "chronic tolerance" has been described in heavy recreational MDMA users (Parrott, 2005(Parrott, , 2013. Tolerance to MDMA may develop due to depletion of 5-HT, potentially caused by MDMA neurotoxicity (Baumann et al., 2008;Jones et al., 2010). ...
The recreational drug 3,4-methylenedioxymethamphetamine (MDMA) has well documented prosocial effects and is currently under clinical investigation as a treatment for patients with PTSD, autism, and other conditions. Early clinical trials have found that MDMA-assisted therapy may have robust long-lasting therapeutic effects, yet the mechanism by which acute treatments produce these long-term effects is unclear. Sensitization to certain behavioral drug effects is a common rodent model used to assess long-lasting neurobiological adaptations induced by acute drug treatments. Nine independent experiments were undertaken to investigate if and how mice sensitize to the prosocial effects of MDMA. When treated with 7.8 mg/kg MDMA and paired every other day for a week, MDMA-induced social interaction increased precipitously across treatment sessions. This previously unreported phenomenon was investigated and found to be heavily influenced by a social context and 5-HT2AR activation. Social sensitization did not appear to develop if mice were administered MDMA in isolation, and pretreatment with MDL100907, a selective 5-HT2AR antagonist, inhibited the development of social sensitization. However, when MDL100907 was administered to mice that had already been sensitized, it did not attenuate social interaction, suggesting that 5-HT2AR activity may be necessary for the development of social sensitization but not the expression of MDMA-induced social behavior. Additional investigation is warranted to further explore the phenomenon of social sensitization and to determine the underlying neurobiological mechanisms.
... Ever since the scheduling of MDMA, the health risks involved in the use of MDMA have been the subject of heated debate. Some believe that the consumption of one dose will cause irreversible health damage (Parrott, 2013(Parrott, , 2014Parrott et al., 2017), while others believe that MDMA is (relatively) harmless (Amoroso, 2018(Amoroso, , 2019Rogers et al., 2009). Especially in the international media, there is much concern about its safety. ...
Background
The recreational drug ecstasy (3,4-methylenedioxymethamphetamine) is currently used world-wide. Severe (including fatal) health incidents related to ecstasy have been reported but a risk assessment of acute non-fatal and fatal ecstasy-related health incidents has never been performed.
Methods
In the current risk assessment review, national data of non-fatal health incidents collected in the Netherlands were combined with the nationwide exposure to ecstasy, that is, last-year prevalence of ecstasy use. In addition, the annual number of ecstasy-related deaths in Great Britain (Scotland, Wales and England) was used to assess the risk of fatal ecstasy-related cases.
Results
In the Netherlands, the estimated risk of a moderate to severe acute health incident following the use of ecstasy is one in 900 pills (0.11%), whereas for cocaine it is one in 1600 doses (0.06%) and for gamma-hydroxybutyrate one in 95 doses (1.05%). With respect to ecstasy-related deaths in Great Britain, the estimated risk of ecstasy alone per user is 0.01–0.06%, which is close to the range of the fatality risk in chronic alcohol users (0.01–0.02%), amphetamine users (0.005%) and cocaine users (0.05%), but much lower than that of opiate use (heroin and morphine: 0.35%).
Conclusion
The current review shows that almost no data are available on the health risks of ecstasy use. The few data that are available show that ecstasy is not a safe substance. However, compared to opiates (heroin, morphine), the risk of acute ecstasy-related adverse health incidents per ecstasy user and per ecstasy use session is relatively low.
... Ecstasy is commonly associated with 3,4-methylenedioxymethamphetamine (MDMA), which produces prosocial, euphoric, and energizing effects (de la Torre et al., 2004). MDMA's biobehavioral effects have been well-characterized (de la Torre et al., 2004;Green et al., 2003;Parrott, 2013); however, street Ecstasy is commonly adulterated with substances in addition to or in lieu of MDMA. Despite the rebranding of Ecstasy as "Molly", crystalline Ecstasy commonly marketed as "pure" MDMA, various cathinone, piperazine, and amphetamine analogs are frequently detected in Ecstasy and "Molly" samples (Brunt et al., 2017;Saleemi et al., 2017). ...
Background:
Ecstasy typically contains adulterants in addition to, or in lieu of, MDMA which may pose a greater risk to users than MDMA itself. The current study aimed to evaluate the effectiveness of adulterant-related informational prompts in reducing Ecstasy use using a novel probability discounting task.
Methods:
An online sample of past-month Ecstasy users (N = 278) were randomized to one of four different framing prompt conditions: no prompt; a prompt describing MDMA's effects; a prompt describing adulterants as inert "filler"; or a prompt describing adulterants as pharmacologically-active, potentially-harmful compounds. Each prompt contained general, potential public-health information that was not specifically related to subsequent behavioral tasks. All participants then completed an identical Drug Purity Discounting Task, in which they indicated the likelihood of using a sample of Ecstasy across different probabilities of the sample being impure, and then completed a hypothetical Ecstasy purchasing task.
Results:
Likelihood of Ecstasy use decreased as impurity probability increased across conditions. Ecstasy use likelihood was highest in the "inert" prompt condition, whereas pharmacologically-active adulterant or adulterant-nonspecific prompts resulted in comparably low likelihood of use. Ecstasy-use likelihood did not differ among conditions when the likelihood of sample impurity was 0. Ecstasy purchasing did not differ among groups. Inelastic purchasing was associated with greater likelihood of using potentially-impure Ecstasy.
Conclusions:
Altogether, these data highlight the necessity of education regarding pharmacologically-active, rather than inert, adulterants in Ecstasy, and suggest that increased access to drug checking kits and services may mitigate some of the harms associated with Ecstasy use.
... Over the last several decades, more than a thousand papers examining the potential short and long-term effect of MDMA use have been published; however, results were inconsistent and at times contradictory given wide variability in the type, quality, participant selection criteria and methodologies utilized, generating considerable controversy [46,48]. For example, there has long been concern about MDMA-induced neurotoxicity based on prior studies on rodents and primates. ...
Though there was initial interest in the use of psychedelic drugs for psychiatric treatment, bad outcomes and subsequent passage of the Substance Act of 1970, which placed psychedelic drugs in the Schedule I category, significantly limited potential progress. More recently, however, there has been renewal in interest and promise of psychedelic research. The purpose of this review is to highlight contemporary human studies on the use of select psychedelic drugs, such as psilocybin, LSD, MDMA and ayahuasca, in the treatment of various psychiatric illnesses, including but not limited to treatment-resistant depression, post-traumatic stress disorder, end-of-life anxiety, and substance use disorders. The safety and efficacy as reported from human and animal studies will also be discussed. Accumulated research to date has suggested the potential for psychedelics to emerge as breakthrough therapies for psychiatric conditions refractory to conventional treatments. However, given the unique history and high potential for misuse with popular distribution, special care and considerations must be undertaken to safeguard their use as viable medical treatments rather than drugs of abuse.
... The use of observational and cross-sectional data in mediation analyses opens up the possibility for alternative directions of causation, such that any sequence of causal ordering of predictor, mediator and outcome variable is possible (Hayes, 2018). While most causal orderings in the current study can be discounted due to logical implausibility, it could be argued that problematic ecstasy use could lead to increased impulsivity and psychological distress through the putative neurotoxic effects of high dose 3,4-methylenedioxymethamphetamine (MDMA; the most common psychoactive constituent of ecstasy) on serotonergic functioning (Parrott, 2013). However, the inclusion of statistical control over level of ecstasy use diminishes the possibility that this is the true underlying relationship in the current results, given that dose rather than problem use is most plausibly associated with any neurotoxic effect from a biological perspective. ...
Background
Ecstasy users who report symptoms of problematic use experience adverse social, psychological, and health-related consequences not reported by non-problem users. Relatively little is known about the risk factors for the development of problematic ecstasy use. Such information would be valuable for targeted intervention, prevention, and education.
Aims
The current study aimed to fill this gap by investigating several hypothesised risk factors for problematic use and the relationships between them.
Methods
Impulsivity, psychological distress, sex, and coping motives for ecstasy use were investigated as predictors of problematic ecstasy use in a cross-sectional online survey.
Results
The sample consisted of 483 individuals (60.5% male, 38.3% female, 1.2% other) aged 18-62 years, reporting ecstasy use on an average of 59.7 occasions (SD = 167.8). Both higher self-reported impulsivity and psychological distress predicted problem ecstasy use, and both these relationships were partially mediated by coping motives. When these variables were examined in a combined mediation model accounting for their covariance, psychological distress still predicted problematic use partially via an effect of coping motives, while impulsivity showed only a direct effect on problem use. No sex differences in problem ecstasy use were observed.
Conclusions
Increased trait impulsivity and psychological distress appear to confer greater risk of problematic ecstasy use. Targeting these factors, as well as coping motives for ecstasy use may be useful in efforts to prevent and reduce problematic ecstasy use among those who use the drug.
... In the laboratory, pure MDMA has been proven sufficiently safe for human consumption when taken a limited number of times in moderate doses [27,34]. This misunderstanding has led to critics of MDMA-assisted psychotherapy citing research showing the dangers of recreational drug use as a reason not to approve this research [41,45,46], which is not comparing like with like. ...
Background:
PTSD is a chronic condition with high rates of comorbidity, but current treatment options are limited and not always effective. One novel approach is MDMA-assisted psychotherapy for people diagnosed with treatment-resistant PTSD, where MDMA is used as a catalyst to facilitate trauma processing during psychotherapy. The aim was to review all current research into MDMA-assisted psychotherapy for PTSD.
Methods:
Articles were identified through PubMed and Science Direct for items published up to 31st March 2019 using terms "treatments for PTSD", "drug treatments for PTSD", "MDMA", "MDMA pathway", "MDMA-assisted psychotherapy" and "MDMA-assisted psychotherapy for PTSD". Articles were identified through Google Scholar and subject-specific websites. Articles and relevant references cited in those articles were reviewed.
Results:
Small-scale studies have shown reduced psychological trauma, however there has been widespread misunderstanding of the aims and implications of this work, most commonly the notion that MDMA is a 'treatment for PTSD', which to date has not been researched. This has harmful consequences, namely dangerous media reporting and impeding research progression in an already controversial field.
Conclusions:
MDMA-assisted psychotherapy may help people who have experienced psychological trauma and who have not been able to resolve their problems through existing treatments, however more research is needed. If this is to get appropriate research attention, we must report this accurately and objectively.
... Regarding anti-depressant actions, AMI induces dose-dependent pluripotent actions of this drug [18,23]. Interestingly, several studies confirm that AMI elicits strong neurotrophic activity via a productive interaction with the brain-derived neurotrophic factor (BDNF) and the neurotrophic tyrosine kinase receptor B (TrkB) system [19,[24][25][26]. Kamińska et al. (2018) reported that chronic treatment with AMI in a unilaterally 6-hydroxydopamine lesion rat model increased dopamine levels. ...
Numerous studies have confirmed that 3,4-Methylenedioxymethamphetamine (MDMA) produces long-lasting changes to the density of the serotonin reuptake transporter (SERT). Amitriptyline (AMI) has been shown to exert neuroprotective properties in neuropathologic injury. Here, we used a SERT-specific radionuclide, 4-[18F]-ADAM, to assess the longitudinal alterations in SERT binding and evaluate the synergistic neuroprotective effect of AMI in a rat MDMA model. In response to MDMA treatment regimens, SERT binding was significantly reduced in rat brains. Region-specific recovery rate (normalized to baseline) in the MDMA group at day 14 was 71.29% ± 3.21%, and progressively increased to 90.90% ± 7.63% at day 35. AMI dramatically increased SERT binding in all brain regions, enhancing average ~18% recovery rate at day 14 when compared with the MDMA group. The immunochemical staining revealed that AMI markedly increased the serotonergic fiber density in the cingulate and thalamus after MDMA-induction, and confirmed the PET findings. Using in vivo longitudinal PET imaging, we demonstrated that SERT recovery was positively correlated with the duration of MDMA abstinence, implying that lower SERT densities in MDMA-induced rats reflected neurotoxic effects and were (varied) region-specific and reversible. AMI globally accelerated the recovery rate of SERT binding and increased SERT fiber density with possible neuroprotective effects.
... The appeal of MDMA mainly derives from its unique profile of acute psychoactive effects, which include amphetamine-like stimulant actions, in parallel with enhanced feelings of empathy and social connection. 1,2 In rodents, MDMA acts as an indirect monoaminergic agonist 3,4 that induces the release of dopamine (DA) and serotonin (5-HT) 5,6 in several brain regions including the nucleus accumbens (NAc). 7 Moreover, depending on the dose, administration regimen, and ambient temperature, MDMA can be toxic for serotonergic (primates and rats) or dopaminergic (mice) neurons. ...
Our previous studies consistently showed that MDMA‐induced locomotor hyperactivity is dramatically increased by coadministration of ethanol (EtOH) in rats, indicating possible potentiation of MDMA abuse liability. Thus, we aimed to identify the brain region(s) and neuropharmacological substrates involved in the pharmacodynamics of this potentiation.
We first showed that potentiation of locomotor activity by the combination of ip administration of EtOH (1.5 g/kg) and MDMA (6.6 mg/kg) is delay sensitive and maximal when both drugs are injected simultaneously. Then, we used the 2‐deoxyglucose quantitative autoradiography technique to assess the impact of EtOH, MDMA, or their combination on local cerebral metabolic rates for glucose (CMRglcs). We showed a specific metabolic activation in the ventral striatum (VS) under MDMA + EtOH versus MDMA or EtOH alone. We next tested if reversible (tetrodotoxin, TTX) or permanent (6‐hydrodoxyopamine, 6‐OHDA) lesion of the VS could affect locomotor response to MDMA and MDMA + EtOH. Finally, we blocked dopamine D1 or glutamate NMDA receptors in the VS and measured the effects of MDMA and MDMA + EtOH on locomotor activity. We showed that bilateral reversible inactivation (TTX) or permanent lesion (6‐OHDA) of the VS prevented the potentiation by EtOH of MDMA‐induced locomotor hyperactivity. Likewise, blockade of D1 or NMDA receptors in the VS also reduced the potentiation of MDMA locomotor activity by EtOH. These data indicate that dopamine D1 and glutamate NMDA receptor‐driven mechanisms in the VS play a key role in the pharmacodynamics of EtOH‐induced potentiation of the locomotor effects of MDMA.
... Some studies have reported damage to serotonin neurons by MDMA, adversely affecting cognitive function. The neuropsychological effects of the drug are still being investigated and will need to be better understood before it can be applied safely [21,22]. ...
Psychedelics are regarded as mind-revealing drugs. They are considered a group of substances that act on serotonergic receptors (serotonin5-HT) and, thus, are also known as serotonergic hallucinogens. The origin of these drugs or substances dates back to various ritual beliefs and cultural practices. Current research has explored and highlighted their therapeutic applications in specific psychiatric disorders, such as anxiety and depression. This review shares insights regarding the history, research, and applications of various better-known psychoactive substances (LSD, ecstasy, psilocybin, cannabis, and more)-as well as the more familiar herbal stimulants caffeine and nicotine. The article also sheds light on the ethical and legal framework in the current era of medical research regarding such substances.
... Despite the challenges of gaining regulatory approval following publication of Ricaurte et al's mistaken findings (Morris 2003), MAPS is currently sponsoring Phase 3 trials of MDMA-assisted psychotherapy for PTSD. Debate continues about the safety profile of MDMA, including whether possible serotonergic damage associated with recreational MDMA use is generalizable to pharmaceutical grade MDMA (Doblin et al. 2014;Parrott 2013Parrott , 2014, as well as the existence of possible long-term neurocognitive deficits secondary to MDMA consumption (Fisk et al. 2011;Halpern et al. 2004Halpern et al. , 2011Krebs et al. 2009;Lyvers 2011;Lyvers and Hasking 2004;Parrott 2011). However, evidence of MDMA-induced dopaminergic toxicity in humans has not materialized since the retraction of Ricaurte et al and regulatory agencies around the world have determined that MDMA's potential therapeutic benefits outweigh its risks in research settings (Doblin et al. 2014). ...
Ensuring the public is informed of retractions has proven difficult for the scientific community. While it is possible that newspapers focus differential attention on publication of scientific articles and their subsequent retractions, this topic has received minimal attention from researchers. To learn more, we analyzed newspaper coverage of the high-profile 2002 article Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA (“ecstasy”) and its retraction in a case study. We searched the 50 largest American newspapers with available online archives for stories about the article’s publication and retraction. Of the 50 newspapers, 26 (52%) covered the article’s publication and 20 (40%) its retraction. Six of the 50 newspapers (12%) published stories on the article’s retraction without covering its initial publication. Of the 26 newspapers covering the article’s publication, only 14 (54%) covered its retraction. Stories about the retraction were balanced, but shorter than those on the article’s publication and often lacking in context and detail. While the decrease in coverage of the article’s retraction was moderate among the entire sample, the much lower retraction coverage in newspapers that had already covered the article’s publication is concerning and emphasizes the need for increased media coverage of retractions.
... A review of empirical research (2013) supported those cognitive impairments following MDMA administration, which could result in a long-term cognitive effect, such as retrospective memory, prospective memory, higher cognition, problem-solving, and social intelligence. It can also result to sleep architecture, sleep apnoea, complex vision, pain, neurohormones, and psychiatric status [54]. Golding et al., (2007) reported that light ecstasy users showed a small signi cant cognitive impairment. ...
Background Numerous studies have confirmed that 3, 4-Methylenedioxymethamphetamine (MDMA) produces long-lasting changes to the serotonergic system and decreases the density of the serotonin reuptake transporter (SERT). However, amitriptyline (AMI) is a potent neuroprotector that can cause devastating neuropathologic injury. Use of 4-[¹⁸F]-ADAM, a SERT-specific radionuclide as a molecular imaging agent, facilitates longitudinal, non-invasive assessment of SERT activity/expression post-MDMA. We used 4-[¹⁸F]-ADAM PET imaging to access the longitudinal alteration of SERT binding and evaluate the synergistic neuroprotective effect of MDMA and SERT inhibition by AMI in rat model.
Materials and Methods The adult male Sprague–Dawley (SD) rats are grouped into four according to drug administration (Group 1: saline, Group 2: MDMA 10mg/kg i.p., Group 3: MDMA 10mg/kg i.p. with AMI 5 mg/kg i.p., Group 4: AMI 5 mg/kg i.p.). All drugs were administrated twice daily for 4 successive days (Day 1 to Day 4). Post-drug 4-[¹⁸F]-ADAM PET scans were performed on day 14, day 21 and day 28 to measure the SERT occupancy/recovery. After the last PET imaging, SERT-positive cells were measured quantitatively using immunochemical staining.
Results In response to MDMA treatment regimens, SERT binding was significantly reduced in rat brain. Recovery rate (normalized to baseline) in the MDMA group, at day 14 was 64.34% ± 2.05%, progressively increased to 70.70% ± 3.96% at day 28. Recovery rate in the MDMA group varies based on region-specific. AMI dramatically increased SERT binding in all brain regions, enhancing average ~24% recovery rate at day 14 when compared with the MDMA group (MDMA 64.34% ± 2.05% vs. MDMA+ AMI 87.76% ± 2.98%), reaching 84.38% ± 2.05% at day 28. The immunochemical staining revealed that MDMA treatment reduced SERT immunoactivity densities in all brain regions, whereas AMI markedly increased the serotonergic fiber density after MDMA-induction that confirmed the PET findings.
Conclusions Using in vivo longitudinal PET imaging, we demonstrated that SERT recovery was positively correlated with the duration of MDMA abstinence, implying the lower SERT densities in MDMA-induced rats reflected neurotoxic effects, varied region-specific, and reversible. AMI globally accelerated the recovery rate of SERT binding and increased SERT fiber density with possible neuroprotective effects.
... The use of ecstasy (3,4-methylenedioxymethamphetamine [MDMA]), also known as Molly when in powder or crystalline form, is well-documented in this population of festival and nightclub attendees ( Krotulski, Mohr, Fogarty, & Logan, 2018 ;. While ecstasy and cocaine are known to be associated with a wide range of adverse effects, including poisonings and deaths Parrott, 2013 ), another potential risk associated with use is adulteitration or contamination with other synthetic drugs. Synthetic cathinones (known as "bath salts " in the US) in particular have been detected as adulterants in ecstasy over the past decade, and may increase the risk of adverse effects associated with use when used unknowingly or in combination with ecstasy ( Oliver et al., 2019 ). ...
Background
Drugs like ecstasy, cocaine, and counterfeit prescription pills can contain fentanyl. We examined knowledge about potential adulteration/contamination of such drugs among people attending electronic dance music (EDM) parties.
Methods
Adults in New York City were surveyed entering randomly selected EDM parties during the summers of 2018 (n=1,029) and 2019 (n=559). Surveys assessed perceptions that: 1) ecstasy/Molly can contain adulterants more dangerous than MDMA, 2) cocaine can contain fentanyl, and 3) prescription pills from non-pharmacy sources can contain fentanyl. We compared prevalence of perceptions between 2018 and 2019.
Results
Prevalence of agreeing that cocaine can contain fentanyl increased from 42.1% to 58.6%, a 39.2% increase (p=.003). Increases in agreement were not significant regarding ecstasy potentially containing adulterants (55.0% vs. 59.0%) and non-pharmacy prescription drugs potentially containing fentanyl (46.8% vs. 52.9%). Those reporting past-year ecstasy use in particular reported increased agreement that ecstasy can be adulterated (from 52.9% to 80.0%, a 51.2% increase; p<.001) and those reporting past-year cocaine use reported increased agreement that cocaine can be adulterated (from 48.2% to 70.7%, a 46.7% increase; p=.016).
Conclusions
Knowledge of potential adulteration or contamination of commonly used drugs in this high-risk scene is increasing. Continued education about possible drug contents is needed.
... Au sujet de la neurotoxicité, des études menées chez l'animal non humain ont montré une diminution significative des taux de marqueurs sérotoninergiques après l'injection de MDMA à hautes doses (ex. 10 mg/kg), mais pas à doses plus faibles (ex. 5 mg/kg ; Insel et al., 1989 ;Stone, Merchant, Hanson, & Gibb, 1987). Chez l'humain, une forte consommation d'ecstasy a également été associée à des taux plus faibles de marqueurs sérotoninergiques, de moins bonnes performances cognitives et un niveau de dépression plus élevé (Parrott & Andrew, 2013). Cependant, ces effets sont moins évidents dans le cas de consommation modérée (ex. ...
Résumé
On estime que le syndrome de stress post-traumatique (PTSD) reste chronique et sévère pour 25 à 50 % des patients malgré une prise en charge psychothérapeutique. La MDMA (« ecstasy ») possèderait des propriétés psychopharmacologiques qui renforcent l’alliance thérapeutique et permettent au patient de travailler sur le contenu traumatique sans être submergé par la peur et l’anxiété. Les résultats d’essais cliniques de phase II confirment que la MDMA améliore efficacement la prise en charge psychothérapeutique des patients atteints de PTSD sans effets secondaires sérieux. Des essais de phases III sont en cours. La Multidisciplinary Association for Psychedelic Studies (MAPS) a mis en ligne une proposition de méthode et forme des thérapeutes pour mener des psychothérapies assistées par la MDMA. La Food and Drug Administration (FDA) et l’European Medicines Agency (EMA) pourraient autoriser cet outil thérapeutique dans les prochaines années.
... Like other abused drugs, amphetamines cause tolerance and psychological addiction and cognitive impairments could arise in habitual users [95][96][97]. Nevertheless, they have already been approved for the treatment of Attentional Deficit Hyperactivity Disorders (ADHD) and narcolepsy [91]. ...
Aphasia is one of the most socially disabling post-stroke deficits. Although traditional therapies have been shown to induce adequate clinical improvement, aphasic symptoms often persist. Therefore, unconventional rehabilitation techniques which act as a substitute or as an adjunct to traditional approaches are urgently needed. The present review provides an overview of the efficacy and safety of the principal approaches which have been proposed over the last twenty years. First, we examined the effectiveness of the pharmacological approach, principally used as an adjunct to language therapy, reporting the mechanism of action of each single drug for the recovery of aphasia. Results are conflicting but promising. Secondly, we discussed the application of Virtual Reality (VR) which has been proven to be useful since it potentiates the ecological validity of the language therapy by using virtual contexts which simulate real-life everyday contexts. Finally, we focused on the use of Transcranial Direct Current Stimulation (tDCS), both discussing its applications at the cortical level and highlighting a new perspective, which considers the possibility to extend the use of tDCS over the motor regions. Although the review reveals an extraordinary variability among the different studies, substantial agreement has been reached on some general principles, such as the necessity to consider tDCS only as an adjunct to traditional language therapy.
... Like other abused drugs, amphetamines cause tolerance and psychological addiction and cognitive impairments could arise in habitual users [95][96][97]. Nevertheless, they have already been approved for the treatment of Attentional Deficit Hyperactivity Disorders (ADHD) and narcolepsy [91]. ...
Aphasia is one of the most socially disabling post-stroke deficits. Although traditional therapies have been shown to induce adequate clinical improvement, aphasic symptoms often persist. Therefore, new rehabilitation techniques which act as a substitute or as an adjunct to traditional approaches are urgently needed. The present review provides an overview of the efficacy and safety of the most innovative approaches which have been proposed over the last twenty years. First, we examined the effectiveness of the pharmacological approach, principally used as an adjunct to language therapy, reporting the mechanism of action of each single drug for the recovery of aphasia. Results are conflicting but promising. Secondly, we discussed the application of Virtual Reality (VR) which has been proved to be useful since it potentiates the ecological validity of the language therapy by using virtual contexts which simulate real-life everyday contexts. Finally, we focused on the use of Transcranial Direct Current Stimulation (tDCS), both discussing its applications at the cortical level and highlighting a new perspective, which considers the possibility to extend the use of tDCS over the motor regions. Although the review revels an extraordinary variability among the different studies, substantial agreement has been reached on some general principles, such as the necessity to consider tDCS only as an adjunct to traditional language therapy.
... A perceived distinction between MDMA (in crystal or powder form) and ecstasy (in pill form) may have contributed to this re-emergence, favoring MDMA as a "safer drug, " even though the main active ingredient in both drugs is MDMA (38). The risks associated with the use of MDMA/ecstasy are disputed (39)(40)(41); however the perceived safety of MDMA may be an important target for intervention in student populations. ...
Background and Aims: Several studies have pointed to relatively high levels of illicit drug use among students in higher education compared to the general population. The aim of the present study was to provide an updated examination of self-reported illicit drug use among Norwegian University and college students.
Methods: Data stem from the SHoT study (Students' Health and Well-being Study), a nationwide cross-sectional survey for higher education in Norway including Norwegian full-time students aged 18–35. Self-reported illicit drug use across a range of specified drugs comprised the outcome variables. Information on gender, age, and study location (geographical area) was also collected and used as stratification variables. The SHoT-survey from 2018 ( N = 50,054) was used for the analyses of associations between demographical variables and illicit drug use, while trends in illicit drug use were estimated by comparing the 2018-results with data from the SHoT-surveys conducted in 2010 and 2014.
Results: The proportion of students reporting having ever tried illicit drugs increased from 2014 to 2018, for both males (30.8 vs. 36.7%) and females (17.5 vs. 24.0%, both p < 0.001), while only minimal changes occurred between 2010 and 2014. The most commonly used illicit drugs during the past 12 months in 2018 were cannabis (15.2%), followed by MDMA (4.0%), cocaine (3.0%), and LSD/psilocybin (2.1%). Illicit drug use showed both linear increase with age, and inverted U-shaped relationships that peaked in the age span from 23 to 28 years of age. Males reported higher illicit drug use compared with females for all drugs. Proportions of illicit drug use varied across geographical areas within the country, with the highest use being reported in the Oslo area (the largest city and capital of Norway).
Conclusions: The present study reports an increase from 2010 to 2018 among Norwegian University and college students in the proportion of those reporting to have tried illicit drugs. Despite varying proportions of use across type of drug, age, gender, and geographical location, the overall high levels of illicit drug use past 12 months confirm the need to address illicit drug use in this population.
... After more than 25 years of research, the spectrum of expert opinion shows no signs of narrowing into consensus. For an illustrative example of such discussion read 63 and Doblin et al. (2013) 142 . ...
Executive Summary
MDMA is well established as a popular psychoactive substance across much of
the Western world. Hundreds of thousands of people break the law to access its
effects, which include increased energy, euphoria, and enhanced sociability. The
categorisation of MDMA as a Class A drug in the UK and Schedule 1 drug
internationally – categories reserved for drugs deemed to pose the highest risk
to individuals and society – has never meaningfully disrupted its supply, nor its
widespread use. MDMA is cheaper and purer than ever before and is available
at the click of a mouse via darknet drug markets.
For several years, MDMA-related adverse events and fatalities have been
increasing in the UK, with some claiming that taking MDMA today is the
riskiest it has ever been. Responses are polarised between those who assert
that the risks of MDMA use necessitate mitigation through prohibition and
increased law enforcement, and those who perceive prohibition to be exacerbating
these risks by exposing users to an unregulated market of pills and powder of
unknown strength and quality. Whichever view you take, current policy is not
meeting its goal of reducing harms, and greater control of MDMA production,
distribution, purchase, and consumption is needed in order to prevent MDMArelated emergencies.
This report examines the acute, sub-acute, and chronic harms related to
MDMA use in detail. We examine the production, distribution, purchase, and
consumption of the drug; related risks and harms; and the impact prohibition
has on these, as well as the potential impact of alternative policies. Crucially,
our evidence shows that many harms associated with MDMA use arise
from its unregulated status as an illegal drug, and that any risks inherent to
MDMA could be more effectively mitigated within a legally regulated market.
10
MDMA: Roadmaps to Regulation
Under prohibition, people purchase MDMA pills, crystal, and powder
from an illegal market, with little certainty as to what these products contain.
Given that illegal drugs are not subject to strict production standards,
consumers are exposed to the risks of poisoning or accidental overdose as a
result of contamination, adulteration, and unknown strength and purity. Naïve
commentators demonise the drug and simply urge young people to ‘just say no’,
whilst failing to account for those who say ‘yes’. In the meantime, preventable
deaths continue to occur, and otherwise law-abiding people are punished
for non-violent offences such as the possession or social supply of MDMA.
Governments and the mainstream media persist in perpetuating the myth that
the War on Drugs is winnable if it were fought harder, and those calling for
drug policy reform – as we do here – are framed as ‘radicals’ who have little or
no regard for the health and wellbeing of citizens.
This characterisation could not be further from the truth. Those calling for
careful reform to existing drug policy include the parents of young people whose
lives have been lost or ruined by harms related to the prohibition of MDMA. We
incorporate their voices in this report alongside those of academics and former
police officers, highlighting the ‘broad church’ of those dedicated to fighting for
reform. This includes scientists undertaking ground-breaking research into the
therapeutic potential of MDMA, who work within a regulatory regime that
makes such research exorbitantly expensive and time-consuming, because of
the Schedule 1 status that MDMA holds in the UK.
As we enter the fourth decade of MDMA’s widespread use, new thinking
is needed on how to better control production and distribution, and on how
to reduce the risks associated with its consumption. There is growing evidence
to support reorienting drug policy away from an ideologically driven criminal
justice-led model to one rooted in pragmatic health and harm reduction
principles. This is reflected in the widespread reform of cannabis laws occurring
in numerous jurisdictions around the world, and the growth of treatment
11
Executive Summary
programmes for heroin users which include prescription heroin and supervised
injecting rooms. These hard-fought policy changes acknowledge the failure of
prohibition to meet its goals and produce a ‘drug-free world’. They are built on
a robust and ever-growing evidence base which demonstrates how permitting
or prescribing the use of legally regulated drugs improves health and safety
outcomes for people who use drugs and their communities at a reduced cost to
the state, whilst also providing wider employment and economic opportunities.
This logic can be extended to the use of MDMA and other currently prohibited
psychoactive substances.
Roadmaps to Regulation: MDMA follows this pragmatic path and pursues
policy aims which many of us share, such as improvements in public health
promotion, targeted harm reduction, evidence-informed policy and practice,
human rights, social justice, participatory democracy, and effective governmental
expenditure. For the first time, we outline detailed recommendations for drug
policy reform to better control the production, distribution, purchase, and
consumption of MDMA products. Reform and the reduction in MDMArelated harms this will bring cannot happen overnight. The changes we outline
here, which culminate in a strictly regulated legal market for MDMA, are to be
phased in gradually and closely evaluated through independent policy research
to ensure health and social outcomes are properly documented, with findings
folded back into the ongoing reform process.
... 3,4-Methylenedioxymethamphetamine (MDMA) as an illicit drug is used by young adults in the world (1). Since MDMA is consumed mainly by the young population, its effects on the reproductive system would be important to be taken into consideration (2,3). This hallucinogenic drug induces apoptotic cell death in different organs (4,5). ...
Background:
3,4-Methylenedioxymethamphetamine (MDMA) disrupts function of the endocrine system and different organs such as heart, blood vessels, kidney, liver and nervous systems. This revision was conducted to evaluate impact of MDMA on apoptosis and Zinc in the MDMA-induced apoptosis of cultured Sertoli cells by measuring Caspase-3 gene expression.
Materials and methods:
In this experimental study, Sertoli cells were incubated with MDMA (0, 0.5, 1, 3 and 5 mM), Zinc (0, 8, 16, 32, 64 μM) and Zinc (8 μM) prior to adding MDMA (5 mM) for 24 and 48 hours. MTT assay was used for evaluating impacts of these conditions on the viability of Sertoli cells. Caspase-3 gene expression level was detected using quantitative reverse transcription PCR (qRT-PCR) in all of the tested groups.
Results:
Finding showed that cellular viability was decreased and level of Caspase-3 mRNA was increased in MDMA treated cells. Additionally, pre-treatment with Zinc (8 μM) attenuated MDMA-induced apoptosis and down-regulated caspase-3. The mean of caspase-3 mRNA level (fold change ± SE) was 3.98 ± 1.18, 0.31 ± 0.28, and 1.72 ± 0.28 in respectively MDMA (5 mM), Zinc (8 μM), and Zinc+MDMA groups vs. control group. The mean of Caspase-3 mRNA (fold change) was not statistically different in the tested groups (P>0.05), unless MDMA (5 mM) group (P=0.008).
Conclusion:
We suggest that MDMA toxicity could be involved in apoptosis of Sertoli cells. In addition, Zinc could reduce MDMA-induced apoptosis by down-regulation of Caspase-3 mRNA levels.
Methylenedioxymethamphetamine (MDMA) is an amphetamine analogue that preferentially stimulates the release of serotonin (5HT) and results in relatively small increases in synaptic dopamine (DA). The ratio of drug‐stimulated increases in synaptic DA, relative to 5HT, predicts the abuse liability; drugs with higher DA:5HT ratios are more likely to be abused. Nonetheless, MDMA is a drug that is misused. Clinical and preclinical studies have suggested that repeated MDMA exposure produces neuroadaptive responses in both 5HT and DA neurotransmission that might explain the development and maintenance of MDMA self‐administration in some laboratory animals and the development of a substance use disorder in some humans. In this paper, we describe the research that has demonstrated an inhibitory effect of 5HT on the acquisition of MDMA self‐administration and the critical role of DA in the maintenance of MDMA self‐administration in laboratory animals. We then describe the circuitry and 5HT receptors that are positioned to modulate DA activity and review the limited research on the effects of MDMA exposure on these receptor mechanisms.
We studied cognitive performance following discharge from a novel rehabilitation facility, treating individuals with psychosis that developed during trips abroad following mandatory military service. Montreal Cognitive Assessment (MoCA), phonetic and semantic fluency, State-Trait Anxiety, and self-Efficiency were administered before discharge, and 3 and 6 months after discharge. Of the 43 participants (30.2% females), 23(54.8%) had cognitive impairment (MoCA <27), and 15(35.7%) had poor phonetic fluency. Anxiety trait and state were high and inversely correlated with self-efficacy (R=-0.48, p = 0.001) and phonetic fluency (R=-0.43, p = 0.004) and was higher among those who experienced physical exposure, females, and those who served in non-combat army units. Six months after discharge, of 32 participants, 28 were working/studying with a 58.1% reduction in smoking and alcohol consumption, and 16 participants stopped substance use. Phonetic fluency improved among the high anxiety state group with no change among the others. High anxiety levels lowered among those who were still using drugs after six months. The anxiety level lowered and 87.1% of the participants were conducting a productive lifestyle at 6 months after discharge, but half still abused cannabis. Bigger sample and longer follow up would be needed to learn more about the impact of rehabilitation.
Rationale
MDMA or Ecstasy has made a resurgence in popularity and the majority of users consist of teenagers and adolescents. Therefore, it is important to determine whether MDMA causes long-term damage and what this damage entails. There is an ongoing debate about possible neurocognitive changes in 3,4-methylenedioxymethamphetamine (MDMA) users related to MDMA's neurotoxic potential. Multiple neuroimaging studies have shown that Ecstasy use leads to lower serotonin transporter (SERT) availability in multiple brain regions. This may express itself in a loss of cognitive functions like memory, attention and executive function. However, there is increasing evidence reporting that MDMA's induced serotonergic adaptations are reversible over time. The question we thus address is whether the recovery of SERT function predicts a recovery of cognitive function.
Objectives
This review aims to investigate MDMA's long-term effects on SERT availability and cognitive functioning.
Methods
A literature search was performed in PubMed. Studies that investigated the effects of MDMA on both SERT availability and cognitive performance were eligible for inclusion.
Results
SERT availability positively correlated with time of abstinence, whereas memory performance did not show this correlation, but remained impaired in MDMA users. No significant correlation between SERT availability and memory function was found (r = 0.232, p = 0.581; r = 0.176, p = 0.677).
Conclusions
The main findings of this review are that MDMA-use leads to an acute decrease in SERT availability and causes an impairment in cognitive functions, mostly memory. However, SERT availability recovers with sustained abstinence while memory function does not. This suggests that SERT availability is not a biomarker for MDMA-induced cognitive impairment and likely also not for MDMA-induced neurotoxicity.
En este último período, ha aumentado el número de personas que deben ser asistidas en las raves y en los servicios de urgencias por intoxicación con drogas de diseño. Los casos mortales tienen gran impacto en los medios de comunicación y redes sociales, por un lado, y en la sociedad, por otro, dado que suele ser una persona joven la que fallece o queda discapacitada. Además de las campañas educativas y preventivas que deben realizar las instituciones gubernamentales, en esta publicación, se emiten recomendaciones elaboradas por profesionales de las sociedades científicas que se vinculan a la atención de estos pacientes (urgencia prehospitalaria, recepción en departamentos de
emergencias, clínica médica, toxicología y terapia intensiva) y se describen aspectos toxicológicos de las drogas. Se debe hacer hincapié en la presentación aguda de estas intoxicaciones como tres probables síndromes: síndrome serotoninérgico (con hipertermia), hiponatremia y delirio con agitación. Se remarca la posibilidad de inicio temprano del tratamiento. Se enumeran formas graves de presentación en intoxicaciones agudas y diagnósticos diferenciales. Se relata una experiencia de atención en nuestro medio en un hospital de campaña.
Title of Book- Recent Changes in Drug Abuse Scenario: The Novel Psychoactive Substances (NPS) Phenomenon.
Title of Chapter - Octodrine: New Questions and Challenges in Sport Supplements.
Publisher - Multidisciplinary Digital Publishing Institute (MDPI).
Date of Publication - January 2019.
ISBN 978-3-03897-507-6 (Pbk); ISBN 978-3-03897-508-3 (PDF).
Available from https://www.mdpi.com/books/pdfview/book/1087
Cannabis is the most frequently abused recreational drug worldwide. Its major psychoactive component, ∆9-tetrahydrocannabinol (∆9-THC), interacts with specific cannabinoid (CB) receptors in the brain. Until today distinct neuropathological alterations have not been described. Opioids are the most frequently consumed drugs of abuse causing death by central respiratory depression. CNS findings include hypoxic-ischemic leukoencephalopathy, spongiform leukoencephalopathy, and a broad spectrum of CNS infections. Fatalities after the consumption of psychostimulants (cocaine, amphetamines, methamphetamine, and related synthetic drugs) have been reported in several autopsy series with cardiovascular and cerebrovascular events as the most frequent causes of death. The latter include intracerebral and subarachnoid hemorrhages as well as hemorrhagic or ischemic stroke. Alterations of neurotransmitters, receptors, second messengers signal transduction systems, and oxidative status have been reported for all of the abovementioned drugs but the findings are fragmentary and inconclusive. Designer drugs and new psychoactive substances (NPS) are a heterogeneous class of noncontrolled substances. The major classes include synthetic opioids, synthetic cannabinoid receptor agonists (“spice”), psychostimulant NPS (“bath salts”), hallucinogenic NPS, dissociative substances, and designer benzodiazepines. Most of these substances mimic the effects of well-established drugs of abuse. However, their consumption is associated with a high incidence of intoxications or fatalities, especially in the context of polydrug abuse. Detailed neuropathological investigations are lacking so far.
Mephedrone and MDMA are both constituents of party drugs, with mephedrone being relatively new compared to MDMA. This review compares current knowledge regarding the patterns of usage and neuropsychobiological effects of both mephedrone and MDMA. Both drugs share common psychoactive effects, the duration of which is significantly shorter with mephedrone use, attributing towards a pattern of binge use among users. Both drugs have also been associated with adverse health, psychiatric, and neurocognitive problems. Whilst there is extensive research into the psychobiological problems induced by MDMA, the evidence for mephedrone is comparatively limited. The adverse effect profile of mephedrone appears to be less severe than that of MDMA. Users often believe it to be safer, although both drugs have been associated with overdoses. The neurotoxic potential of mephedrone appears to be low, whereas MDMA can cause long-term damage to the serotonergic system, although this needs further investigation. The abuse liability of mephedrone is significantly greater than that of MDMA, raising concerns regarding the impact of lifetime usage on users. Given that mephedrone is relatively new, the effects of long-term exposure are yet to be documented. Future research focused on lifetime users may highlight more severe neuropsychobiological effects from the drug.
MDMA (3,4-methylendioxymethamphetamine), also known as Ecstasy, is a stimulant drug recreationally used by young adults usually in dance clubs and raves. Acute MDMA administration increases serotonin, dopamine and noradrenaline by reversing the action of the monoamine transporters. In this work, we review the studies carried out over the last 30 years on the neuropsychobiological effects of MDMA in humans and mice and summarise the current knowledge. The two species differ with respect to the neurochemical consequences of chronic MDMA, since it preferentially induces serotonergic dysfunction in humans and dopaminergic neurotoxicity in mice. However, MDMA alters brain structure and function and induces hormonal, psychomotor, neurocognitive, psychosocial and psychiatric outcomes in both species, as well as physically damaging and teratogen effects. Pharmacological and genetic studies in mice have increased our knowledge of the neurochemical substrate of the multiple effects of MDMA. Future work in this area may contribute to developing pharmacological treatments for MDMA-related disorders.
The increasing use of illegal drugs by pregnant women causes a public health concern because it is associated with health risks for mothers and their developing children. One of such drugs is MDMA (3,4-methylenedioxymethamphetamine) or ecstasy due to its high consumption in relevant age and sex groups and its adverse effects on human and rodent developing brains. To thoroughly review the current knowledge on the developmentally neurotoxic potential of MDMA we systematically collected and summarized articles investigating developmental neurotoxicity (DNT) of MDMA in humans and animals in in vivo and in vitro. In addition, we summarized the findings in a putative adverse outcome pathway (AOP). From an initial 299 articles retrieved from the bibliographic databases Web of Science, PubMed and DART, we selected 39 articles according to inclusion/exclusion criteria for data collection after title/abstract and full text screening. Of these 3 where epidemiological studies, 34 where in vivo studies in mice and rats and 2 were in vitro studies. The three epidemiological studies reported from the same longitudinal study and suggested that MDMA exposure during pregnancy impairs neuromotor function in infants. In rat, postnatal exposure towards MDMA also caused locomotor deficits as well as impaired spatial learning that might be associated with decreased serotonin levels in the hippocampus. In vitro MDMA caused cytotoxicity at high concentrations and effects on the serotonergic and neuritogenic alterations at lower concentrations which are in line with some of the in vivo alterations observed. Considering the adverse outcomes of developmental MDMA described in humans and in rodents we summarized the first putative AOP on developmental compound exposure leading to impaired neuromotor function in children. For generation of this AOP, MDMA exposure was taken as a model compound. In addition, we hypothesized a second AOP involving developmental disturbance of the dopaminergic system. However, further in vitro mechanistic studies are needed to understand the molecular initiating event(s) (MIE) triggering the downstream cascades and obtain consistent evidences causally linking the adverse outcome to effects at the cellular, organ and organism level.
Recent pill‐related deaths of young people at music festivals in Australia have led to a concerted push for on‐site pill testing as a means for preventing such events. However, whether pill testing (also termed ‘safety checking’) is an effective harm reduction strategy remains uncertain. This narrative review concludes that pill testing currently lacks evidence of efficacy sufficient to justify publicly funded national roll‐out of on‐site pill testing programs. Australian governments, addiction specialists and public health experts should collaborate in conducting properly designed field studies aimed at confirming clear benefits from such programs in reducing pill‐related harm.
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Methoxetamine (MXE) is a novel psychoactive substance that can induce several short-term effects on emotional states and behavior. However, little is known about the persistent emotional and behavioral effects of MXE. Moreover, neurotoxic effects of MXE have been hypothesized, but never demonstrated in vivo. To clarify these issues, rats received repeated treatment with MXE every other day (0.1–0.5 mg/kg, i.p., × 5), and 7 days later they were challenged with MXE (0.1–0.5 mg/kg, i.p.). Behavioral effects of MXE were first evaluated by measuring emission of ultrasonic vocalizations and locomotor activity after each administration. Thereafter, persistent behavioral effects of MXE were evaluated, starting 8 days after challenge, through elevated plus maze, spontaneous alternation, novel object recognition, and marble burying tests. After completion of behavioral analysis, neurotoxic effects of MXE were evaluated by measuring densities of dopamine transporter, tyrosine hydroxylase, and serotonin transporter in various brain regions. Repeated treatment and challenge with MXE affected neither calling behavior nor locomotor activity of rats. Conversely, rats previously treated with MXE exhibited behavioral alterations in the elevated plus maze, marble burying and novel object recognition tests, suggestive of increased anxiety and impaired non-spatial memory. Noteworthy, the same rats displayed dopaminergic damage in the medial prefrontal cortex, nucleus accumbens, caudate-putamen, substantia nigra pars compacta, and ventral tegmental area, along with accumbal serotonergic damage. Our findings show for the first time that repeated administration of MXE induces persistent behavioral abnormalities and neurotoxicity in rats, which can help elucidating the risks associated with human MXE consumption.
To establish patterns of MDMA (ecstasy) use and relate these to other substance use, health and social problems related to ecstasy use, a multi-site chain-referral sample was recruited via the 'dance scene' in Glasgow. Two hundred and twenty-nine participants were interviewed, including 20 controls and 209 people who had used ecstasy at least once. All users used ecstasy in the context of polydrug use, in particular stimulant and hallucinogen use were significantly related to ecstasy use. Extent of ecstasy use was not related to sociodemographic data, but the group were substantially involved in illegal activities including other drug use, drug selling, buying stolen goods and a range of fiddles and criminal activities. Respondents were classified in terms of their frequency and quantity of ecstasy use (into light, medium and heavy groups) and in terms of whether or not their use pattern over the year before interview was stable or erratic. At most, users took ecstasy about once a week. Extent of drug use in general, rather than ecstasy use in particular, was predictive of more days' illness, self-attributed depression and experiences of paranoia and memory loss. Some people binged on ecstasy, mostly by taking multiple tablets and tended to binge, but others had mixed alcohol and other drugs. These data do not suggest that problems after ecstasy use are either common, or related to extent of use in a straightforward way. Pattern of ecstasy use may be important, but must be considered in context of overall substance use.
Background Globally, millions of subjects regularly use ecstasy, a drug popular due to its empathogenic and entactogenic effects. Dilutional
hyponatraemia, mainly caused by direct stimulation of antidiuretic hormone (ADH) secretion by ecstasy, is among the many side
effects of the drug (active substance 3, 4-methylenedioxymethamphetamine, MDMA). Severe, symptomatic hyponatraemia related
to the use of MDMA has been reported in more than 30 cases. The mortality of this complication is high and mainly females
are involved. Dramatic cases that reach the literature probably represent the tip of the iceberg. We decided to study the
incidence of hyponatraemia in subjects using MDMA at an indoor rave party.
A widely used illicit recreational drug among young adults, 3,4-methylenedioxymethamphetamine (MDMA) or ecstasy, is an indirect monoaminergic agonist/reuptake inhibitor affecting the serotonin system. Preclinical studies found prenatal exposure related to long-term learning and memory impairments. There are no studies of sequelae of prenatal MDMA exposure in humans, despite potential harmful effects to the fetus.
A total of 96 women in the United Kingdom (28 MDMA users; 68 non-MDMA) were interviewed about recreational drug use during pregnancy. Their infants were seen at 12 months using standardized assessments of cognitive, language, and motor development (Preschool Language Scale, Bayley Mental and Motor Development and Behavior Rating Scales [Mental Development Index, Psychomotor Development Index, Behavioral Rating Scale]). Mothers completed the Child Domain Scale of the Parenting Stress Index, The Home Observation of the Environment Scale (in interview), the Brief Symptom Inventory, and the Drug Abuse Screening Test. Women were primarily middle class with some university education, in stable partner relationships, and polydrug users. MDMA and other drug effects were assessed through multiple regression analyses controlling for confounding variables, and analysis of covariance comparing heavier versus lighter and nonexposed groups.
Amount of prenatal MDMA exposure predicted poorer infant mental and motor development at 12 months in a dose-dependent manner. Heavily exposed infants were delayed in motor development. Lighter-exposed infants were comparable to nonexposed infants. There were no effects on language, emotional regulation, or parenting stress.
Findings document persistent neurotoxic effects of heavier prenatal MDMA exposure on motor development through the first year of life.
Psychosocial and recreational drugs are generally taken in order to feel better, yet their regular use often leads to increased distress. For instance, MDMA [Ecstasy] is a very powerful euphoriant, but its positive effects last for only a few hours, and they are followed by a more prolonged recovery period, when negative moods predominate. Regular Ecstasy/MDMA use also Leads to various forms of psychobiological distress. This same general pattern holds for amphetamine, nicotine, alcohol, cannabis and the other psychosocial drugs. They can all generate positive feelings for a period, yet their regular use tends to have detrimental rather than beneficial consequences. This article looks at the psychobiological reasons why all these psychosocial drugs tend to increase distress.
Research has raised significant concern regarding the affective consequences of synthetic drug use. However, little evidence from well-controlled longitudinal studies exists on these consequences. The aim of this study was to determine whether use of meth/amphetamine (speed) and ±3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is independently predictive of subsequent depressive symptoms in adolescents.
A sample of 3880 adolescents from secondary schools in disadvantaged areas of Quebec, Canada, were followed over time (2003-2008). Logistic regression was used to test the association between meth/amphetamine and MDMA use in grade 10 (ages 15-16 years) and elevated depressive symptoms on an abridged Center for Epidemiologic Studies-Depression scale in grade 11, controlling for pre-existing individual and contextual characteristics.
After adjustment, both MDMA use (OR 1.7, 95% CI 1.1 to 2.6) and meth/amphetamine use (OR 1.6, 95% CI 1.1 to 2.3) in grade 10 significantly increased the odds of elevated depressive symptoms in grade 11. These relationships did not vary by gender or pre-existing depressive symptoms. Increased risk was particularly observed in concurrent usage (OR 1.9, 95% CI 1.2 to 2.9).
Adolescent use of meth/amphetamine and MDMA (particularly concurrent use) is independently associated with subsequent depressive symptoms. Further enquiry must determine whether these associations reflect drug-induced neurotoxicity and whether adolescence is a period of increased vulnerability to the hazards of synthetic drug exposure.
3,4-methylenedioxymethamphetamine (MDMA) or “Ecstasy” is one of the most widely used illicit recreational drugs among young adults. MDMA is an indirect monoaminergic agonist and reuptake inhibitor that primarily affects the serotonin system. Preclinical studies in animals have found prenatal exposure related to neonatal tremors and long-term learning and memory impairments. To date, there are no prospective studies of the sequelae of prenatal exposure to MDMA in humans, despite concerns about its potential for harmful effects to the fetus. The present study is the first to prospectively identify MDMA-using women during pregnancy and to document patterns and correlates of use with neonatal and early infancy outcomes of offspring.
Recent evidence suggests that recreational cocaine use is on the increase, with the UK reporting one of the highest levels of use in the EU (EMCDDA 2010). Nevertheless, very few studies have addressed the neuropsychological effects associated with non-dependent recreational cocaine use.
The current study aimed to assess whether recreational cocaine users show neuropsychological deficits on a battery of tests, previously shown to be sensitive to cocaine-dependent and psychosis-prone individuals. Schizotypal traits were also measured.
Recreational cocaine users (n = 17) were compared with controls (n = 24) on drug use patterns, the General Health Questionnaire, the Brief Schizotypal Personality Questionnaire (SPQ-B) and four neuropsychological tasks: spatial working memory, intra/extra-dimensional set shifting, the Stocking of Cambridge and the rapid visual processing.
Relative to controls, recreational cocaine users produced significantly more errors on the intra/extra-dimensional set shift task and completed fewer stages, made significantly more six box stage errors on the spatial working memory task, and made significantly more errors and fewer hits, with overall poorer detection rates on the rapid visual processing task. Recreational cocaine users reported significantly higher scores on the cognitive perceptual and disorganised thinking SPQ-B subscales and total SPQ-B scores compared to controls.
Recreational cocaine users displayed impairments on tasks tapping sustained attention, attentional shifting and spatial memory and reported higher schizotypal trait expression. These findings are consistent with the emerging literature suggesting subtle cognitive deficits, putatively reflecting underlying dopaminergic dysfunction, in non-dependent, recreational cocaine users.
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.
High doses of the recreational drug 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") have been well-documented to reduce the expression of serotonergic markers in several forebrain regions of rats and nonhuman primates. Neuroimaging studies further suggest that at least one of these markers, the plasma membrane serotonin transporter (SERT), may also be reduced in heavy Ecstasy users. Such effects, particularly when observed in experimental animal models, have generally been interpreted as reflecting a loss of serotonergic fibers and terminals following MDMA exposure. This view has been challenged, however, based on the finding that MDMA usually does not elicit glial cell reactions known to occur in response to central nervous system (CNS) damage. The aim of this review is to address both sides of the MDMA-neurotoxicity controversy, including recent findings from our laboratory regarding the potential of MDMA to induce serotonergic damage in a rat binge model. Our data add to the growing literature implicating neuroregulatory mechanisms underlying MDMA-induced serotonergic dysfunction and questioning the need to invoke a degenerative response to explain such dysfunction.
(+/-)3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a recreational drug and brain serotonin (5-HT) neurotoxin. Under certain conditions, MDMA can also damage brain dopamine (DA) neurons, at least in rodents. Human MDMA users have been found to have reduced brain 5-HT transporter (SERT) density and cognitive deficits, although it is not known whether these are related. This study sought to determine whether MDMA users who take closely spaced sequential doses, which engender high plasma MDMA concentrations, develop DA transporter (DAT) deficits, in addition to SERT deficits, and whether there is a relationship between transporter binding and cognitive performance.
Sixteen abstinent MDMA users with a history of using sequential MDMA doses (two or more doses over a 3- to 12-h period) and 16 age-, gender-, and education-matched controls participated. Subjects underwent positron emission tomography with the DAT and SERT radioligands, [11C]WIN 35,428 and [11C]DASB, respectively. Subjects also underwent formal neuropsychiatric testing.
MDMA users had reductions in SERT binding in multiple brain regions but no reductions in striatal DAT binding. Memory performance in the aggregate subject population was correlated with SERT binding in the dorsolateral prefrontal cortex, orbitofrontal cortex, and parietal cortex, brain regions implicated in memory function. Prior exposure to MDMA significantly diminished the strength of this relationship.
Use of sequential MDMA doses is associated with lasting decreases in brain SERT, but not DAT. Memory performance is associated with SERT binding in brain regions involved in memory function. Prior MDMA exposure appears to disrupt this relationship. These data are the first to directly relate memory performance to brain SERT density.
The present study is the first to prospectively compare a group of recreational Ecstasy users when dance clubbing on 3,4-methylenedioxymethamphetamine (MDMA) and when clubbing during abstinence from Ecstasy/MDMA.
Twelve normal healthy volunteers (mean age = 23.2 years) were assessed at a Saturday night dance club under self-administered MDMA. On the other weekend they went to the same dance club without taking MDMA (order counterbalanced). Both conditions involved 5 test sessions conducted at similar times: pre-drug baseline, 1 h post-drug clubbing, 2.5 h post-drug clubbing, and 2 and 4 days later. The assessments included body and ambient temperature, physical activity (pedometer), as well as self-ratings for mood state, physical activity, thermal comfort and thirst. Saliva samples were analyzed for MDMA, cortisol and testosterone.
The cortisol levels increased significantly by 800% when dance clubbing on MDMA, while testosterone increased significantly by 75%; neither neuroendocrine measure was altered during abstinence. Saliva analyses confirmed the presence of MDMA when dancing on Ecstasy and its absence when dancing off Ecstasy. The pedometer values and self-rated levels of dancing were similar at both weekends. Hot and cold flushes and feeling hot increased significantly under MDMA. The mean body temperature did not change significantly, although there was a borderline trend for increased values after MDMA. Feelings of happiness and excitement increased under MDMA, although they were not significantly greater than when clubbing during abstinence.
Neurohormonal release may be an important part of the acute MDMA experience. The large cortisol increase provides further data on the bioenergetic stress model of recreational Ecstasy/MDMA.
MDMA (3,4-methylenedioxymethamphetamine) or 'ecstasy' is a ring-substituted amphetamine derivative, which is widely used as a recreational drug, most particularly at dances and raves. Around 80-95% of dancers/ravers report using ecstasy/MDMA, compared to 5-15% of young people in general. This paper will consider the possible contribution of stimulatory environmental conditions to the neuropsychobiological effects of MDMA. Animal research shows that heat and crowding potentiate the acute effects of MDMA. Social interaction and intravenous drug self-administration in laboratory rats are significantly enhanced when MDMA is given under hot ambient temperatures. Loud noise and physical activity can also contribute to the general overarousal. Furthermore, MDMA impairs homeostatic thermal control in rats, leading them to overheat in hot environments. The human implications of these findings are that the hot, noisy and overcrowded conditions at raves may be providing the ideal environment to heighten the acute drug response. In recreational users, the acute medical dangers of MDMA comprise a constellation of hyperthermia-related abreactions, which generally only occur when it has been taken in hot and crowded environments. MDMA is well established as a serotonergic neurotoxin in laboratory animals, but heat and overcrowding increase the degree of distal axon terminal loss. If this also occurs in humans, then the stimulatory environments of clubs and raves may heighten the likelihood of adverse neuropsychological sequelae in recreational ecstasy users. Consistent with this prediction, the extent of self-reported dancing/exercise when on MDMA has recently been shown to be associated with significantly more psychobiological problems afterwards.
Both hallucinogens and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin.
To assess the differential effects of MDMA and hallucinogen use on cerebral serotonin transporter (SERT) and serotonin(2A) receptor binding.
A positron emission tomography study of 24 young adult drug users and 21 nonusing control participants performed with carbon 11 ((11)C)-labeled 3-amino-4-[2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile (DASB) and fluorine 18 ((18)F)-labeled altanserin, respectively. Scans were performed in the user group after a minimum drug abstinence period of 11 days, and the group was subdivided into hallucinogen-preferring users (n = 10) and MDMA-preferring users (n = 14).
Twenty-four young adult users of MDMA and/or hallucinogenic drugs and 21 nonusing controls.
In vivo cerebral SERT and serotonin(2A) receptor binding.
Compared with nonusers, MDMA-preferring users showed significant decreases in SERT nondisplaceable binding potential (neocortex, -56%; pallidostriatum, -19%; and amygdala, -32%); no significant changes were seen in hallucinogen-preferring users. Both cortical and pallidostriatal SERT nondisplaceable binding potential was negatively correlated with the number of lifetime MDMA exposures, and the time of abstinence from MDMA was positively correlated with subcortical, but not cortical, SERT binding. A small decrease in neocortical serotonin(2A) receptor binding in the serotonin(2A) receptor agonist users (both user groups) was also detected.
We found evidence that MDMA but not hallucinogen use is associated with changes in the cerebral presynaptic serotonergic transmitter system. Because hallucinogenic drugs primarily have serotonin(2A) receptor agonistic actions, we conclude that the negative association between MDMA use and cerebral SERT binding is mediated through a direct presynaptic MDMA effect rather than by the serotonin(2A) agonistic effects of MDMA. Our cross-sectional data suggest that subcortical, but not cortical, recovery of SERT binding might take place after several months of MDMA abstinence.
Ecstasy is a recreational drug whose active ingredient, 3,4-methylenedioxymethamphetamine (MDMA), acts predominantly on the serotonergic system. Although MDMA is known to be neurotoxic in animals, the long-term effects of recreational Ecstasy use in humans remain controversial but one commonly reported consequence is mild cognitive impairment particularly affecting verbal episodic memory. Although event-related potentials (ERPs) have made significant contributions to our understanding of human memory processes, until now they have not been applied to study the long-term effects of Ecstasy. The aim of this study was to examine the effects of past Ecstasy use on recognition memory for both verbal and non-verbal stimuli using ERPs.
We compared the ERPs of 15 Ecstasy/polydrug users with those of 14 cannabis users and 13 non-illicit drug users as controls.
Despite equivalent memory performance, Ecstasy/polydrug users showed an attenuated late positivity over left parietal scalp sites, a component associated with the specific memory process of recollection. CONLUSIONS: This effect was only found in the word recognition task which is consistent with evidence that left hemisphere cognitive functions are disproportionately affected by Ecstasy, probably because the serotonergic system is laterally asymmetrical. Experimentally, decreasing central serotonergic activity through acute tryptophan depletion also selectively impairs recollection, and this too suggests the importance of the serotonergic system. Overall, our results suggest that Ecstasy users, who also use a wide range of other drugs, show a durable abnormality in a specific ERP component thought to be associated with recollection.
This study investigated the acute mood effects of oral MDMA, methamphetamine, and placebo in a double-blind laboratory study.
Fifty-two healthy participants comprised abstinent recreational users of stimulant drugs, 27 female and 25 male, mean age 24.8 years. Three test sessions involved acute 100 mg oral 3.4-methylendioxymethamphetamine (MDMA), 0.42 mg/kg oral methamphetamine, and matching placebo. Drug administration was counterbalanced, testing was double-blind, and medical supervision was present throughout. Car-driving performance on a laboratory simulator was assessed after 3 and 24 h, with the findings being presented elsewhere. Positive and negative moods (PANAS self-ratings) were completed before drug administration, 3, 4.5, and 24 h later. Blood samples were taken to monitor drug plasma levels.
Following MDMA, there were no significant increases in positive moods, whereas negative moods were significantly higher than under placebo. Methamphetamine led to significant increases in both positive and negative moods. The MDMA findings contrast with the elated moods, typically noted by dance clubbers on Ecstasy. However, they are consistent with some previous laboratory findings, since a wide array of positive and negative mood changes have been demonstrated. One possible explanatory factor was the neutral environmental situation, particularly if a primary action of MDMA is to intensify ongoing psychological states. Other explanatory factors, such as dosage, gender, post-drug timing, neurohormonal aspects, and social factors, are also discussed.
In the laboratory, acute methamphetamine led to significantly higher positive moods. However, against expectations, MDMA did not generate a significant increase in positive moods.
Our group has conducted several Internet investigations into the biobehavioural effects of self-reported recreational use of MDMA (3,4-methylenedioxymethamphetamine or Ecstasy) and other psychosocial drugs. Here we report a new study examining the relationship between self-reported Ecstasy use and traces of MDMA found in hair samples.
In a laboratory setting, 49 undergraduate volunteers performed an Internet-based assessment which included mood scales and the University of East London Drug Use Questionnaire, which asks for history and current drug use. They also provided a hair sample for determination of exposure to MDMA over the previous month.
Self-report of Ecstasy use and presence in hair samples were consistent (p < 0.00001). Both subjective and objective measures predicted lower self-reported ratings of happiness and higher self-reported stress. Self-reported Ecstasy use, but not presence in hair, was also associated with decreased tension.
Different psychoactive drugs can influence long-term mood and cognition in complex and dynamically interactive ways. Here we have shown a good correspondence between self-report and objective assessment of exposure to MDMA. These data suggest that the Internet has potentially high utility as a useful medium to complement traditional laboratory studies into the sequelae of recreational drug use.
Users of ±3,4-methylenedioxymethamphetamine (MDMA), "ecstasy," report that the drug produces unusual psychological effects, including increased empathy and prosocial feelings. These "empathogenic" effects are cited as reasons for recreational ecstasy use and also form the basis for the proposed use of MDMA in psychotherapy. However, they have yet to be characterized in controlled studies. Here, we investigate effects of MDMA on an important social cognitive capacity, the identification of emotional expression in others, and on socially relevant mood states.
Over four sessions, healthy ecstasy-using volunteers (n = 21) received MDMA (.75, 1.5 mg/kg), methamphetamine (METH) (20 mg), and placebo under double-blind, randomized conditions. They completed self-report ratings of relevant affective states and undertook tasks in which they identified emotions from images of faces, pictures of eyes, and vocal cues.
MDMA (1.5 mg/kg) significantly increased ratings of feeling "loving" and "friendly", and MDMA (.75 mg/kg) increased "loneliness". Both MDMA (1.5 mg/kg) and METH increased "playfulness"; only METH increased "sociability". MDMA (1.5 mg/kg) robustly decreased accuracy of facial fear recognition relative to placebo.
The drug MDMA increased "empathogenic" feelings but reduced accurate identification of threat-related facial emotional signals in others, findings consistent with increased social approach behavior rather than empathy. This effect of MDMA on social cognition has implications for both recreational and therapeutic use. In recreational users, acute drug effects might alter social risk-taking while intoxicated. Socioemotional processing alterations such as those documented here might underlie possible psychotherapeutic benefits of this drug; further investigation of such mechanisms could inform treatment design to maximize active components of MDMA-assisted psychotherapy.
"ECSTASY" (MDMA) AND RELATED DRUGS ARE AMPHETAMINE DERIVATIVES that also have some of the pharmacological properties of mescaline. They have become popular with participants in "raves," because they enhance energy, endurance, sociability and sexual arousal. This vogue among teenagers and young adults, together with the widespread belief that "ecstasy" is a safe drug, has led to a thriving illicit traffic in it. But these drugs also have serious toxic effects, both acute and chronic, that resemble those previously seen with other amphetamines and are caused by an excess of the same sympathomimetic actions for which the drugs are valued by the users. Neurotoxicity to the serotonergic system in the brain can also cause permanent physical and psychiatric problems. A detailed review of the literature has revealed over 87 "ecstasy"-related fatalities, caused by hyperpyrexia, rhabdomyolysis, intravascular coagulopathy, hepatic necrosis, cardiac arrhythmias, cerebrovascular accidents, and drug-related accidents or suicide. The toxic or even fatal dose range overlaps the range of recreational dosage. The available evidence does not yet permit an accurate assessment of the size of the problem presented by the use of these drugs.
Many recreational ecstasy/MDMA users display neuropsychobiological deficits, whereas others remain problem free. This review will investigate some of the drug and non-drug factors which influence the occurrence of these deficits, Acute and chronic MDMA usage are both important. Intensive use within a session is often associated with more problems. In term of lifetime usage, novice users generally remain unimpaired, whereas most heavy users report memory or other psychobiological problems which they attribute to ecstasy. These complaints are confirmed by objective deficits in working memory, attention, frontal-executive, and episodic memory tasks. Psychobiological deficits include disturbed sleep, sexual dysfunction, reduced immuno-competence, and increased oxidative stress. Further MDMA-retated factors which may contribute to these changes, include acute and chronic tolerance, and drug dependence. Around 90-95% of ecstasy/MDMA users also take cannabis, and this can independently contribute to the adverse neuropsychobiological profiles; although in some situations the acute co-use of these two drugs may be interactive rather than additive, since cannabis has relaxant and hypothermic properties. Alcohol, nicotine, amphetamine, and other drugs, can also affect the psychobiological profiles of ecstasy polydrug users in complex ways. Pure MDMA users are rare but they have been shown to display significant neurocognitive deficits. Psychiatric aspects are debated in the context of the diathesisstress model. Here the stressor of ecstasy polydrug drug use, interacts with various predisposition factors (genetic, neurochemical, personality), to determine the psychiatric outcome. Recreational MDMA is typically taken in hot and crowded dances/raves. Prolonged dancing, feeling hot, and raised body temperature, can also be associated with more psychobiological problems. This is consistent with the animal literature, where high ambient temperature and other metabolic stimulants boost the acute effects of MDMA, and cause greater serotonergic neurotoxicity. In conclusion, the neuropsychobiological effects of MDMA are modulated by a wide range of drug and non-drug factors. These multiple influences are integrated within a bioenergetic stress model, where factors which heighten acute metabolic distress lead to more neuropsychobiological problems.
The lack of data about the lethal consequences of taking ecstasy has led to high profile reports of deaths in the media and also the idea that ecstasy is safe. The United Kingdom accounts for most of the ecstasy tablets—normally containing methylenedioxymethamphetamine (MDMA) or 3,4-methylenedioxyamphetamine (MDA)—seized in the European Union.1 The rate of deaths related to taking ecstasy in people aged 15–24 during 1995 and 1996 in England was 18 and between 1995 and 1997 in Scotland was 11.2 The risk of using ecstasy varies between one death in 2000 first time users to one death in 50 000 first time users.2
The National Programme on Substance Abuse Deaths was established after the …
Serotonergic neurotoxicity following MDMA is well-established in laboratory animals, and neuroimaging studies have found lower serotonin transporter (SERT) binding in abstinent Ecstasy/MDMA users. Serotonin is a modulator for many different psychobiological functions, and this review will summarize the evidence for equivalent functional deficits in recreational users. Declarative memory, prospective memory, and higher cognitive skills are often impaired. Neurocognitive deficits are associated with reduced SERT in the hippocampus, parietal cortex, and prefrontal cortex. EEG and ERP studies have shown localised reductions in brain activity during neurocognitive performance. Deficits in sleep, mood, vision, pain, psychomotor skill, tremor, neurohormonal activity, and psychiatric status, have also been demonstrated. The children of mothers who take Ecstasy/MDMA during pregnancy have developmental problems. These psychobiological deficits are wide-ranging, and occur in functions known to be modulated by serotonin. They are often related to lifetime dosage, with light users showing slight changes, and heavy users displaying more pronounced problems. In summary, abstinent Ecstasy/MDMA users can show deficits in a wide range of biobehavioral functions with a serotonergic component.
Twenty recreational drug users were asked to describe the psychological and physiological eÄects they experienced under MDMA (3,4-methylenedioxymethamphetamine). The subjects comprised 11 males and nine females, in the age range 18-31 years. Five subjects had taken MDMA once, nine had taken it 2-9 times, while six subjects had taken itá10 times. Each subject completed a modified Profile of Mood States Questionnaire (POMS), an Ecstasy EÄect Questionnaire, and a structured interview, covering past experience with MDMA. Increased feelings of elation, agreeableness, energy, and mental confusion were reported on-drug (p< 0001), together with faster heart rate, feeling hot, increased sweating and dehydration, dilated pupils, and tight jaw (trismus). Coming oÄ-Ecstasy led to feelings of lethargy, moodiness, insomnia, depression, irritability, and paranoia. Bad MDMA trips were reported by 25 per cent of the sample, following a variety of unpleasant experiences. Chronic pharmacodynamic tolerance was not apparent, since although regular users all described their first MDMA experience as 'the most intense', later trips were aÄected by knowledge and expectancy, rather than any diminution in drug response. Acute pharmacodynamic tolerance was, however, evident, with a period between drugs being described as necessary in order to maintain drug eÄectiveness. This may help explain the low addiction potential of MDMA. #1997 by John Wiley & Sons, Ltd.
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