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.

MDMA enhances empathy-like behaviors in mice via 5-HT release in the nucleus accumbens.

MDMA (3,4-methylenedioxymethamphetamine) is a psychoactive drug with powerful prosocial effects. While MDMA is sometimes termed an "empathogen," empirical studies have struggled to clearly demonstrate these effects or pinpoint underlying mechanisms. Here, we paired the social transfer of pain and analgesia-behavioral tests modeling empathy in mice-with region-specific neuropharmacology, optogenetics, and transgenic manipulations to explore MDMA's action as an empathogen. We report that MDMA, given intraperitoneally or infused directly into the nucleus accumbens (NAc), robustly enhances the social transfer of pain and analgesia. Optogenetic stimulation of 5-HT release in the NAc recapitulates the effects of MDMA, implicating 5-HT signaling as a core mechanism. Last, we demonstrate that systemic MDMA or optogenetic stimulation of NAc 5-HT inputs restores deficits in empathy-like behaviors in the Shank3-deficient mouse model of autism. These findings demonstrate enhancement of empathy-related behaviors by MDMA and implicate 5-HT signaling in the NAc as a core mechanism mediating MDMA's empathogenic effects.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Historical Perspective and Overview.

BACKGROUND: Psychedelic drugs have recently emerged as plausibly effective pharmacological agents for the management of depression, anxiety, and other neuropsychiatric conditions, including those that are treatment-resistent. The latter half of the 20th century marked a revolution in the treatment of mental illnesses, exemplified by the introduction of selective serotonin reuptake inhibitors and other pharmacological agents. Nevertheless, mental illness remains a major public health crisis, affecting nearly one billion individuals worldwide. AREAS OF UNCERTAINTY: Because of the decades-long status of several psychedelics as Schedule I drugs, there have not been very many large, double-blind, randomized controlled trials of psychedelics. Owing to small sample sizes, there may be rare yet serious adverse events that have not been reported in the clinical trials thus far. THERAPEUTIC ADVANCES: Esketamine, a dissociative hallucinogen drug, was approved for the management of major depressive disorder by the Food and Drug Administration in 2019. As of January 2024, two Phase III trials of 3,4-methylenedioxymethamphetamine (MDMA), a synthetic drug that inhibits the serotonin transporter, have been completed; the results indicate that MDMA is superior to existing pharmacological treatments for post-traumatic stress disorder. A phase III trial of psilocybin, a naturally occurring serotonin receptor partial agonist, is currently underway. The following series details the current state of research in psychedelic therapeutics, including lysergic acid diethylamide (LSD), N-N-dimethyltryptamine (DMT) and ayahuasca, psilocybin, ibogaine, MDMA, and ketamine. LIMITATIONS: While initial clinical trials of psychedelics for depression were very promising, trials of psilocybin with larger sample sizes (100+ participants) suggest that its remission rate is 25%-29%. This is about the same as the remission rate of antidepressants, which is roughly 30% according to the landmark STAR*D trial. CONCLUSIONS: Psychedelic drugs and structural derivatives offer a great deal of promise for the management of a wide range of psychiatric morbidities. It is imperative that clinicians become familiar with these novel agents and learn how to integrate psychedelic therapy with the rest of their care through open communication and referral.

Psychedelic Therapy: A Primer for Primary Care Clinicians-3,4-Methylenedioxy-methamphetamine (MDMA).

BACKGROUND: After becoming notorious for its use as a party drug in the 1980s, 3,4-methylenedioxy-methampetamine (MDMA), also known by its street names "molly" and "ecstasy," has emerged as a powerful treatment for post-traumatic stress disorder (PTSD). AREAS OF UNCERTAINTY: There are extensive data about the risk profile of MDMA. However, the literature is significantly biased. Animal models demonstrating neurotoxic or adverse effects used doses well beyond the range that would be expected in humans (up to 40 mg/kg in rats compared with roughly 1-2 mg/kg in humans). Furthermore, human samples often comprise recreational users who took other substances in addition to MDMA, in uncontrolled settings. THERAPEUTIC ADVANCES: Phase III clinical trials led by the Multidisciplinary Association for Psychedelic Studies (MAPS) have shown that MDMA-assisted psychotherapy has an effect size of d = 0.7-0.91, up to 2-3 times higher than the effect sizes of existing antidepressant treatments. 67%-71% of patients who undergo MDMA-assisted psychotherapy no longer meet the diagnostic criteria for PTSD within 18 weeks. We also describe other promising applications of MDMA-assisted psychotherapy for treating alcohol use disorder, social anxiety, and other psychiatric conditions. LIMITATIONS: Thus far, almost all clinical trials on MDMA have been sponsored by a single organization, MAPS. More work is needed to determine whether MDMA-assisted therapy is more effective than existing nonpharmacological treatments such as cognitive behavioral therapy. CONCLUSIONS: Phase III trials suggest that MDMA is superior to antidepressant medications for treating PTSD. Now that MAPS has officially requested the Food and Drug Administration to approve MDMA as a treatment for PTSD, legal MDMA-assisted therapy may become available as soon as 2024.

Effects of the designer drug 4-methylamphetamine on core temperature and serotonin levels in the striatum and hippocampus of rats.

New psychoactive substances (NPS) are typically synthesized in clandestine laboratories in an attempt to chemically modify already federally regulated drugs in an effort to circumvent the law. Drugs derived from a phenethylamine pharmacophore, such as 4-chloroamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), reliably induce thermogenesis and serotonergic deficits in the striatum and hippocampus of rodents. 4-methylamphetamine (4-MA), a relative newcomer to the NPS scene, was originally investigated in the mid-1900 s as a potential anorexigenic agent. With its phenethylamine pharmacophore, 4-MA was hypothesized to produce similar toxicological alterations as its chemical analogs. In the present study, three doses (1.0, 2.5, and 5.0 mg/kg, ip.) of 4-MA were administered to rats twice daily for two days. Core temperature data were calculated and analyzed as temperature area under the curve (TAUC). On the second day of dosing, a hypothermic response to 4-MA (2.5 and 5.0 mg/kg) was noted between 0.5 and 2.0 h post-treatment. Only the highest dose of 4-MA decreased body weight on the second day of treatment and maintained this reduction in weight for seven days after treatment ceased. None of the doses of 4-MA evaluated significantly altered serotonin levels in the hippocampus or striatum seven days after final treatment. The present findings demonstrate that the 4-methyl substitution to amphetamine generates a pharmacological and toxicological profile that differs from other similar phenethylamine analogs.

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

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

Conflict monitoring and emotional processing in 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine users - A comparative neurophysiological study.

In stimulant use and addiction, conflict control processes are crucial for regulating substance use and sustaining abstinence, which can be particularly challenging in social-affective situations. Users of methamphetamine (METH, "Ice") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") both experience impulse control deficits, but display different social-affective and addictive profiles. We thus aimed to compare the effects of chronic use of the substituted amphetamines METH and MDMA on conflict control processes in different social-affective contexts (i.e., anger and happiness) and investigate their underlying neurophysiological mechanisms. For this purpose, chronic but recently abstinent users of METH (n = 38) and MDMA (n = 42), as well as amphetamine-naïve healthy controls (n = 83) performed an emotional face-word Stroop paradigm, while event-related potentials (ERPs) were recorded. Instead of substance-specific differences, both MDMA and METH users showed smaller behavioral effects of cognitive-emotional conflict processing (independently of emotional valence) and selective deficits in emotional processing of anger content. Both effects were underpinned by stronger P3 ERP modulations suggesting that users of substituted amphetamines employ altered stimulus-response mapping and decision-making. Given that these processes are modulated by noradrenaline and that both MDMA and METH use may be associated with noradrenergic dysfunctions, the noradrenaline system may underlie the observed substance-related similarities. Better understanding the functional relevance of this currently still under-researched neurotransmitter and its functional changes in chronic users of substituted amphetamines is thus an important avenue for future research.

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

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

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.

Can research on entactogens contribute to a deeper understanding of human sexuality?

In recent years, scientific research into the therapeutic potential of psychedelic compounds has experienced a resurgence of interest. New studies have shown promising results, supporting the use of psychedelic drugs in treating various psychiatric disorders, including treatment-resistant depression, post-traumatic stress disorder, and even alcohol addiction. The FDA has recognized 3,4-methylenedioxymethamphetamine (MDMA) as a breakthrough therapy to treat symptoms of post-traumatic stress disorder. At the same time, interviews with recreational MDMA users have documented experiences of emotional intimacy while using MDMA, often without the desire for penetrative sex. However, some people have reported that MDMA increases their sexual arousal and specifically use it to enhance their sexual performance. This study aims to analyze current and planned research on the psychophysiological effects of entactogens on human sexuality. With their prosocial potential, the pharmacokinetic and neuroendocrine effects of entactogens may recreate the subjective experience of emotional intimacy, the initiation of intimate relationships, or even feelings of 'falling in love' with previously neutral individuals while under the influence of entactogens. This includes MDMA-induced sexual arousal-like effects observed through subjective behavioral perceptions of desire and arousal and specific physiological markers such as oxytocin and prolactin. Modern MDMA-assisted psychotherapy (MDMA-AP) protocols are transparent and follow strict ethical guidelines. However, despite these proposed ethical principles, little consideration has been given to the potential neurobehavioral effects of entactogens on the sexuality of participants in MDMA-AP protocols. The psychophysiological and sexual effects of entactogens should be discussed more openly in current MDMA-AP protocols, including the potential experience of the phenomenon of sexualized pharmacotransference.

Does MDMA have treatment potential in sexual dysfunction? A systematic review of outcomes across the female and male sexual response cycles.

INTRODUCTION: Sexual health, an integral component of overall well-being, is frequently compromised by common yet underdiagnosed sexual dysfunctions. Traditional interventions encompass pharmaceutical and psychological treatments. Unconventional therapies, like MDMA, offer hope for sexual dysfunction. This review delves into MDMA's effects on sexual responsiveness and its potential role in treating sexual dysfunction. OBJECTIVES: The purpose of this review is to elucidate effects of MDMA on different domains of the female and male sexual response cycles. METHODS: We conducted a systematic review on the effects of MDMA on each domain of the female and male sexual response cycles. PubMed, MEDLINE, and EMBASE were queried, and results were screened using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Search terms utilized were "MDMA" or "ecstasy" in combination with "desire," "arousal," "lubrication," "orgasm," "pleasure," "libido," "erection," and "ejaculation." Inclusion criteria for this review were MDMA use by study subjects and sexual outcomes in at least 1 domain of the female and/or male sexual response cycles were described and measured. Randomized controlled trials, cohort studies (both prospective and retrospective), surveys, and literature reviews published between January 2000 and June 2022 were included. Case reports and studies that did not address conditions of interest were excluded from analysis. Duplicated search results were screened out. The remaining studies were then read in full text to ensure they met inclusion and exclusion criteria for analysis. RESULTS: We identified 181 studies, of which 6 met criteria for assessment of the female sexual response cycle and 8 met criteria for assessment of the male sexual response cycle. Four of 6 studies reported increased sexual desire with MDMA use among women. Arousal and lubrication were improved with MDMA use in 3 of 4 studies, but they were not affected in 1 randomized control study. In men, 7 studies evaluated the effects of MDMA on desire and/or arousal, 5 studies measured impact on erection, 3 on orgasm, and 2 on ejaculation. Sixty percent of interview-based studies reported increased sexual desire in men, while 40% reported mixed or no effect. Two studies reported impairment of erection, 2 reported mixed effects, and 1 reported fear of erection impairment. In both men and women, all studies evaluating orgasm reported delay in achieving orgasm but increased intensity and pleasure if achieved. Primary outcome measures were variable and largely qualitative. CONCLUSION: Our findings suggest that MDMA generally increases sexual desire and intensifies orgasm when achieved. While producing conflicting evidence on sexual arousal in both sexes, MDMA may impair erectile and ejaculatory function in men.

Functional imaging studies of acute administration of classic psychedelics, ketamine, and MDMA: Methodological limitations and convergent results.

Functional magnetic resonance imaging (fMRI) is increasingly used to non-invasively study the acute impact of psychedelics on the human brain. While fMRI is a promising tool for measuring brain function in response to psychedelics, it also has known methodological challenges. We conducted a systematic review of fMRI studies examining acute responses to experimentally administered psychedelics in order to identify convergent findings and characterize heterogeneity in the literature. We reviewed 91 full-text papers; these studies were notable for substantial heterogeneity in design, task, dosage, drug timing, and statistical approach. Data recycling was common, with 51 unique samples across 91 studies. Fifty-seven studies (54%) did not meet contemporary standards for Type I error correction or control of motion artifact. Psilocybin and LSD were consistently reported to moderate the connectivity architecture of the sensorimotor-association cortical axis. Studies also consistently reported that ketamine administration increased activation in the dorsomedial prefrontal cortex. Moving forward, use of best practices such as pre-registration, standardized image processing and statistical testing, and data sharing will be important in this rapidly developing field.

Drug-induced social connection: both MDMA and methamphetamine increase feelings of connectedness during controlled dyadic conversations.

MDMA is a stimulant-like drug with distinctive empathogenic effects. Its pro-social effects, such as feelings of connectedness, may contribute to both its popularity as a recreational drug and its apparent value as an adjunct to psychotherapy. However, little is known about the behavioral processes by which MDMA affects social interactions. This investigation examined the effects of MDMA (100 mg versus placebo; N = 18) on feelings of connectedness with an unfamiliar partner during a semi-structured casual conversation. A separate study examined the effects of a prototypic stimulant methamphetamine (MA; 20 mg versus placebo; N = 19) to determine the pharmacological specificity of effects. Oxytocin levels were obtained in both studies. Compared to placebo, both MDMA and MA increased feelings of connection with the conversation partners. Both MDMA and MA increased oxytocin levels, but oxytocin levels were correlated with feeling closer to the partner only after MDMA. These findings demonstrate an important new dimension of the pro-social effects of MDMA, its ability to increase feelings of connectedness during casual conversations between two individuals. Surprisingly, MA had a similar effect. The findings extend our knowledge of the social effects of these drugs, and illustrate a sensitive method for assessing pro-social effects during in-person dyadic encounters.

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.

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.

Amphetamine-type Stimulants: Novel Insights into their Actions and use Patterns.

This review focuses on the effects and mechanisms of action of amphetamine-type stimulants (ATS) and their adverse effects on the cardiovascular, nervous, and immune systems. ATS include amphetamine (AMPH), methamphetamine (METH, "crystalmeth," or "ice"), methylenedioxymethamphetamine (MDMA, "ecstasy," or "Molly"), MDMA derivatives (e.g., methylenedioxyamphetamine [MDA] and methylenedioxy-N-ethylamphetamine [MDEA]), khat, and synthetic cathinones. The first section of this paper presents an overview of the historical aspects of ATS use, their initial clinical use, and regulations. The second part reviews the acute and chronic impact and the most salient clinical effects of ATS on the central nervous and cardiovascular systems, skin, and mouth. The chemical structure, pharmacokinetics, and classic and non-canonical pharmacological actions are covered in the third section, briefly explaining the mechanisms involved. In addition, the interactions of ATS with the central and peripheral immune systems are reviewed. The last section presents data about the syndemic of ATS and opioid use in the North American region, focusing on the increasing adulteration of METH with fentanyl.

Acute effects of MDMA and LSD co-administration in a double-blind placebo-controlled study in healthy participants.

There is renewed interest in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. Although acute subjective effects of LSD are mostly positive, negative subjective effects, including anxiety, may occur. The induction of overall positive acute subjective effects is desired in psychedelic-assisted therapy because positive acute experiences are associated with greater therapeutic long-term benefits. 3,4-Methylenedioxymethamphetamine (MDMA) produces marked positive subjective effects and is used recreationally with LSD, known as "candyflipping." The present study investigated whether the co-administration of MDMA can be used to augment acute subjective effects of LSD. We used a double-blind, randomized, placebo-controlled, crossover design with 24 healthy subjects (12 women, 12 men) to compare the co-administration of MDMA (100 mg) and LSD (100 µg) with MDMA and LSD administration alone and placebo. Outcome measures included subjective, autonomic, and endocrine effects and pharmacokinetics. MDMA co-administration with LSD did not change the quality of acute subjective effects compared with LSD alone. However, acute subjective effects lasted longer after LSD + MDMA co-administration compared with LSD and MDMA alone, consistent with higher plasma concentrations of LSD (Cmax and area under the curve) and a longer plasma elimination half-life of LSD when MDMA was co-administered. The LSD + MDMA combination increased blood pressure, heart rate, and pupil size more than LSD alone. Both MDMA alone and the LSD + MDMA combination increased oxytocin levels more than LSD alone. Overall, the co-administration of MDMA (100 mg) did not improve acute effects or the safety profile of LSD (100 µg). The combined use of MDMA and LSD is unlikely to provide relevant benefits over LSD alone in psychedelic-assisted therapy. Trial registration: ClinicalTrials.gov identifier: NCT04516902.

Influence of adrenalectomy on the gut microbiome and MDMA-induced hyperthermia.

The increased use of the stimulant drug, 3,4-methylenedioxymethamphetamine (MDMA), more commonly known as Ecstasy, Molly or X, has been linked to the development of life-threatening hyperthermia in human and animal models. The current study aimed to investigate the role of the gut-adrenal axis in MDMA-induced hyperthermia by assessing the influence of the acute exogenous supplementation with norepinephrine (NE) or corticosterone (CORT) to adrenalectomized (ADX) rats following MDMA administration. MDMA (10 mg/kg, sc) resulted in significant increase of body temperature in SHAM animals compared to ADX animals at 30-, 60- and 90-min timepoints post-MDMA treatment. The attenuated MDMA-mediated hyperthermic response seen in ADX animals was partially restored by the exogenous administration of NE (3 mg/kg, ip) or CORT (3 mg/kg, ip) 30 min after MDMA treatment. Additionally, 16 S rRNA analysis revealed distinct changes in the gut microbiome composition and diversity notable by the higher abundance of minor phyla Actinobacteria, Verrucomicrobia and Proteobacteria in ADX rats compared to control and SHAM rats. Furthermore, MDMA administration resulted in marked changes in the dominant phyla Firmicutes and Bacteroidetes and minor phyla Actinobacteria, Verrucomicrobia and Proteobacteria in ADX animals. The most notable changes in the gut microbiome upon CORT treatment were reported with increase in Bacteroidetes and decrease in Firmicutes phyla whereas NE treatment resulted in increase in Firmicutes and decrease in Bacteroidetes and Proteobacteria post treatment. These results suggest a correlation between the sympathoadrenal axis, gut microbiome structure and diversity and MDMA-mediated hyperthermia.