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.

Crystal structure of an antibody specifically recognizing 3,4-methyl enedioxy methamphetamine through the epoxide moiety.

3,4-methylenedioxymethamphetamine (MDMA) or publicly known as "ecstasy" is a drug abuse substance. Since antibodies that detect MDMA typically also recognize its chemical analogue, methamphetamine (METH), we identified antibodies specifically recognizing MDMA, but not METH, named 1bB11 and 1bF12, using phage display. The crystal structure of 1bB11 in complex with MDMA was determined at 3.2 Å resolution. Key interactions were found between the epoxide moiety of MDMA and S34 and Y36 of the light chain. Additional interaction with E33 of the heavy chain contributes to anchoring MDMA. Mutagenesis-based biochemical analysis confirmed the importance of these residues in MDMA binding. Comparing the structure of 1bB11 to a scFv6H4, which binds both METH and MDMA, revealed opposite binding orientations. Taken together, our data provides a structural framework for selective binding to MDMA by the 1bB11 antibody, paving a way to develop a highly specific antibody for diagnosis.

Is it now time to prepare psychiatry for a psychedelic future?

Australia has just rescheduled two drugs controlled under the United Nations Psychotropic Drug Conventions, psilocybin and MDMA, as treatments for treatment-resistant depression and post-traumatic stress disorder respectively. This feature explores the reasons for these developments, the opportunities and challenges they provide to psychiatry communities and how along with health systems these communities might respond to these developments.

A simple polyarginine membrane electrochemical sensor for the determination of MDMA and MDA.

In this study, a simple electrochemical sensor based on l-arginine membrane (P-L-arg/GCE) was developed for rapid and sensitive detection of MDMA and MDA. A polyarginine membrane was obtained through one-step direct electropolymerization, which provides more reaction sites for the analyte and improves the sensitivity of the sensor. Following the optimized selection parameters, the MDMA detection range was established at 1.0 × 10-7∼3.5 × 10-5 mol L-1, with a detection limit of 3.3 × 10-8 mol L-1. Similarly, the detection range for MDA was established at 1.0 × 10-7∼5.3 × 10-5 mol L-1 with a detection limit of 3.3 × 10-8 mol L-1. Additionally, the potential oxidation mechanism of MDMA and MDA during the REDOX process was analyzed by cyclic voltammetry. Furthermore, the proposed sensor exhibited superior selectivity, excellent reproducibility, and satisfactory stability. The proposed sensors can be used for reliable monitoring of MDMA or MDA in human urine and hair samples, respectively, and it has acceptable analytical reliability and enormous potential for practical applications.

Mind over matter: the microbial mindscapes of psychedelics and the gut-brain axis.

Psychedelics have emerged as promising therapeutics for several psychiatric disorders. Hypotheses around their mechanisms have revolved around their partial agonism at the serotonin 2 A receptor, leading to enhanced neuroplasticity and brain connectivity changes that underlie positive mindset shifts. However, these accounts fail to recognise that the gut microbiota, acting via the gut-brain axis, may also have a role in mediating the positive effects of psychedelics on behaviour. In this review, we present existing evidence that the composition of the gut microbiota may be responsive to psychedelic drugs, and in turn, that the effect of psychedelics could be modulated by microbial metabolism. We discuss various alternative mechanistic models and emphasize the importance of incorporating hypotheses that address the contributions of the microbiome in future research. Awareness of the microbial contribution to psychedelic action has the potential to significantly shape clinical practice, for example, by allowing personalised psychedelic therapies based on the heterogeneity of the gut microbiota.

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.

Attitudes toward psychedelics and psychedelic-assisted therapy among potential mental health service users and the general population in Australia.

OBJECTIVE: Despite rapid advances in psychedelic sciences and the increasing number of countries legalizing psychedelics for the treatment of mental illnesses, the attitudes, knowledge and readiness of both mental health consumers and the general population remain largely unknown. METHODS: A cross-sectional survey was conducted among Australians, targeting individuals with mental illness as potential mental health service users. A sub-sample of individuals free of mental illness was also surveyed to assess attitudes in the general population. Participants completed the Attitudes on Psychedelics Questionnaire, the Basic Knowledge of Psychedelics Test and a questionnaire by Corrigan et al. to capture attitudes toward psychedelic therapy by mental health service users. RESULTS: Of the 502 respondents, 64.5% self-identified as having a mental illness. A significant proportion favored legalizing psychedelics for medical use (43%) and were open to their use (52.4%), yet fewer viewed their effects positively (24%) or considered them safe (33%). Most participants reported to be psychedelic naive (61%). Participants with mental illness had significantly more experience with psychedelics than participant free of mental illness (44.1% vs 29.7%). Experience, perceived knowledge and actual knowledge significantly predicted attitudes toward legalization, effects, risks and openness to psychedelics. CONCLUSIONS: While a large proportion of Australians are in favor of legalizing psychedelics for medical purposes, concerns about safety remain. People with self-identified mental illness, those with previous recreational psychedelic experience and those with greater knowledge of psychedelics were more likely to have positive attitudes toward psychedelics and psychedelic-assisted therapy.

A thematic analysis of MDMA-related harm and harm reduction experiences and knowledge in Aotearoa New Zealand.

BACKGROUND: Methylenedioxymethamphetamine (MDMA) is a popular drug worldwide and use is prevalent in Aotearoa New Zealand. Although associated with some significant harms, including fatalities, MDMA is ultimately less harmful than other commonly consumed drugs. We aimed to expand the understanding of MDMA harm and harm reduction strategies from a consumer perspective so that national harm reduction efforts can be better informed. METHODS: We conducted 14 semi-structured focus group discussions including 60 people (aged 18-67, median = 21) who use MDMA in the Southern region of Aotearoa New Zealand to explore their thoughts and experiences regarding MDMA associated harm and harm reduction. Reflexive thematic analysis was conducted from a critical realist perspective. RESULTS: Five themes were generated; (1) Mindset and setting matters; (2) Looking after your body and mind, not overdoing it; (3) Other substances increase risk and harm; (4) Trusted friends and peers are protective; and (5) Valid information is key for healthy self-determination; and one subtheme 5.1) Drug checking is essential harm reduction. CONCLUSIONS: We discuss the implications for MDMA consumers and aim to inform national drug policy and the harm reduction practices of consumers and organisations, for the ultimate purpose of reducing MDMA-related harm in Aotearoa New Zealand.

Harm reduction behaviours and harm experiences of people who use 3,4-methylenedioxymethamphetamine (MDMA) in Aotearoa New Zealand.

BACKGROUND: 3,4-Methylenedioxymethamphetamine (MDMA) is drug of high prevalence in Aotearoa New Zealand and is the primary drug analysed by legal drug checking services. We aimed to address the gap in literature pertaining to MDMA-related harm reduction behaviour and harm experiences within the country. METHODS: An online survey was used to assess the harm reduction behaviours (e.g., limiting consumption, planning use, seeking information) of people who use MDMA, in addition to their use of reagent testing and the major national drug checking and harm reduction service, KnowYourStuffNZ. RESULTS: In total, 915 people completed the survey (60.7% females, aged 18-65, median = 24, IQR = 20-28). Frequency of various MDMA-related harm reduction behaviours differed, although these were carried out relatively frequently by most participants. Those who reported experiencing harm (physical, psychological, spiritual, social) from MDMA, or another drug presumed to be MDMA, reported less frequent harm reduction behaviours than non-harmed consumers. Reagent testing of MDMA had been conducted by 42.3% of the sample. Approximately 27% of the sample had used KnowYourStuffNZ services. Of KnowYourStuffNZ clients, 95.9% reported learning about harm reduction, and 53.3% reported changing their behaviour because of the service. Reasons for not using the KnowYourStuffNZ service were primarily lack of availability in local area (32.8%) or at relevant events (51.8%), and lack of concern with substance quality (29.8%). MDMA harm was reported by 14.4% of the sample, whilst reported harm was more common from consumption of presumably non-MDMA substances, self-reported as being mistaken for MDMA. Harm was primarily physical or psychological. Potential MDMA dependence was apparent in 6.9% of the sample. CONCLUSIONS: The findings highlight potential targets for harm reduction education and interventions and emphasize the need for greater availability of readily accessible drug checking services in Aotearoa New Zealand.

Aggressive behaviours associated with MDMA and psychedelics: a narrative review.

OBJECTIVE: Monoamine neurotransmitters play a role in aggression, especially when altered by illicit substances. However, some literature suggests that not all illicit substances may lead to aggression, notably psychedelics. This narrative review investigates the associations between serotonergic psychedelics and MDMA on aggressive behaviour. METHODS: PubMed and PsycINFO were searched for original, peer-reviewed articles evaluating the effects of serotonergic psychedelics and 3,4-methyl enedioxy methamphetamine (MDMA) on violent and aggressive behaviour using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: After removing duplicates, a total of 555 articles were screened, with 16 meeting the inclusion criteria. One additional article was obtained through reference screening bringing the total to 17 articles. Of these 17 articles, 14 studies focused on MDMA and three on serotonergic psychedelics. Findings were mixed, with some results demonstrating increased aggression following psychedelics and others suggesting protective effects. Limitations in the current literature include varied definitions of psychedelics, lack of standardised objective outcome measures and failure to control for confounding. CONCLUSION: As psychedelic research continues to expand, further assessment on the effects of serotonergic psychedelics and MDMA on aggressive behaviour is required.

[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.

Role of the gut-brain axis via the subdiaphragmatic vagus nerve in stress resilience of 3,4-methylenedioxymethamphetamine in mice exposed to chronic restrain stress.

3,4-Methylenedioxymethamphetamine (MDMA) is the most widely used illicit substance worldwide. Nevertheless, recent observational studies demonstrated that lifetime MDMA use among U.S. adults was associated with a lower risk of depression and suicide thoughts. We recently reported that the gut-brain axis may contribute to MDMA-induced stress resilience in mice. To further explore this, we investigated the effects of subdiaphragmatic vagotomy (SDV) in modulating the stress resilience effects of MDMA in mice subjected to chronic restrain stress (CRS). Pretreatment with MDMA (10 mg/kg/day for 14 days) blocked anhedonia-like behavior and reduced expression of synaptic proteins and brain-derived neurotrophic factor in the prefrontal cortex (PFC) of CRS-exposed mice. Interestingly, SDV blocked the beneficial effects of MDMA on these alterations in CRS-exposed mice. Analysis of gut microbiome revealed alterations in four measures of α-diversity between the sham + MDMA + CRS group and the SDV + MDMA + CRS group. Moreover, specific microbes differed between the vehicle + CRS group and the MDMA + CRS group, and further differences in microbial composition were observed among all four groups. Untargeted metabolomics analysis showed that SDV prevented the increase in plasma levels of three compounds [lactic acid, 1-(2-hydroxyethyl)-2,2,6-tetramethyl-4-piperidinol, 8-acetyl-7-hydroxyvumaline] observed in the sham + MDMA + CRS group. Interestingly, positive correlations were found between the plasma levels of two of these compounds and the abundance of several microbes across all groups. In conclusion, our data suggest that the gut-brain axis via the subdiaphragmatic vagus nerve might contribute to the stress resilience of MDMA.

The functional connectome of 3,4-methyldioxymethamphetamine-related declarative memory impairments.

The chronic intake of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") bears a strong risk for sustained declarative memory impairments. Although such memory deficits have been repeatedly reported, their neurofunctional origin remains elusive. Therefore, we here investigate the neuronal basis of altered declarative memory in recurrent MDMA users at the level of brain connectivity. We examined a group of 44 chronic MDMA users and 41 demographically matched controls. Declarative memory performance was assessed by the Rey Auditory Verbal Learning Test and a visual associative learning test. To uncover alterations in the whole brain connectome between groups, we employed a data-driven multi-voxel pattern analysis (MVPA) approach on participants' resting-state functional magnetic resonance imaging data. Recent MDMA use was confirmed by hair analyses. MDMA users showed lower performance in delayed recall across tasks compared to well-matched controls with moderate-to-strong effect sizes. MVPA revealed a large cluster located in the left postcentral gyrus of global connectivity differences between groups. Post hoc seed-based connectivity analyses with this cluster unraveled hypoconnectivity to temporal areas belonging to the auditory network and hyperconnectivity to dorsal parietal regions belonging to the dorsal attention network in MDMA users. Seed-based connectivity strength was associated with verbal memory performance in the whole sample as well as with MDMA intake patterns in the user group. Our findings suggest that functional underpinnings of MDMA-related memory impairments encompass altered patterns of multimodal sensory integration within auditory processing regions to a functional heteromodal connector hub, the left postcentral gyrus. In addition, hyperconnectivity in regions of a cognitive control network might indicate compensation for degraded sensory processing.

Behavioral metabolomics: how behavioral data can guide metabolomics research on neuropsychiatric disorders.

INTRODUCTION: Metabolomics produces vast quantities of data but determining which metabolites are the most relevant to the disease or disorder of interest can be challenging. OBJECTIVES: This study sought to demonstrate how behavioral models of psychiatric disorders can be combined with metabolomics research to overcome this limitation. METHODS: We designed a preclinical, untargeted metabolomics procedure, that focuses on the determination of central metabolites relevant to substance use disorders that are (a) associated with changes in behavior produced by acute drug exposure and (b) impacted by repeated drug exposure. Untargeted metabolomics analysis was carried out on liquid chromatography-mass spectrometry data obtained from 336 microdialysis samples. Samples were collected from the medial striatum of male Sprague-Dawley (N = 21) rats whilst behavioral data were simultaneously collected as part of a (±)-3,4-methylenedioxymethamphetamine (MDMA)-induced behavioral sensitization experiment. Analysis was conducted by orthogonal partial least squares, where the Y variable was the behavioral data, and the X variables were the relative concentrations of the 737 detected features. RESULTS: MDMA and its derivatives, serotonin, and several dopamine/norepinephrine metabolites were the greatest predictors of acute MDMA-produced behavior. Subsequent univariate analyses showed that repeated MDMA exposure produced significant changes in MDMA metabolism, which may contribute to the increased abuse liability of the drug as a function of repeated exposure. CONCLUSION: These findings highlight how the inclusion of behavioral data can guide metabolomics data analysis and increase the relevance of the results to the phenotype of interest.

Chronic 3,4-Methylenedioxymethamphetamine (MDMA) Use Is Related to Glutamate and GABA Concentrations in the Striatum But Not the Anterior Cingulate Cortex.

BACKGROUND: 3,4-Methylenedioxymethamphetamine (MDMA) is a widely used recreational substance inducing acute release of serotonin. Previous studies in chronic MDMA users demonstrated selective adaptations in the serotonin system, which were assumed to be associated with cognitive deficits. However, serotonin functions are strongly entangled with glutamate as well as γ-aminobutyric acid (GABA) neurotransmission, and studies in MDMA-exposed rats show long-term adaptations in glutamatergic and GABAergic signaling. METHODS: We used proton magnetic resonance spectroscopy (MRS) to measure the glutamate-glutamine complex (GLX) and GABA concentrations in the left striatum and medial anterior cingulate cortex (ACC) of 44 chronic but recently abstinent MDMA users and 42 MDMA-naïve healthy controls. While the Mescher-Garwood point-resolved-spectroscopy sequence (MEGA-PRESS) is best suited to quantify GABA, recent studies reported poor agreement between conventional short-echo-time PRESS and MEGA-PRESS for GLX measures. Here, we applied both sequences to assess their agreement and potential confounders underlying the diverging results. RESULTS: Chronic MDMA users showed elevated GLX levels in the striatum but not the ACC. Regarding GABA, we found no group difference in either region, although a negative association with MDMA use frequency was observed in the striatum. Overall, GLX measures from MEGA-PRESS, with its longer echo time, appeared to be less confounded by macromolecule signal than the short-echo-time PRESS and thus provided more robust results. CONCLUSION: Our findings suggest that MDMA use affects not only serotonin but also striatal GLX and GABA concentrations. These insights may offer new mechanistic explanations for cognitive deficits (e.g., impaired impulse control) observed in MDMA users.

The Safety and Efficacy of Psychedelic-Assisted Therapies for Older Adults: Knowns and Unknowns.

Psychedelics and related compounds have shown efficacy for the treatment of a variety of conditions that are prevalent among older adults, including mood disorders, the psychological distress associated with a serious medical illness, post-traumatic stress disorder (PTSD), and prolonged grief disorder. Psychedelics also have properties that could help provide therapeutic benefits for patients with dementing disorders, as well as promoting personal growth among healthy older adults. This article focuses on psilocybin, a classic psychedelic, and MDMA, a substituted amphetamine with properties similar to classic psychedelics. Both act on the 5HT2A receptor. Psychedelics can be safely administered to healthy adults in controlled conditions. However, both psilocybin and MDMA can increase blood pressure and heart rate, which could be a concern if used in older adults with cardiovascular disease. Very few older adults or patients with serious comorbidities have been included in clinical trials of psychedelics to date, raising the question of how generalizable study results are for the patients that most geropsychiatrists will be treating. Research on the neurophysiologic and mechanistic effects of psychedelics in older adults could also provide insights into the aging brain that could have clinical applications in the future. Given the potential of psychedelic compounds to benefit older adults, more research is needed to establish safety and efficacy among older adults, particularly those with multi-morbidity.

Psychedelics for Patients With Cancer: A Comprehensive Literature Review.

OBJECTIVE: To assess the role of psychedelics in the treatment of anxiety or depression among patients with cancer. DATA SOURCES: PubMed search from inception to March 11, 2022, using the terms anxiety, depression, psychedelics, psilocybin, lysergic acid, methylenedioxymethamphetamine, or ayahuasca. STUDY SELECTION AND DATA EXTRACTION: Studies assessing patients with cancer receiving psychedelics for the treatment of anxiety or depression. DATA SYNTHESIS: Five unique randomized, double-blind, placebo-controlled trials were conducted. Significant reductions were found in 2 trials with 2 anxiety scales (State-Trait Anxiety Inventory-State, State-Trait Anxiety Inventory-Trait) and in 1 trial with 2 additional anxiety scales (Hamilton Rating Scale-Anxiety, Hospital Anxiety and Depression Scale-Anxiety). Significant reductions were found in 2 trials in 2 depression scales (Hospital Anxiety and Depression Scale-Depression, Beck Depression Inventory) and in 1 trial with an additional depression scale (Hamilton Rating Scale-Depression). Two studies assessed for clinically relevant reductions in anxiety and depression scores, and they occurred much more commonly in psychedelic-treated patients than those given placebo. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: There is a new potential option for treating patients with anxiety and depression along with cancer, which is important given the generally lackluster benefits with traditional antidepressants. Only a few sessions may also provide benefits extending out for 6 to 12 months and possibly beyond that. However, the studies were small, had many methodological limitations, and there were increases in blood pressure and heart rate. CONCLUSIONS: Psychedelics have a unique mechanism of action that might be well suited for treating anxiety and depression associated with cancer. This offers new promise for patients who are not being sufficiently treated with current antianxiety or antidepressant medications.

MDMA targets miR-124/MEKK3 via MALAT1 to promote Parkinson's disease progression.

BACKGROUND: Parkinson's disease (PD) is a well-known neurodegenerative disease that is usually caused by the progressive loss of dopamine neurons and the formation of Lewy vesicles. 3,4-Methylenedioxymethamphetamine (MDMA) has been reported to cause damage to human substantia nigra neurons and an increased risk of PD, but the exact molecular mechanisms need further investigation. METHODS: MPTP- and MPP+-induced PD cells and animal models were treated with Nissl staining to assess neuronal damage in the substantia nigra (SN) area; immunohistochemistry to detect TH expression in the SN; TUNEL staining to detect apoptosis in the SN area; Western blotting to detect the inflammatory factors NF-κB, TNF-α, IL-6 and mitogen-activated protein kinase kinase kinase 3 (MEKK3); Griess assay for NO; RT‒qPCR for metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and miR-124 expression; Cell proliferation was assessed by CCK-8. Dual luciferase reporter genes were used to verify targeting relationships. RESULTS: MDMA promoted MALAT1 expression, and knockdown of MALAT1 alleviated the MDMA-induced inhibition of SH-SY5Y cell proliferation, inflammation, NO release, SN neuronal injury, and TH expression inhibition. Both inhibition of miR-124 and overexpression of MEKK3 reversed the neuroprotective effects exhibited by knockdown of MALAT1. CONCLUSION: MDMA promotes MALAT1 expression and inhibits the targeted downregulation of MEKK3 by miR-124, resulting in upregulation of the expression of MEKK3 and finally jointly promoting PD progression.

Psychedelic-Assisted Therapy in Military and Veterans Healthcare Systems: Clinical, Legal, and Implementation Considerations.

PURPOSE OF REVIEW: This review discusses the current and projected landscape of psychedelic-assisted therapy (PAT), with a focus on clinical, legal, and implementation considerations in Department of Defense (DoD) and Department of Veterans Affairs (VA) healthcare systems. RECENT FINDINGS: 3,4-Methylenedioxymethamphetamine (MDMA)- and psilocybin-assisted therapy have shown promising outcomes in efficacy, safety, tolerability, and durability for PTSD and depression, respectively. MDMA-assisted therapy is already approved by the Food and Drug Administration (FDA) on an Expanded Access ("compassionate use") basis for PTSD, with full approval projected for 2024. Psilocybin-assisted therapy is projected to be FDA-approved for depression soon thereafter. Other psychedelics are in earlier stages of development. The VA is currently conducting PAT clinical trials. Although there are clear legal pathways for the VA and DoD to conduct PAT trials, a number of implementation barriers exist, such as the very high number of clinical hours necessary to treat each patient, resource requirements to support treatment infrastructure, military-specific considerations, and the high level of evidence necessary for PAT to be recommended in clinical practice guidelines. Ongoing considerations are whether and how PAT will be made available to VA and DoD beneficiaries, feasibility and cost-effectiveness, and ethical safeguards that must be implemented to prioritize access to PAT given the likelihood of extremely limited initial availability. However, with imminent FDA approval of PATs and considerable national interest in these treatments, DoD and VA policymakers must be prepared with clearly delineated policies and plans for how these healthcare systems will approach PAT.

MDMA-assisted psychotherapy for post-traumatic stress disorder: The devil is in the detail.

Recent years have seen escalating media, public and scientific interest in psychedelic medicine. Australia and New Zealand have been late to this research; however, in the past 2 years, rapid developments suggest that this is changing. Here, we argue for the need to critically review existing evidence in this field to guide future directions. We focus on (±)3,4-methylenedioxymethamphetamine-assisted psychotherapy for post-traumatic stress disorder, currently the most advanced area of clinical psychedelic research. Food and Drug Administration approval of this approach is likely in 2023, based on a series of promising findings. We provide a detailed overview of Phase 2 and 3 studies published to date. We identify several concerns related to this body of evidence, including methodological/design limitations and broader factors - such as robust involvement of advocacy groups in research and reliance on non-government financing leading to simplistic public messaging - that compound the methodological issues identified. We propose steps for future improvement, including the need for large, high-quality, independent efficacy trials with design enhancements, effectiveness trials and for researchers to consider their own engagement with media and public messaging around these modalities. We argue that, notwithstanding promising findings to date, rigorous and dispassionate science is needed to move the field forward and safeguard the welfare of participants.