Co-exposure to gamma-hydroxybutyrate is associated with attenuated neuropsychiatric and stimulant effects of metamfetamine.

INTRODUCTION: Acute metamfetamine toxicity is characterized by stimulant effects and neuropsychiatric disturbance, which is attenuated by gamma-aminobutyric acid type A receptor agonists including benzodiazepines. We utilized clinical registry data to examine the effect of co-exposure to a gamma-aminobutyric acid type B receptor agonist (gamma-hydroxybutyrate) in illicit drug cases with analytically confirmed exposure to metamfetamine. METHODS: The Emerging Drugs Network of Australia Victoria is an ethics board-approved prospective registry collecting clinical and analytical data (utilising blood samples) on emergency department illicit drug presentations. Comparison groups were defined by analytically confirmed exposure: lone metamfetamine, metamfetamine plus gamma-hydroxybutyrate, metamfetamine plus benzodiazepine, metamfetamine plus gamma-hydroxybutyrate plus benzodiazepine. Cases with co-exposure to other stimulants or sedatives were excluded. RESULTS: Median metamfetamine blood concentrations were significantly greater in metamfetamine plus gamma-hydroxybutyrate (n = 153, median = 0.20 mg/L, interquartile range: 0.10-0.32 mg/L, 95 per cent confidence interval: 0.20-0.23 mg/L) and metamfetamine plus gamma-hydroxybutyrate plus benzodiazepine (n = 160, median = 0.20 mg/L, interquartile range: 0.10-0.30 mg/L, 95 per cent confidence interval: 0.20-0.30 mg/L) positive groups compared to gamma-hydroxybutyrate negative groups including metamfetamine (n = 81, median = 0.10 mg/L, interquartile range: 0.05-0.21 mg/L, 95 per cent confidence interval: 0.09-0.18 mg/L) and metamfetamine plus benzodiazepine (n = 73, median = 0.10 mg/L, interquartile range: 0.06-0.20 mg/L, 95 per cent confidence interval: 0.09-0.20 mg/L) groups (P < 0.0004). Presenting heart rate in metamfetamine plus gamma-hydroxybutyrate cases (n = 153, median = 72 beats per minute, interquartile range: 63-86 beats per minute, 95 per cent confidence interval: 70-78 beats per minute) was significantly lower than metamfetamine plus benzodiazepine cases (n = 73, median = 84 beats per minute, interquartile range: 73-98 beats per minute, 95 per cent confidence interval: 80-90 beats per minute, P < 0.0001), and lone metamfetamine cases (n = 81, median = 110 beats per minute, interquartile range: 87-131 beats per minute, 95 per cent confidence interval: 93-120 beats per minute, P < 0.0001). Presenting temperature in metamfetamine plus gamma-hydroxybutyrate cases (median = 35.8 °C, interquartile range: 35.0-36.2 °C, 95 per cent confidence interval 35.6-35.9 °C) was significantly lower than metamfetamine plus benzodiazepine cases (median 36.2 °C, interquartile range 35.7-36.6 °C, 95 per cent confidence interval, 36.0-36.4 °C, P = 0.017), and lone metamfetamine cases (median = 36.5 °C, interquartile range: 35.8-37.1 °C, 95 per cent confidence interval: 36.2-36.7 °C, P < 0.0001). Median presenting systolic blood pressure was significantly (P ≤ 0.001) lower in benzodiazepine positive groups (metamfetamine plus benzodiazepine median = 120 mmHg, interquartile range: 109-132 mmHg, 95 per cent confidence interval: 116-124 mmHg and metamfetamine plus benzodiazepine plus gamma-hydroxybutyrate median = 124 mmHg, interquartile range: 110-137 mmHg, 95 per cent confidence interval: 120-129 mmHg). Incidence of sedation (Glasgow Coma Scale less than 9) was significantly greater in metamfetamine plus gamma-hydroxybutyrate cases (63 per cent) compared to metamfetamine plus benzodiazepine cases (27 per cent, P < 0.0001) and lone metamfetamine cases (15 per cent, P < 0.0001). Incidence of agitation was significantly lower in metamfetamine plus gamma-hydroxybutyrate plus benzodiazepine cases (17 per cent, P < 0.0001) and metamfetamine plus gamma-hydroxybutyrate cases (34 per cent, P = 0.0004) compared to lone metamfetamine cases (58 per cent). DISCUSSION: Differences in gamma-aminobutyric acid type A and B receptor physiology may offer a gamma-aminobutyric acid type B agonist-facilitated alternative pharmacodynamic mechanism able to attenuate metamfetamine stimulant and neuropsychiatric toxicity. CONCLUSION: Metamfetamine intoxicated patients with analytically confirmed co-exposure to gamma-hydroxybutyrate had significantly reduced heart rate, body temperature and incidence of agitation compared to patients with lone metamfetamine exposure. Metamfetamine intoxicated patients with analytically confirmed co-exposure to a benzodiazepine had significantly reduced systolic blood pressure compared to patients with lone metamfetamine exposure. We hypothesize that gamma-aminobutyric acid type B receptor agonists may be beneficial in the management of acute metamfetamine toxicity.

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.

Spontaneous pneumomediastinum and surgical emphysema presenting as rhinolalia following ecstasy ingestion: a case report.

BACKGROUND: We present a unique case of rhinolalia as the first recognizable sign of spontaneous pneumomediastinum and surgical emphysema following drug use. CASE PRESENTATION: This case presents a 17-year-old white male experiencing rhinolalia following ecstasy ingestion at a rave. Subsequent chest X-ray revealed extensive surgical emphysema, along with a continuous diaphragm sign indicative of pneumomediastinum. Computed tomography confirmed the diagnosis. The patient was managed conservatively with strict monitoring and 6 hourly electrocardiograms. Follow-up computed tomography on day 3 showed resolution of pneumomediastinum and surgical emphysema, and the patient was safely discharged. Notably, the patient experienced a temporary rhinolalia during the acute phase, which resolved spontaneously as his condition improved. CONCLUSIONS: This case underscores the importance of considering spontaneous pneumomediastinum and surgical emphysema in the differential diagnosis of young individuals presenting with acute symptoms after drug use.

Assessment of a Single Quadrupole Mass Spectrometer Combined with an Atmospheric Solids Analysis Probe for the On-Site Identification of Amnesty Bin Drugs.

The surging number of people who abuse drugs has a great impact on healthcare and law enforcement systems. Amnesty bin drug analysis helps monitor the "street drug market" and tailor the harm reduction advice. Therefore, rapid and accurate drug analysis methods are crucial for on-site work. An analytical method for the rapid identification of five commonly detected drugs ((3,4-methylenedioxymethamphetamine (MDMA), cocaine, ketamine, 4-bromo-2,5-dimethoxyphenethylamine, and chloromethcathinone)) at various summer festivals in the U.K. was developed and validated employing a single quadrupole mass spectrometer combined with an atmospheric pressure solids analysis probe (ASAP-MS). The results were confirmed on a benchtop gas chromatography-mass spectrometry instrument and included all samples that challenged the conventional spectroscopic techniques routinely employed on-site. Although the selectivity/specificity step of the validation assessment of the MS system proved a challenge, it still produced 93% (N = 279) and 92.5% (N = 87) correct results when tested on- and off-site, respectively. A few "partly correct" results showed some discrepancies between the results, with the MS-only unit missing some low intensity active ingredients (N-ethylpentylone, MDMA) and cutting agents (caffeine, paracetamol, and benzocaine) or detecting some when not present. The incorrect results were mainly based on library coverage. The study proved that the ASAP-MS instrument can successfully complement the spectroscopic techniques used for qualitative drug analysis on- and off-site. Although the validation testing highlighted some areas for improvement concerning selectivity/specificity for structurally similar compounds, this method has the potential to be used in trend monitoring and harm reduction.

Bile acids and the gut microbiome are involved in the hyperthermia mediated by 3,4-methylenedioxymethamphetamine (MDMA).

Hyperthermia induced by phenethylamines, such as 3,4-methylenedioxymethamphetamine (MDMA), can lead to life-threatening complications and death. Activation of the sympathetic nervous system and subsequent release of norepinephrine and activation of uncoupling proteins have been demonstrated to be the key mediators of phenethylamine-induced hyperthermia (PIH). Recently, the gut microbiome was shown to also play a contributing role in PIH. Here, the hypothesis that bile acids (BAs) produced by the gut microbiome are essential to PIH was tested. Changes in the serum concentrations of unconjugated primary BAs cholic acid (CA) and chenodeoxycholic acid (CDCA) and secondary BA deoxycholic acid (DCA) were measured following MDMA (20 mg/kg, sc) treatment in antibiotic treated and control rats. MDMA-induced a significant hyperthermic response and reduced the serum concentrations of three BAs 60 min post-treatment. Pretreatment with antibiotics (vancomycin, bacitracin and neomycin) in the drinking water for five days resulted in the depletion of BAs and a hypothermic response to MDMA. Gut bacterial communities in the antibiotic-treated group were distinct from the MDMA or saline treatment groups, with decreased microbiome diversity and alteration in taxa. Metagenomic functions inferred using the bioinformatic tool PICRUSt2 on 16S rRNA gene sequences indicated that bacterial genes associated to BA metabolism are less abundant in the antibiotic-MDMA treated group. Overall, these findings suggest that gut bacterial produced BAs might play an important role in MDMA-induced hyperthermia.

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.

Qualitative transformations of street-seized ecstasy over a decade: A case study in Rio de Janeiro (Brazil).

The illegal drug market is constantly evolving, with new drugs being created and existing ones being modified. Adulterants are often added to the mix, and the primary substance may be secretly replaced by a new one. Once-known tablets can now be vastly different from what they are sold as, all due to the pursuit of profit and evasion of current drug regulations. These alterations in drug composition pose a threat to society, as their effects are still not well understood. Therefore, it is crucial for police intelligence and public health development to obtain the chemical profiles of illicit drugs. This study presents the chemical fingerprinting of ecstasy tablets seized in the state of Rio de Janeiro (Brazil) between 2012 and 2021. The tablet samples were weighed, extracted, diluted with methanol, and acidified before analysis using gas chromatography high-resolution mass spectrometry and attenuated total reflection Fourier transform infrared spectroscopy. The major constituents found were MDMA and clobenzorex, with fewer occurrences of MDA, MDEA, and 2C-B. The results also indicate that the occurrence of mega-events in the study location impacted the chemical fingerprints of ecstasy. A total of 27 combinations of cutting agents, including caffeine, ephedrine, and anesthetics, were identified. Samples composed of clobenzorex were observed throughout the evaluated period in areas near highways, suggesting that this product is mainly used by truck drivers. These findings can help police intelligence units anticipate the behavior of the illicit market during major events, identify traffic routes, and support public health initiatives.

What is needed for the roll-out of psychedelic treatments?

PURPOSE OF REVIEW: The pace of psychedelic treatments continues to increase. Regulation and coherent clinical guidance have not been established. A philosophical divide limits effective resolution of a practice delivery quandary: is this primarily a pharmacological or psychotherapeutic intervention? RECENT FINDINGS: Lykos (formerly MAPS) has submitted its new drug application (NDA) request to the FDA for 3-4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for PTSD and is expecting a response by the summer of 2024. Australia endorsed psilocybin and MDMA for regulated use in 2023. Multiple phase II and III clinical trials are also being conducted in the United States and Europe to study the use of psilocybin. Currently, Colorado and Oregon have legalized psilocybin in different manners. In Colorado, plants containing psilocybin, ibogaine, dimethyltryptamine (DMT) and mescaline (other than peyote) are now legal to possess, share and cultivate. Guidelines for regulated treatment with psilocybin containing mushrooms are in process with service delivery to begin early in 2025. In Oregon, clients must complete a preparation session with a licensed facilitator before consuming psilocybin products at a licensed service center. A prescription is not required. It is expected that other states will follow suit with a ballot measure likely in Massachusetts this year. Additionally, in the United States, the DEA, state boards, pharmaceutical distributors, and professional liability carriers all share mounting concerns about the in-home use of compounded ketamine used as a psychedelic therapeutic via remote prescribing. SUMMARY: Psychedelic treatments are rapidly entering the mainstream of medical care delivery in the United States. Clinical guidelines are urgently needed to ensure well tolerated practice and coherent regulation. The delivery of this guidance is limited by a core philosophical disagreement. Resolution of this conflict will be needed to deliver coherent clinical guidelines. Current research and clinical experience provide a solid foundation for practical clinical guidance and the introduction of psychedelics into healthcare.

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.

[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 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.

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.

Dextromethorphan moderates reward deficiency associated with central serotonin transporter availability in 3,4-methylenedioxy-methamphetamine-treated animals.

BACKGROUND: The neurotoxicity of 3,4-methylenedioxy-methamphetamine (MDMA) to the serotonergic system is well-documented. Dextromethorphan (DM), an antitussive drug, decreased morphine- or methamphetamine (MA)-induced reward in rats and may prevent MDMA-induced serotonergic deficiency in primates, as indicated by increased serotonin transporter (SERT) availability. We aimed to investigate the effects of DM on reward, behavioral sensitization, and neurotoxicity associated with loss of SERT induced by chronic MDMA administration in rats. METHODS: Conditioned place preference (CPP) and locomotor activity tests were used to evaluate drug-induced reward and behavioral sensitization; 4-[ 18 F]-ADAM/animal-PET and immunohistochemistry were used to explore the effects of DM on MDMA-induced loss of SERT. RESULTS: MDMA significantly reduced SERT binding in the rat brain; however, co-administration of DM significantly restored SERT, enhancing the recovery rate at day 14 by an average of ~23% compared to the MDMA group. In confirmation of the PET findings, immunochemistry revealed MDMA reduced SERT immunoactivity in all brain regions, whereas DM markedly increased the serotonergic fiber density after MDMA induction. CONCLUSION: Behavioral tests and in vivo longitudinal PET imaging demonstrated the CPP indexes and locomotor activities of the reward system correlate negatively with PET 4-[ 18 F]ADAM SERT activity in the reward system. Our findings suggest MDMA induces functional abnormalities in a network of brain regions important to decision-making processes and the motivation circuit. DM may exert neuroprotective effects to reverse MDMA-induced neurotoxicity.

Chemical cousins with contrasting behavioural profiles: MDMA users and methamphetamine users differ in social-cognitive functions and aggression.

Methamphetamine (METH, "Crystal Meth") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") share structural-chemical similarities but have distinct psychotropic profiles due to specific neurochemical actions. Previous research has suggested that their impact on social cognitive functions and social behaviour may differ significantly, however, direct comparisons of METH and MDMA users regarding social cognition and interaction are lacking. Performances in cognitive and emotional empathy (Multifaceted Empathy Test) and emotion sensitivity (Face Morphing Task), as well as aggressive social behaviour (Competitive Reaction Time Task) were assessed in samples of n = 40 chronic METH users, n = 39 chronic MDMA users and n = 86 stimulant-naïve controls (total N = 165). Self-reports and hair samples were used to obtain subjective and objective estimates of substance use patterns. METH users displayed diminished cognitive and emotional empathy towards positive stimuli, elevated punitive social behaviour regardless of provocation, and self-reported heightened trait anger relative to controls. MDMA users diverged from the control group only by exhibiting a distinct rise in punitive behaviour when faced with provocation. Correlation analyses indicated that both higher hair concentrations of MDMA and METH may be associated with reduced cognitive empathy. Moreover, greater lifetime MDMA use correlated with increased punitive behaviour among MDMA users. Our findings confirm elevated aggression and empathy deficits in chronic METH users, while chronic MDMA users only displayed more impulsive aggression. Dose-response correlations indicate that some of these deficits might be a consequence of use. Specifically, the dopaminergic mechanism of METH might be responsible for social-cognitive deficits.

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.

Driving under the influence of cocaine and MDMA: Relationship between blood concentrations and results from clinical test of impairment.

The general use of cocaine is increasing in recent years, while the trend for 3,4-methylenedioxymethamphetamine (MDMA) is less clear. The relationship between blood concentrations and impairment is poorly understood, which complicates interpretation. The aims of this study were to report prevalence and blood concentrations of cocaine and MDMA in drugged drivers, and to investigate the relationship between blood concentrations and impairment. Samples of whole blood were collected from apprehended drivers in the period 2000-2022, and a clinical test of impairment (CTI) was simultaneously performed. The samples were initially analyzed for cocaine and MDMA using gas chromatography-mass spectrometry (until 2009 and 2012, respectively), and later using ultra-high-performance liquid chromatography-tandem mass spectrometry. Overall, cocaine was detected in 2,331 cases and MDMA in 2,569 cases. There were 377 and 85 mono cases of cocaine and MDMA, respectively. In the mono cases, the median cocaine concentration was 0.09 mg/L (range: 0.02-1.15 mg/L), and 54% of the drivers were clinically impaired. The median MDMA concentration was 0.19 mg/L (range: 0.04-1.36 mg/L), and 38% were clinically impaired. There was a statistically significant difference in the median cocaine concentration between drivers assessed as not impaired (0.07 mg/L) and drivers assessed as impaired (0.10 mg/L) (P = 0.009). There was also a significant effect of the blood concentration of cocaine (adjusted odds ratio [aOR] = 6.42, 95% confidence interval [CI] = 1.13-36.53, P = 0.036) and driving during the evening/night-time (aOR = 2.17, 95% CI = 1.34-3.51, P = 0.002) on the probability of being assessed as impaired on the CTI. No significant differences were found for MDMA. Many drivers are not assessed as impaired on a CTI following cocaine or especially MDMA use. For cocaine, a relationship between blood concentrations and impairment was demonstrated, but this could not be shown for MDMA.

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.