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The article examines Lykos Therapeutics' recent failure to gain U.S. Food and Drug Administration (FDA) approval for its 3,4-methylenedioxy-methamphetamine (MDMA)-assisted therapy for post-traumatic stress disorder (PTSD) and the subsequent challenges it faces. Topics discussed include the potential shift in psychedelic research strategies, the impact of Lykos's difficulties on future clinical trials, and the ongoing debate about the integration of psychedelics with psychotherapy.

Methylone is one of the most common synthetic cathinones popularized as a substitute for 3,4-methylenedioxymethamphetamine (MDMA, midomafetamine) owing to its similar effects among users. Both psychostimulants exhibit similar chemistry (i.e., methylone is a β-keto analog of MDMA) and mechanisms of action. Currently, the pharmacology of methylone remains scarcely explored in humans. Herein, we aimed to evaluate the acute pharmacological effects of methylone and its abuse potential in humans when compared with that of MDMA following oral administration under controlled conditions. Seventeen participants of both sexes (14 males, 3 females) with a previous history of psychostimulant use completed a randomized, double-blind, placebo-controlled, crossover clinical trial. Participants received a single oral dose of 200 mg of methylone, 100 mg of MDMA, and a placebo. The variables included physiological effects (blood pressure, heart rate, oral temperature, pupil diameter), subjective effects using visual analog scales (VAS), the short form of the Addiction Research Center Inventory (ARCI), the Evaluation of Subjective Effects of Substances with Abuse Potential questionnaire (VESSPA-SSE), and the Sensitivity to Drug Reinforcement Questionnaire (SDRQ), and psychomotor performance (Maddox wing, psychomotor vigilance task). We observed that methylone could significantly increase blood pressure and heart rate and induce pleasurable effects, such as stimulation, euphoria, wellbeing, enhanced empathy, and altered perception. Methylone exhibited an effect profile similar to MDMA, with a faster overall onset and earlier disappearance of subjective effects. These results suggest that abuse potential of methylone is comparable to that of MDMA in humans. [ABSTRACT FROM AUTHOR]

It has recently been demonstrated that aromatic bromination at C(2) abolishes all typical psychomotor, and some key prosocial effects of the entactogen MDMA in rats. Nevertheless, the influence of aromatic bromination on MDMA-like effects on higher cognitive functions remains unexplored. In the present work, the effects of MDMA and its brominated analog 2Br-4,5-MDMA (1 mg/kg and 10 mg/kg i.p. each) on visuospatial learning, using a radial, octagonal Olton maze (4 × 4) which may discriminate between short-term and long-term memory, were compared with their influence on in vivo long-term potentiation (LTP) in the prefrontal cortex in rats. The results obtained indicate that MDMA diminishes both short- and long-term visuospatial memory but increases LTP. In contrast, 2Br-4,5-MDMA preserves long-term visuospatial memory and slightly accelerates the occurrence of short-term memory compared to controls, but increases LTP, like MDMA. Taken together, these data are consistent with the notion that the modulatory effects induced by the aromatic bromination of the MDMA template, which abolishes typical entactogenic-like responses, might be extended to those effects affecting higher cognitive functions, such as visuospatial learning. This effect seems not to be associated with the increase of LTP in the prefrontal cortex. [ABSTRACT FROM AUTHOR]

Impairment in social functioning is a common source of morbidity across many mental health disorders, yet there is a dearth of effective and easily implemented interventions to support social functioning. MDMA/ecstasy and classic psychedelics (psilocybin, LSD, peyote, mescaline) represent two potential treatments for impairments in social functioning, as evidence suggests these compounds may be supportive for alleviating social difficulties. Using a nationally representative sample of U.S. adults from the National Survey on Drug Use and Health (2015–2019) (N = 214,505), we used survey-weighted multivariable ordinal and logistic regression to examine the associations between lifetime use of the aforementioned compounds and impairments in social functioning in the past year. Lifetime MDMA/ecstasy use was associated with lowered odds of three of our four social impairment outcomes: difficulty dealing with strangers (aOR 0.92), difficulty participating in social activities (aOR 0.90), and being prevented from participating in social activities (aOR 0.84). Lifetime mescaline use was also associated with lowered odds of difficulty dealing with strangers (aOR 0.85). All other substances either shared no relationship with impairments in social functioning or conferred increased odds of our outcomes. Future experimental studies can assess whether these relationships are causal. [ABSTRACT FROM AUTHOR]

The introduction of new stimulants seems not to hamper the still widespread consumption of MDMA (3,4-methylenedioxymethamphetamine) among young people, especially in determined nightlife settings. Herein, we present two different MDMA-related deaths, providing pathological, histopathological and toxicological data integration. A hypothesis for the mechanisms of the deaths is also discussed. Case 1: an insulin-dependent 16-year-old girl died in a discotheque after the ingestion of MDMA. Before dying she presented seizure, bruxism, trismus, sweating and reduced consciousness. Biochemistry showed hyperglycaemia and hyponatraemia. Toxicological analyses revealed blood MDMA concentration of 1750 ng/mL. Autopsy, accompanied by histological examination, identified cerebral oedema due to hypotonic hyponatraemia as cause of death. Case 2: a 16-year-old girl collapsed during dancing at a rave party. She died 15 hours later in hospital. Autopsy and histology revealed epicardial haemorrhage, hepatitis and disseminated intravascular coagulation. Toxicological analyses revealed blood MDMA concentration of 3700 ng/ml. Cause of death was identified as fulminant liver failure. Since death is not strictly correlated with MDMA blood concentration, to better understand the aetiology of the death after MDMA consumption an integrated and multidisciplinary approach is strongly recommended. [ABSTRACT FROM AUTHOR]

Momentous shifts in British nightlife were catalysed by the drug ecstasy during the 1990s. This article explores the tension between older attitudes towards women's drug use and new discourses of feminine pleasure by using materials produced by Lifeline, a Manchester-based drugs harm reduction charity. These leaflets provided advice to young women about how to navigate nightclubs when taking ecstasy. By reading these sources against the grain, this article recovers the pleasures occluded by them and reconstructs what ecstasy and rave meant to young women, beyond the narratives of risk and harm presented to them through the media. [ABSTRACT FROM AUTHOR]

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The use of recreational drugs like ephedrine, norephedrine, 3,4-methylenedioxymethamphetamine (MDMA), and mescaline can lead to intoxication and, at worst, to death. One reason for a fatal course of intoxication with these drugs might lie in cardiac arrhythmias. To the best of our knowledge, their inotropic effects have not yet been studied in isolated human cardiac preparations. Therefore, we measured inotropic effects of the hallucinogenic drugs ephedrine, norephedrine, mescaline, and MDMA in isolated mouse left atrial (mLA) and right atrial (mRA) preparations as well as in human right atrial (hRA) preparations obtained during cardiac surgery. Under these experimental conditions, ephedrine, norephedrine, and MDMA increased force of contraction (mLA, hRA) and beating rate (mRA) in a time- and concentration-dependent way, starting at 1–3 µM but these drugs were less effective than isoprenaline. Mescaline alone or in the presence of phosphodiesterase inhibitors did not increase force in mLA or hRA. The positive inotropic effects of ephedrine, norephedrine, or MDMA were accompanied by increases in the rate of tension and relaxation and by shortening of time of relaxation and, moreover, by an augmented phosphorylation state of the inhibitory subunit of troponin in hRA. All effects were greatly attenuated by cocaine (10 µM) or propranolol (10 µM) treatment. In summary, the hallucinogenic drugs ephedrine, norephedrine, and MDMA, but not mescaline, increased force of contraction and increased protein phosphorylation presumably, in part, by a release of noradrenaline in isolated human atrial preparations and thus can be regarded as indirect sympathomimetic drugs in the human atrium. [ABSTRACT FROM AUTHOR]

Background: Drug-related deaths in the US continue to increase. Sentinel surveillance of high-risk populations can provide early warning for shifts in trends. Nightclub/festival attendees have high levels of drug use, so we explored whether use among this population can serve as a potential bellwether or indicator for use-related mortality in the general population. Methods: Trends in past-year cocaine and methamphetamine use were estimated from nightclub/festival attendees in New York City (NYC) and among NY residents, and trends were estimated for related death rates in NYC (2014/15–2019/20). Using national data from England and Wales (2010–2019), trends in past-year cocaine and ecstasy use (among the full population and among nightclub attendees) and related deaths were also estimated. Results: In NY/NYC, cocaine use remained stable in the general population, but use among nightclub/festival attendees and cocaine-related deaths doubled. Methamphetamine use among nightclub/festival attendees and death rates also more than doubled while use among the general population remained stable. In UK countries, increases in cocaine and ecstasy use were larger for infrequent/frequent nightclub attendees than in the general population, with 3.6- and 8-fold increases in related deaths, respectively. In UK countries, the association between nightclub attendance and death rates increased in a dose-response-like manner with larger associations detected when death rates were lagged by one year. Conclusions: Patterns of use among nightclub/festival attendees, more so than patterns in the general population, were similar to patterns of drug-related deaths. Use among this subpopulation could possibly serve as a bellwether for use-related outcomes. Continued surveillance is recommended. [ABSTRACT FROM AUTHOR]

Background: Psychedelics are receiving renewed attention within Western medicine as they represent potential treatments for many difficult-to-treat mental health disorders. However, psychedelic science is limited in its focus and inclusion of racial and ethnic minorities. Hence, this study examines whether race and ethnicity moderate the associations that naturalistic 3,4-methylenedioxymethamphetamine (MDMA)/ecstasy use and psilocybin use share with major depressive episodes (MDEs). Method: Data for this project are from The National Survey on Drug Use and Health (2005–2019). Participants were adults aged 18 years and older (unweighted N = 596,187). This study used multivariable logistic regression to test the interaction between race and ethnicity and MDMA/ecstasy use and psilocybin use for predicting lifetime, past year, and past year severe MDEs. Results: Race and ethnicity significantly moderated the associations between MDMA/ecstasy use and psilocybin use and MDEs. For White participants, MDMA/ecstasy use and psilocybin use each were associated with lowered odds of all three MDE outcomes (adjusted odds ratio (aOR) range: 0.82–0.92). For Hispanic participants, MDMA/ecstasy use and psilocybin use each conferred lowered odds of only a past year MDE (MDMA/ecstasy aOR: 0.82; psilocybin aOR: 0.79). For Non-Hispanic Racial Minority participants, MDMA/ecstasy and psilocybin use did not confer lowered odds of any MDE outcomes. Conclusion: Race and ethnicity have an impact on the associations that psychedelics share with mental health outcomes. Future research should explore the impact of identity and discrimination on the effects of psychedelics and should explore whether these substances can serve as effective treatments for minorities when used in culturally informed contexts. [ABSTRACT FROM AUTHOR]

Suicide is one of the leading causes of death amongst adolescents and decades of research have failed to curb suicide rates within this population. There is thus a need to better understand factors that correlate with adolescent suicidal thoughts and behaviors (STBs). MDMA/ecstasy and classic psychedelics represent two areas for exploration, as use of these substances has been associated with both increased and lowered odds of STBs. Thus, the goal of this study was to test the associations between MDMA/ecstasy and classic psychedelics (psilocybin, peyote, mescaline, LSD) and STBs in a nationally representative sample of U.S. adolescents. We tested these associations in a sample of adolescents aged 12–17 years old from the National Survey on Drug Use and Health (2004–2019) (N = 262,617) using survey-weighted multivariable logistic regression models. Lifetime psilocybin use was associated with lowered odds of lifetime suicidal thinking, planning, and attempts (aOR range 0.77–0.85). Conversely, LSD was associated with increased odds of these same outcomes (aOR range 1.20–1.35). MDMA/ecstasy, peyote, and mescaline did not share associations with STBs. Our study demonstrates that individual classic psychedelics share varying relationships to STBs among adolescents. Future cross-sectional and longitudinal studies are needed to further elucidate the link between classic psychedelic use and STBs in youth. [ABSTRACT FROM AUTHOR]

Background and Aims: Hallucinogen use is potentially harmful. Information on whether such use has increased in recent decades is lacking. This study assessed overall and age‐specific time trends in the prevalence of 12‐month hallucinogen use in the US general population. Design: Cross‐sectional. Setting: Data from the US National Survey on Drug Use and Health, 2002–19. Participants: Respondents aged ≥ 12 years (n = 1 006 051). Measurements Predictors were continuous years. Outcome variables included any hallucinogen use and use of lysergic acid diethylamide (LSD), ecstasy and phencyclidine (PCP) in the past year. Socio‐demographic variables (gender, age, race/ethnicity, educational level and family income) were covariates. Findings Overall, hallucinogen use increased between 2015 and 2019 [prevalence difference (PD) = +0.44, P < 0.05]. Since 2002, hallucinogen use has increased in adults aged ≥ 26 years (PD, 2002–14 = +0.24, P < 0.05; PD, 2015–19 = +0.45, P < 0.001) and decreased in adolescents aged 12–17 years (PD, 2002–14 = −1.60, P < 0.0001; PD, 2015–19 = −0.73, P < 0.001). Ecstasy use has decreased in adolescents (PD, 2002–14 = −0.56, P < 0.001), adults aged 18–25 years (PD, 2015–19 = −0.96, P < 0.01) and ≥ 26 years (PD, 2015–19 = −0.13, P < 0.05). LSD use between 2002 and 2019 increased overall (PD = +0.71, P < 0.0001) and in all age groups (12–17: PD = +0.67, P < 0.001; 18–25: PD = +3.12, P < 0.0001; ≥ 26: PD = +0.36, P < 0.0001). Conversely, PCP use between 2002 and 2019 decreased overall (PD = –0.06, P < 0.001), in adolescents (PD = –0.24, P < 0.001) and young adults (PD = –0.32, P < 0.0001). Conclusions: Since 2002, hallucinogen use in the United States has decreased among adolescents but increased in adults and is now estimated to affect more than 3 million adults aged 26+ years and more than 5.5 million adults aged 18+ years. [ABSTRACT FROM AUTHOR]

The aim of this study is to define, for the first time, human methylone and HMMC plasma pharmacokinetics following controlled administration of 50–200 mg methylone to 12 male volunteers. A new LC-MS/MS method was validated to quantify methylone, MDMA, and their metabolites in plasma. The study was a randomized, cross-over, double-blinded and placebo-controlled study, with a total of 468 plasma samples collected. First, 10 µL of MDMA-d5, MDA-d5 and methylone-d3 internal standards were added to 100 µL of plasma. Two mL of chloroform and ethyl acetate 9:1 (v/v) were then added, mixed well and centrifuged. The supernatant was fortified with 0.1 mL acidified methanol and evaporated under nitrogen. Samples were reconstituted with a mobile phase and injected into the LC-MS/MS instrument. The method was fully validated according to OSAC guidelines (USA). Methylone plasma concentrations increased in a dose-proportional manner, as demonstrated by the increasing maximum concentration (Cmax) and area under the curve of concentrations (AUC). Methylone Cmax values were reported as 153, 304, 355 and 604 ng/mL, AUC0–24 values were reported as 1042.8, 2441.2, 3524.4 and 5067.9 h·ng/mL and T1/2 values as 5.8, 6.4, 6.9 and 6.4 h following the 50, 100, 150 and 200 mg doses, respectively. Methylone exhibited rapid kinetics with a Tmax of 1.5 h for the 50 mg dose and 2 h approximately after all the other doses. HMMC exhibited faster kinetics compared to methylone, with a Cmax value that was 10–14-fold lower and an AUC0–24 value that was 21–29-fold lower. Methylone pharmacokinetics was linear across 50–200 mg oral doses in humans, unlike the previously described non-linear oral MDMA pharmacokinetics. An LC-MS/MS method for the quantification of methylone, MDMA and their metabolites in human plasma was achieved. Methylone exhibited linear pharmacokinetics in humans with oral doses of 50–200 mg. [ABSTRACT FROM AUTHOR]

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. • Anti-MDMA antibodies 1bB11 and 1bF12 were discovered based on phage display. • 1bB11 and 1bF12 specifically recognize MDMA, not METH. • 1bB11 EL2 and MDMA complex was determined at 3.2 Å resolution. • The epoxide moiety of MDMA is a key for recognition by 1bB11. [ABSTRACT FROM AUTHOR]

Despite the surge of interest in psychedelic research in the past decade, largely due to the promise of psychedelics for improving mental health outcomes, there has been comparatively little discussion about the social and environmental consequences of psychedelic drug use. While there is growing evidence to suggest psychedelics could foster a greater connection to the natural world and improve social relationships, such positive repercussions are far from guaranteed. In this commentary, we focus on LSD, psilocybin and especially MDMA, and outline three insights we came to see as crucial to creating beneficial outcomes: 1) the importance of setting and rituals, 2) the establishment of boundaries, and 3) understanding the long-term commitment required. These insights are grounded in the history of psychedelics, which is intimately intertwined with ritualised use, yet the process of commercialisation of these substances threatens to strip away important contextual factors. Creating boundaries around when, how and with whom psychedelics are used have been found to protect recreational users from harm and could also be instrumental in steering commercial interests to align with socio-environmental goals. Finally, far from being a 'quick fix' for social or environmental problems, the use of psychedelics requires sustained engagement to integrate the insights obtained. Whereas we remain optimistic about the transformative potential of psychedelics for social relationships and the environment, we also emphasise the need for a more cautious, considered approach if we are to harness the benefits and minimise the challenges of psychedelic drug use. [ABSTRACT FROM AUTHOR]

The misrepresentation of illicit drugs in unregulated markets increases the risk of adverse health events. This study analyzed drug checking data to compare represented, expected, and actual content of alleged MDMA samples, estimate trends in the quality of the MDMA supply, document the presence of adulterants, compare patterns of adulteration, and validate drug checking against law enforcement data. The study analyzed 4719 alleged MDMA samples submitted to the DrugsData drug checking service between 1999–2023. Measures captured characteristics and quality of the MDMA supply, including represented content, expected and actual content, sample form, and specific adulterants. Tests of association were conducted using Pearson's chi-square or Spearman's rho, and tests for trends were performed using joinpoint regression. Most samples (75 %) were expected to contain MDMA, but this varied significantly by represented content (p<0.001). About half the samples (48 %) contained MDMA-only, which also varied significantly by represented content (p<0.001). MDMA-only prevalence declined from 1999–2009 (57.4–15.2 %, p<0.05), recovered from 2009–2017 (15.2–56.0 %, p<0.05), and increased more moderately from 2017–2023 (56.0–74.1 %, p<0.05). Overall, 199 unique adulterants were detected in the MDMA supply across 25 years. We confirmed robust correlations in adulterant prevalence trends between drug checking and law enforcement seizure data. While users typically expected alleged MDMA samples to contain only MDMA, more than half of the submitted MDMA samples were misrepresented in some manner. Despite high levels of misrepresentation, MDMA quality has stabilized at relatively high levels in recent years • About half of alleged MDMA samples tested between 1999−2023 contained only MDMA. • MDMA quality fluctuated across time but stabilized at high levels in recent years. • Overall, 199 unique adulterants were detected in the unregulated MDMA supply. • Molly-powder had higher MDMA concentrations than traditional pressed tablets/pills. [ABSTRACT FROM AUTHOR]

A Danish fitness chain recently introduced a new concept called Bubbles & Squat. Here, fitness training is combined with free champagne and music. In this paper, we examine this new way of bringing parties, alcohol and physical culture together by exploring the possible meaning of it through existential philosophical analysis. We draw in particular on Nietzsche’s distinction between the Apolline and the Dionysiac, as well as his account of great health. On this basis, we analyse Bubbles & Squat as a case of Dionysiac intoxication, excess and ecstasy sneaking into contemporary Apolline fitness culture. In the last part of the paper, we raise the question if adding parties and bubbles to fitness training may, perhaps paradoxically, be healthy for the participants in an existential sense because it contributes to existential balance between the Dionysiac and the Apolline. We conclude that the philosophical framework presented in this paper can contribute to a new understanding of a general physical cultural phenomenon that the case of Bubbles & Squat represents. [ABSTRACT FROM AUTHOR]

The amphetamine‐type stimulants (ATS) adulteration is currently a common phenomenon that endangers the health of consumers. Among the most common adulterants are new psychoactive substances (NPS), such as synthetic cathinones. This development demands new, low‐cost, and simple detection strategies. In this work, we present, for the first time, the electrochemical detection of two NPSs, the amphetamine 3,4‐methylenedioxymethamphetamine (MDMA) and the synthetic cathinone α‐pyrrolidinopentiophenone (α‐PVP), using an electrochemical biosensor based on cytochrome P450 2D6 (CYP2D6). This biosensor was constructed by electrochemical reduction of the 4‐nitrobenzenediazonium salt on a carbon screen‐printed electrode (C‐SPE), with subsequent reduction of the nitro group into amines, and finally covalent binding with the CYP2D6 enzyme. The biosensor voltammetric response of the molecules studied allowed reaching limits of detection (LOD) of 0.0017 and 0.0022 μg/mL, and limits of quantification (LOQ) of 0.0059 and 0.0076 μg/mL for MDMA and α‐PVP, respectively. [ABSTRACT FROM AUTHOR]

Misophonia is a disorder characterized by negative physical and emotional reactions to certain trigger sounds, such as chewing food. Up to 50% of population samples endorse some symptoms of misophonia, with about 20% having symptoms that impair normal life functioning. Most misophonia patients exhibit intense negative emotions and autonomic arousal (the fightflight-freeze response) in response to a trigger, similarly to how someone with post-traumatic stress disorder (PTSD) might respond to a trauma trigger. Curiously, misophonia trigger sounds are often most distressing when coming from a specific person, suggesting the disorder may be responsive to interpersonal relationship factors. Treatment of misophonia is currently limited to the use of hearing modifications (e.g., earplugs or headphones) and psychotherapy, but many patients continue to suffer despite these best efforts. Phase 3 clinical trials suggest that MDMA is efficacious at treating the symptoms of autonomic arousal, negative emotions, and interpersonal suffering found in PTSD. As such, we propose that MDMA may represent an ideal treatment for some suffering from severe misophonia. In this perspective article, we review the symptoms of misophonia, and outline how MDMA may be uniquely suited for treating it, perhaps using a protocol analogous to the MAPS Phase 3 studies for PTSD. [ABSTRACT FROM AUTHOR]

Primary intracranial spindle cell sarcoma is an extremely rare mesenchymal tumor, the molecular pathogenesis of which is poorly understood. Because of the lack of specific markers, diagnosis sometimes relies on ruling out all possible differential diagnoses, often making it difficult to reach a definitive diagnosis. In this case study, we report a 69 year-old female patient for whom the integration of multi-layered molecular analyses contributed to making the diagnosis. The disease exhibited aggressive clinical behavior, requiring two sequential surgeries because of rapid regrowth within a short period. Primary and recurrent tumors exhibited similar histological features, in which spindle-shaped cells arranged in interlacing fascicles without any specific architectures, implicating sarcomatous tumors. In immunohistochemistry testing, tumor cells were immunopositive for vimentin but lacked any specific findings that contribute to narrowing down the differential diagnoses. Seeking further diagnostic clues, we performed DNA methylation-based analysis. The copy number analysis revealed MDM2 gene amplification and loss of heterozygosity of 22q. Moreover, dimension reduction clustering analysis implicated a methylation pattern comparable to aggressive types of sarcomas. In addition, an in-house next-generation sequencing panel ("Todai-OncoPanel") analysis identified somatic mutations in DICER1, NF2, and ATRX genes. Taken all together, we finally made the diagnosis of primary intracranial spindle cell sarcoma, DICER1 -mutant, with MDM2 gene amplification. This case report suggests that even for the tumors with insufficient morphological and immuno-histological diagnostic clues, integration of multi-layered molecular analyses can contribute to making the diagnoses as well as to understanding the rare tumors by elucidating unexpected genetic and epigenetic features. [ABSTRACT FROM AUTHOR]