Comparative oral monotherapy of psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, ayahuasca, and escitalopram for depressive symptoms: systematic review and Bayesian network meta-analysis.

OBJECTIVE: To evaluate the comparative effectiveness and acceptability of oral monotherapy using psychedelics and escitalopram in patients with depressive symptoms, considering the potential for overestimated effectiveness due to unsuccessful blinding. DESIGN: Systematic review and Bayesian network meta-analysis. DATA SOURCES: Medline, Cochrane Central Register of Controlled Trials, Embase, PsycINFO, ClinicalTrial.gov, and World Health Organization's International Clinical Trials Registry Platform from database inception to 12 October 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials on psychedelics or escitalopram in adults with depressive symptoms. Eligible randomised controlled trials of psychedelics (3,4-methylenedioxymethamphetamine (known as MDMA), lysergic acid diethylamide (known as LSD), psilocybin, or ayahuasca) required oral monotherapy with no concomitant use of antidepressants. DATA EXTRACTION AND SYNTHESIS: The primary outcome was change in depression, measured by the 17-item Hamilton depression rating scale. The secondary outcomes were all cause discontinuation and severe adverse events. Severe adverse events were those resulting in any of a list of negative health outcomes including, death, admission to hospital, significant or persistent incapacity, congenital birth defect or abnormality, and suicide attempt. Data were pooled using a random effects model within a Bayesian framework. To avoid estimation bias, placebo responses were distinguished between psychedelic and antidepressant trials. RESULTS: Placebo response in psychedelic trials was lower than that in antidepression trials of escitalopram (mean difference -3.90 (95% credible interval -7.10 to -0.96)). Although most psychedelics were better than placebo in psychedelic trials, only high dose psilocybin was better than placebo in antidepression trials of escitalopram (mean difference 6.45 (3.19 to 9.41)). However, the effect size (standardised mean difference) of high dose psilocybin decreased from large (0.88) to small (0.31) when the reference arm changed from placebo response in the psychedelic trials to antidepressant trials. The relative effect of high dose psilocybin was larger than escitalopram at 10 mg (4.66 (95% credible interval 1.36 to 7.74)) and 20 mg (4.69 (1.64 to 7.54)). None of the interventions was associated with higher all cause discontinuation or severe adverse events than the placebo. CONCLUSIONS: Of the available psychedelic treatments for depressive symptoms, patients treated with high dose psilocybin showed better responses than those treated with placebo in the antidepressant trials, but the effect size was small. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42023469014.

Cognitive functioning associated with acute and subacute effects of classic psychedelics and MDMA - a systematic review and meta-analysis.

Classic psychedelics and MDMA have a colorful history of recreational use, and both have recently been re-evaluated as tools for the treatment of psychiatric disorders. Several studies have been carried out to assess potential long-term effects of a regular use on cognition, delivering distinct results for psychedelics and MDMA. However, to date knowledge is scarce on cognitive performance during acute effects of those substances. In this systematic review and meta-analysis, we investigate how cognitive functioning is affected by psychedelics and MDMA during the acute drug effects and the sub-acute ("afterglow") window. Our quantitative analyses suggest that acute cognitive performance is differentially affected by psychedelics when compared to MDMA: psychedelics impair attention and executive function, whereas MDMA primarily affects memory, leaving executive functions and attention unaffected. Our qualitative analyses reveal that executive functioning and creativity may be increased during a window of at least 24 h after the acute effects of psychedelics have subsided, whereas no such results have been observed for MDMA. Our findings may contribute to inform recommendations on harm reduction for recreational settings and to help fostering differential approaches for the use of psychedelics and MDMA within a therapeutic framework.

The entactogen 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) as a treatment aid in psychotherapy and its safety concerns.

The phenylethylamine, 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy'), is the prototypical example of an entactogen. Its original placement in highly restrictive drug usage categories in the US and UK, led to an inevitable restriction on MDMA neuroscience research and treatment. The dominant pharmacological effects of MDMA are its properties of release and inhibition of reuptake of amine neurotransmitter transporters for dopamine, norepinephrine, and serotonin. MDMA is an agonist of a wide range of receptors; its mood-altering effects are mediated via 5-HT2A receptors; this receptor may also mediate its effects on body temperature, analgesia, and anxiolytic properties. The mechanisms underlying MDMA's entactogenic properties of sociability and interpersonal closeness are not known but release and involvement of oxytocin, a peptide thought by some to be involved in social bonding, has been suggested. Adverse effects of MDMA are mostly transient; acute multiorgan adverse effects occurring during raves or crowded dance gatherings include dehydration, hyperthermia, seizures, rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure. Deaths following MDMA taken by itself are rare compared to fatalities following coadministration with other drugs. A recent FDA-approved phase 3 clinical trial of MDMA for post-traumatic stress disorder (PTSD) led to the conclusion that MDMA-assisted therapy represents a potential breakthrough treatment meriting expedited clinical evaluation. Despite the ongoing deliberations by the FDA and EMA for approval of MDMA treatment of PTSD, the Australian Therapeutic Goods Administration (TGA) recently announced that after an evaluation of the therapeutic value, benefits, and risks of MDMA, it will permit its prescribing for the treatment of PTSD. Further examples of regulatory relaxation toward MDMA-assisted psychotherapy are underway. These include the FDA's recently approved clinical trial to assess MDMA's efficacy in the treatment of "asociality" in patients with schizophrenia and an open trial of MDMA treatment for alcohol-use disorder which showed decreased alcohol consumption. There are also ongoing studies on the little understood startle response, anxiety associated with life-threatening illness, and social anxiety in autistic adults.

Effect of MDMA-assisted therapy on mood and anxiety symptoms in advanced-stage cancer (EMMAC): study protocol for a double-blind, randomised controlled trial.

BACKGROUND: Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several centres have reported that one dose of the serotonergic psychedelic psilocybin, combined with therapeutic support, improves these symptoms for up to 6 months in this patient group. Drawing upon related therapeutic mechanisms, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy may have the potential to achieve similar, positive mental health outcomes in this group. Preliminary evidence also supports the tolerability of MDMA-assisted therapy for anxiety and depression in advanced-stage cancer. METHODS: Up to 32 participants with advanced-stage cancer and associated depression and anxiety will be randomised in a 1:1 ratio into one of two blinded parallel treatment arms. The intervention group will receive 120 mg (+ 60 mg optional supplemental dose) MDMA-assisted therapy. The psychoactive control group will receive 20 mg oral (+ 10 mg optional supplemental dose) methylphenidate-assisted therapy. For each medication-assisted therapy session, participants will undergo two 90-min therapeutic support sessions in the week preceding, and one 90-min support session the day after the experimental session. A battery of measures (mood, anxiety, quality of life, mystical experience, spiritual wellbeing, attitudes towards death, personality traits, holistic health and wellbeing, connectedness, demoralisation, expectations, qualitative data and safety measures) will be assessed at baseline and through to the end of the protocol. Participants will be followed up until either 12 months post-randomisation or death, whichever occurs first. DISCUSSION: This study will examine the effect of MDMA-assisted therapy on symptoms of anxiety and depression in advanced-stage cancer. Potential therapeutic implications include establishing the safety and effectiveness of a novel treatment that may relieve mental suffering in patients with life-threatening illness. TRIAL REGISTRATION: Trial registered on Australian New Zealand Clinical Trials Registry. REGISTRATION NUMBER: ACTRN12619001334190p. Date registered: 30/09/2019. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378153&showOriginal=true&isReview=true.

[MDMA-assisted therapy for PTSD].

MDMA is a potential novel treatment for post-traumatic stress disorder (PTSD). Our goal is to review current knowledge on MDMA and its use in MDMA-assisted psychotherapy for PTSD. Literature searches were done on PubMed, Web of Science and Google Scholar and references reviewed in identified articles. MDMA-assisted therapy for PTSD usually consists of a few preparatory sessions before two or three sessions where one or two oral doses of MDMA are given along with supportive psychotherapy. The therapy is delivered in the presence of two therapists for about eight hours each time. In addition, the patient receives up to 9 integrative sessions in due course. This use of MDMA as a part of psychotherapy for PTSD is proposed to lessen the psychological distress that often arises in the processing of traumatic events to facilitate the treatment process and reduce the risk of drop-out. Recent studies indicate that MDMA-assisted psychotherapy reduces PTSD symptoms and is generally well tolerated. These studies are necessary if this MDMA-assisted treatment is to be approved by licensing authorities. There is an urgent need for new effective treatments for PTSD and for comparisons between this MDMA-assisted psychotherapy and currently approved psychotherapies with and without MDMA-use.

A taxonomy of regulatory and policy matters relevant to psychedelic-assisted therapy in Australia.

OBJECTIVES: The Australian government recently rescheduled psilocybin and 3,4-methylenedioxymethamphetamine for limited clinical uses. This change has raised various regulatory concerns and challenges for the field of psychedelic-assisted therapy. To provide clarity, we aimed to comprehensively catalogue the matters relating to psychedelic-assisted therapy that are or could be regulated. METHODS: We conducted a desktop review of the literature and current regulatory sources, semi-structured interviews with professionals who had expertise in fields relating to psychedelic-assisted therapy and a framework analysis to generate a taxonomy of relevant regulatory matters. In relation to each matter, we further identified what type of regulation (if any) currently applies to that matter, any uncertainty as to how the matter should be addressed in clinical practice in the context of current regulation and whether there are conflicting views as to how the matter could or should be further regulated. RESULTS: The taxonomy is structured into six main regulatory domains, three of which have a substantial proportion of matters with uncertainty or conflicting views: Service Establishment, Practitioner, and Treatment Delivery. Key examples of such matters include the location of services and facilities required, which professionals are eligible to become psychedelic therapists, and with what qualifications and experience. Matters in the remaining three domains, Patient Evaluation, Drug Supply and Service Oversight, appear by comparison relatively settled, with regulation either well-established or thought unnecessary. CONCLUSIONS: The taxonomy provides a roadmap for health services establishing and implementing a psychedelic-assisted therapy program, or for government and other policymakers when determining areas that may require further regulation.

Side-effects of mdma-assisted psychotherapy: a systematic review and meta-analysis.

Evidence suggests that MDMA-assisted psychotherapy (MDMA-AP) has therapeutic potential for treatment of psychiatric illness. We conducted the first comprehensive systematic review and meta-analysis of the side effects of MDMA-AP across indications. We also assessed the quality of side effects-reporting in published trials of MDMA-AP. PubMed, EMBASE, PsycINFO, MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL) were systematically searched. Phase 2 and 3 MDMA-AP studies were included; Phase 1 studies, which assessed MDMA without psychotherapy, were not. Quality of side effects-reporting was assessed against the CONSORT Harms 2022 guidelines. We also compared numbers of adverse events reported in publications to those recorded in ClinicalTrial.gov registers. Thirteen studies were included, with eight contributing to the meta-analysis. In Phase 2 studies, MDMA-AP was associated with increased odds of any side effect during medication sessions (OR = 1.67, 95%CI (1.12, 2.49)) and in the 7 days following (OR = 1.59, 95%CI (1.12, 2.24)) relative to control conditions. In Phase 3 studies, MDMA-AP was associated with increased odds of any adverse event during the treatment period relative to placebo-assisted psychotherapy (OR = 3.51, 95%CI (2.76, 4.46)). The majority of RCTs were rated as having high risk of bias. Certainty of the evidence was rated as very low to moderate according to the GRADE framework. No included RCT had adequate adherence to the CONSORT Harms 2022 recommendations and reporting rates were also low. Compared to placebo, MDMA-AP was associated with increased odds of side effects, which were largely transient and mild or moderate in severity. However, identified limitations in existing evidence indicate that further investigation is needed to better characterize the safety profile of MDMA-AP and guide implementation.

The 3,4-methylenedioxymethamphetamine enhances early visual processing for salient socio-emotional stimuli.

The 3,4-methylenedioxymethamphetamine (MDMA) has long been used non-medically, and it is currently under investigation for its potential therapeutic benefits. Both uses may be related to its ability to enhance empathy, sociability, emotional processing and its anxiolytic effects. However, the neural mechanisms underlying these effects, and their specificity to MDMA compared to other stimulants, are not yet fully understood. Here, using electroencephalography (EEG), we investigated the effects of MDMA and a prototypic stimulant, methamphetamine (MA), on early visual processing of socio-emotional stimuli in an oddball emotional faces paradigm. Specifically, we examined whether MDMA or MA enhance the processing of facial expressions, compared to placebo, during the early stages of visual perception. MDMA enhanced an event-related component that is sensitive to detecting faces (N170), specifically for happy and angry expressions compared to neutral faces. MA did not affect this measure, and neither drug altered other components of the response to emotional faces. These findings provide novel insights into the neural mechanisms underlying the effects of MDMA on socio-emotional processing and may have implications for the therapeutic use of MDMA in the treatment of social anxiety and other psychiatric disorders.

Characterization of the Neurochemical and Behavioral Effects of the Phenethylamine 2-Cl-4,5-MDMA in Adolescent and Adult Male Rats.

BACKGROUND: The proliferation of novel psychoactive substances (NPS) in the drug market raises concerns about uncertainty on their pharmacological profile and the health hazard linked to their use. Within the category of synthetic stimulant NPS, the phenethylamine 2-Cl-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA) has been linked to severe intoxication requiring hospitalization. Thereby, the characterization of its pharmacological profile is urgently warranted. METHODS: By in vivo brain microdialysis in adolescent and adult male rats we investigated the effects of 2-Cl-4,5-MDMA on dopamine (DA) and serotonin (5-HT) neurotransmission in two brain areas critical for the motivational and rewarding properties of drugs, the nucleus accumbens (NAc) shell and the medial prefrontal cortex (mPFC). Moreover, we evaluated the locomotor and stereotyped activity induced by 2-Cl-4,5-MDMA and the emission of 50-kHz ultrasonic vocalizations (USVs) to characterize its affective properties. RESULTS: 2-Cl-4,5-MDMA increased dialysate DA and 5-HT in a dose-, brain area-, and age-dependent manner. Notably, 2-Cl-4,5-MDMA more markedly increased dialysate DA in the NAc shell and mPFC of adult than adolescent rats, while the opposite was observed on dialysate 5-HT in the NAc shell, with adolescent rats being more responsive. Furthermore, 2-Cl-4,5-MDMA stimulated locomotion and stereotyped activity in both adolescent and adult rats, although to a greater extent in adolescents. Finally, 2-Cl-4,5-MDMA did not stimulate the emission of 50-kHz USVs. CONCLUSIONS: This is the first pharmacological characterization of 2-Cl-4,5-MDMA demonstrating that its neurochemical and behavioral effects may differ between adolescence and adulthood. These preclinical data could help understanding the central effects of 2-Cl-4,5-MDMA by increasing awareness on possible health damage in users.

Altered States and Social Bonds: Effects of MDMA and Serotonergic Psychedelics on Social Behavior as a Mechanism Underlying Substance-Assisted Therapy.

There has been renewed interest in the use of 3,4-methylenedioxy-methamphetamine (MDMA) and serotonergic psychedelics in the treatment of multiple psychiatric disorders. Many of these compounds are known to produce prosocial effects, but how these effects relate to therapeutic efficacy and the extent to which prosocial effects are unique to a particular drug class is unknown. In this article, we present a narrative overview and compare evidence for the prosocial effects of MDMA and serotonergic psychedelics to elucidate shared mechanisms that may underlie the therapeutic process. We discuss 4 categories of prosocial effects: altered self-image, responses to social reward, responses to negative social input, and social neuroplasticity. While both categories of drugs alter self-perception, MDMA may do so in a way that is less related to the experience of mystical-type states than serotonergic psychedelics. In the case of social reward, evidence supports the ability of MDMA to enhance responses and suggests that serotonergic psychedelics may also do so, but more research is needed in this area. Both drug classes consistently dampen reactivity to negative social stimuli. Finally, preclinical evidence supports the ability of both drug classes to induce social neuroplasticity, promoting adaptive rewiring of neural circuits, which may be helpful in trauma processing. While both MDMA and serotonergic psychedelics produce prosocial effects, they differ in the mechanisms through which they do this. These differences affect the types of psychosocial interventions that may work best with each compound.

Adverse drug effects as a deterrent against willingness to use in the future among nightclub/festival attendees.

INTRODUCTION: It is largely unknown whether adverse effects experienced from recreational drug use affect willingness to use again. This study determined whether adverse effects from select party drugs affect reported willingness to use again in the next month among a high-risk population-people who attend electronic dance music parties at nightclubs or dance festivals. METHODS: Adults (age ≥ 18) entering nightclubs/festivals were surveyed in New York City in 2018-2022 (n = 2981). Participants were asked about past-month use of common party drugs (cocaine, ecstasy, lysergic acid diethylamide [LSD] and ketamine), whether they had experienced a harmful or very unpleasant effect after use in the past 30 days, and whether they intend to use again in the next 30 days if offered by a friend. The relationship between having experienced an adverse outcome and willingness to use again was examined in a bivariable and multivariable manner. RESULTS: Experiencing an adverse effect after past-month cocaine (adjusted prevalence ratio [aPR] = 0.58, 95% confidence interval [CI] 0.35-0.95) or ecstasy use (aPR = 0.45, 95% CI 0.25-0.80) was associated with lower risk for willingness to use again. Adverse effects related to LSD use were related to lower risk of being willing to use again in the bivariable model, but in multivariable models, risk was not attenuated for willingness to use LSD or ketamine again. DISCUSSION AND CONCLUSIONS: Personally experienced adverse effects can deter willingness to use certain party drugs again in this high-risk population. Interventions targeting cessation of recreational party drug use can likely benefit from focusing on deleterious effects of use that have been experienced.

Past Is Prologue: Ethical Issues in Pediatric Psychedelics Research and Treatment.

Recent clinical trials of psychedelic drugs aim to treat a range of psychiatric conditions in adults. MDMA and psilocybin administered with psychotherapy have received FDA designation as "breakthrough therapies" for post-traumatic stress disorder (PTSD) and treatment-resistant depression (TRD) respectively. Given the potential benefit for minors burdened with many of the same disorders, calls to expand experimentation to minors are inevitable. This essay examines psychedelic research conducted on children from 1959 to 1974, highlighting methodological and ethical flaws. It provides ethics and policy recommendations for psychedelics research involving children and adolescents, including recognizing that the psychedelic experience is an ineffable one that makes informed proxy consent for parents, guardians, and others especially challenging. Psychedelic experiences are associated with novel benefits and risks, such as significant personality changes, shifts in fundamental values, and possible re-exposure to traumatic memories. These effects may alter the process of personality development in minors. Recommendations for ethically sound psychedelics research in minors include strict adherence to eligibility criteria, including a comprehensive family and individual psychiatric, substance use, and trauma history. An age-appropriate assent process that includes considerations related to the use of therapeutic touch should be developed. In addition, oversight by data safety monitoring boards and patient and family advocates, coupled with the adoption of pharmacoequity best practices, will help to ensure safety and fairness of psychedelics research in children.

MDMA/ecstasy use and psilocybin use are associated with lowered odds of psychological distress and suicidal thoughts in a sample of US adults.

BACKGROUND: Suicide is one of the leading causes of death worldwide and rates within the United States have risen over the past two decades. Hence, there is a critical need for novel tools to treat suicidal ideation and related mental health conditions. 3,4-Methylenedioxymethamphetamine (MDMA)/ecstasy and classic psychedelics may be two such tools. AIMS: The aim of this study was to assess non-causal associations between MDMA/ecstasy and classic psychedelic use and psychological distress and suicide risk. METHODS: In this study, we examined the aforementioned associations among 484,732 adult participants in the National Survey on Drug Use and Health (2008-2019). RESULTS: Lifetime MDMA/ecstasy use was associated with reduced odds of past year suicidal thinking (10% reduced odds; odds ratio (OR) = 0.90; 95% confidence interval, CI = (0.84-0.97); p < 0.01) and past year suicidal planning (OR = 0.88; 95% CI = (0.78-0.99); p < 0.05). Furthermore, lifetime psilocybin use was associated with reduced odds of past month psychological distress (OR = 0.78; 95% CI = (0.73-0.84); p < 0.001) and past year suicidal thinking (OR = 0.90; 95% CI = (0.83-0.96); p < 0.01). Finally, lysergic acid diethylamide (LSD) was associated with increased odds of past year suicidal thinking (OR = 1.07; 95% CI = (1.00-1.15); p < 0.05). CONCLUSION: MDMA/ecstasy and psilocybin use are associated with reduced odds of suicidal thinking and related outcomes-though experimental studies are needed to determine whether these associations are causal. These findings call for more research into the efficacy of MDMA/ecstasy and classic psychedelics for treating psychological distress and suicidal thoughts and behaviors, and for updated drug legislation that allows for further investigation into these substances.

Lifetime use of MDMA/ecstasy and psilocybin is associated with reduced odds of major depressive episodes.

BACKGROUND: Depression is a major mental health issue worldwide, with high rates of chronicity and non-recovery associated with the condition. Existing treatments such as antidepressant medication and psychological treatments have modest effectiveness, suggesting the need for alternative interventions. AIM: The aim of this study was to examine the relationships between MDMA (3,4-methylenedioxymethamphetamine)/ecstasy and psilocybin use and major depressive episodes (MDEs). METHODS: This observational study used data from a large (N = 213,437) nationally representative sample of US adults to test the association of lifetime use of MDMA/ecstasy, psilocybin and other classic psychedelics (lysergic acid diethylamide (LSD), peyote, mescaline), other illegal substances (e.g. cocaine, phencyclidine (PCP)), and legal/medicinal substances of misuse (e.g. pain relievers, tranquilizers) with lifetime, past year, and past year severe MDEs. RESULTS: Results revealed that lifetime MDMA/ecstasy use was associated with significantly lowered odds of a lifetime MDE (adjusted odds ratio (aOR) = 0.84; p < 0.001), past year MDE (aOR = 0.84; p < 0.001), and past year severe MDE (aOR = 0.82; p < 0.001). Psilocybin was associated with significantly lowered odds of a past year MDE (aOR = 0.90; p < 0.05) and past year severe MDE (aOR = 0.87; p < 0.05). All other substances either shared no relationship with a MDE or conferred increased odds of an MDE. CONCLUSIONS: These results suggest that MDMA/ecstasy and psilocybin use is associated with lower risk of depression. Experimental studies are needed to test whether there is a causal association between use of these compounds and the alleviation of depressive symptoms.

Protective effects of atorvastatin and rosuvastatin on 3,4-methylenedioxymethamphetamine (MDMA)-induced spatial learning and memory impairment.

3,4-Methylenedioxymethamphetamine (MDMA) or "Ecstasy", which has been used for recreational purposes, is shown to impair memory and brain functions. Statins, beyond their efficient cholesterol-lowering impact through inhibition of HMG-COA reductase enzyme, possess multiple actions referred to as pleiotropic effects. In this regard, we aimed to investigate the neuroprotective effects of atorvastatin and rosuvastatin on MDMA-induced neurotoxicity. Adult male Wistar rats received atorvastatin (5, 10, and 20 mg/kg; orally) and rosuvastatin (5, 10, 20 mg/kg; orally) for 21 consecutive days. Then, spatial memory and learning were evaluated by Morris water maze (MWM) test. Rats were intraperitoneally injected with MDMA (2.5, 5, and 10 mg/kg) 30 min before the first training session in 4 training days of MWM task. Afterward, rats were euthanized and their hippocampuses were dissected to evaluate reactive oxygen species (ROS) production, lipid peroxidation (LPO), and caspase-3 and -9 activities. Our findings showed that MDMA (5 and 10 mg/kg) significantly impaired spatial memory functions and dramatically increased ROS production, LPO, and caspase-3 and -9 activities compared to control. Also, atorvastatin (5, 10, and 20 mg/kg) and rosuvastatin (20 mg/kg) significantly improved memory performances and inhibited the elevation of ROS, LPO, and caspase-3 and -9 activities induced by MDMA. In conclusion, the results indicated that MDMA-induced cognitive impairment is followed by oxidative stress and activation of apoptotic pathways in the hippocampus. However, atorvastatin and rosuvastatin suppressed these deleterious consequences of MDMA and revealed protective effects against activation of pathways leading to cell damage.

Lack of evidence for positive reinforcing and prosocial effects of MDMA in pair-housed male and female rats.

3,4-Methylenedioxymethamphetamine (MDMA) is classified as an entactogen, producing feelings of emotional openness and relatedness. One unique feature of MDMA is that people tend to selectively take this drug in social and/or intimate situations. Although MDMA is recognized as having abuse liability, preclinical studies report that it has weak reinforcing effects in animals. The objective of this study was to characterize the positive reinforcing and prosocial effects of MDMA in a translational model of the social environment in which two rats have simultaneous and contingent access to MDMA in close physical proximity. To this end, MDMA self-administration was examined on both fixed and progressive ratio schedules of reinforcement in six groups of rats: (1) isolated males, (2) isolated females, (3) male-male dyads, (4) female-female dyads, (5) male-female dyads, and (6) female-male dyads. For pair-housed rats, data from both rats were analyzed. Next, social preferences were examined in a partner preference test. MDMA failed to produce positive reinforcing effects under all conditions examined. Across a 30-fold dose range (0.01-1.0 mg/kg/infusion), MDMA did not maintain higher responding than saline on both schedules of reinforcement and in all groups tested. In partner preference tests, a history of shared exposure to MDMA did not establish a social preference, and acute administration of MDMA failed to establish a preference for another MDMA-treated rat. These data suggest that social contact does not increase the positive reinforcing effects of MDMA in rats, and that neither contingent nor noncontingent MDMA administration establishes a social preference in rats.

Self-reported PTSD is associated with increased use of MDMA in adolescents with substance use disorders.

Background: Adolescent patients with a substance use disorder (SUD) often fulfil the criteria for a co-occurring post-traumatic stress disorder (PTSD). However, it is not clear if these dual-diagnosed adolescents present with unique levels of substance use and how their substance use relates to PTSD symptom clusters. Objective: To investigate substance use in adolescents with co-occurring PTSD and SUD. Additionally, we explored how the use of specific substances is related to specific PTSD symptom clusters. Method: We recruited n = 121 German adolescent SUD patients, in three groups: no history of traumatic events (TEs) (n = 35), TEs but not PTSD (n = 48), probable PTSD (n = 38). All groups were administered a trauma questionnaire and were asked to report their past-month substance use. Results: Adolescents with probable PTSD and SUD report a higher frequency of MDMA use than adolescents with no PTSD and no TE (PTSD vs. noTE: U = 510.5, p = .016; PTSD vs. TE: U = 710.0, p = .010). The use of MDMA was more frequent in adolescents with avoidance symptoms (X2 (1) = 6.0, p = .014). Participants report using substances at a younger age (PTSD vs. noTE: U = 372.0, p = .001; PTSD vs. TE: U = 653.5, p = .022) and PTSD symptom onset was on average 2.2 years earlier than first MDMA use (t (26) = -2.89, p = .008). Conclusions: Adolescent SUD patients with probable PTSD are more likely to use MDMA than SUD patients without PTSD. The use of MDMA was associated with reported avoidance symptoms. The first age of MDMA use is initiated after PTSD onset. It is unclear whether the association of MDMA use with avoidance symptoms is due to efforts to reduce these symptoms or a result of regular MDMA use.

Antecedentes: Los pacientes adolescentes con un trastorno por uso de sustancias (TUS) a menudo cumplen los criterios para un trastorno de estrés postraumático concurrente (TEPT). Sin embargo, no está claro si estos adolescentes con diagnóstico dual presentan niveles únicos de consumo de sustancias y cómo su consumo de sustancias se relaciona con los conglomerados de síntomas del TEPT.Objetivo: Investigar el uso de sustancias en adolescentes con concurrencia de TEPT y TUS. Además, exploramos cómo el uso de sustancias específicas se relaciona con grupos específicos de síntomas de TEPT.Método: Reclutamos un n=121 pacientes adolescentes alemanes con TUS, en tres grupos: sin antecedentes de eventos traumáticos (no ETs) (n=35), ETs pero no TEPT (n=48), probable TEPT (n=38). A todos los grupos se les administró un cuestionario sobre traumas y se les pidió que informaran sobre su consumo de sustancias durante el mes anterior.Resultados: Los adolescentes con probable TEPT y TUS informan una mayor frecuencia de uso de MDMA que los adolescentes sin TEPT y sin ETs (TEPT versus no ETs: U= 510.5, p= .016; TEPT versus ETs: U= 710.0, p=.010). El uso de MDMA fue más frecuente en adolescentes con síntomas de evitación (X² (1) = 6.0, p = .014). Los participantes informan que consumen sustancias a una edad más temprana (TEPT versus no ETs: U= 372.0, p= .001; TEPT frente a TE: U= 653.5, p= .022) y el inicio de los síntomas del TEPT fue en promedio 2.2 años antes del primer uso de MDMA (t (26) = −2.89, p = .008).Conclusiones: Los pacientes adolescentes con TUS con probable TEPT son más propensos a usar MDMA que los pacientes con TUS sin TEPT. El uso de MDMA se asoció con el reporte de síntomas de evitación. La primera edad de uso de MDMA se inicia después del inicio del TEPT. No está claro si la asociación del uso de MDMA con los síntomas de evitación se debe a los esfuerzos por reducir estos síntomas o al resultado del uso regular de MDMA.

Three regulatory compliant test systems show no signs of MDMA-related genotoxicity.

3,4 Methylenedioxymethamphetamine (MDMA)-assisted therapy has been recently found to be highly effective for treatment of posttraumatic stress disorder (PTSD). Previous studies have been inconclusive in elucidating potential MDMA genotoxicity. We performed three regulatory compliant studies to investigate the potential of genotoxic effects of MDMA treatment in humans: (1) an in vitro bacterial reverse mutation (Ames) assay, (2) an in vitro chromosome aberration test in Chinese hamster ovary cells, and (3) an in vivo micronucleus study in male Sprague Dawley rats. MDMA was found to not have genotoxic effects in any of the assays at or above clinically relevant concentrations.

Role of acute social stress in the rewarding effects of MDMA in adolescent mice.

Drug use among adolescents is a serious problem in our society, as some individuals develop dependence and addiction. MDMA/Esctasy is one of the most typically used substances by this age group. It is well known that environmental factors can alter the rewarding properties of drugs and the propensity to drug-related disorders. In this sense, exposure to social stress induces long-term effects in mice, enhancing the rewarding effects of MDMA in the conditioned place preference (CPP) paradigm. On the other hand, previous research has not provided conclusive results regarding the short-term effects of social defeat on MDMA reward in adolescent animals, probably due to the use of very low or very high doses. Thus, in the present study, we set out to evaluate whether exposure to social defeat immediately before each conditioning session with an intermediate dose of MDMA (2.25 mg/kg) modulates the rewarding effect of this drug in adolescent animals. Our results indicate that both control and socially defeated mice acquired CPP, but only stressed mice showed reinstatement. These findings indicate that social defeat induces an increase in the rewarding effect of MDMA, suggesting that this type of stress is a potential factor in the development of MDMA addiction.

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study.

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.