Previous research has demonstrated that epigenetic changes in specific hypothalamic-pituitary-adrenal (HPA) genes may predict successful psychotherapy in post-traumatic stress disorder (PTSD). A ...recent Phase 3 clinical trial reported high efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for treating patients with severe PTSD compared to a therapy with placebo group (NCT03537014). This raises important questions regarding potential mechanisms of MDMA-assisted therapy. In the present study, we examined epigenetic changes in three key HPA axis genes before and after MDMA and placebo with therapy. As a pilot sub-study to the parent clinical trial, we assessed potential HPA epigenetic predictors for treatment response with genomic DNA derived from saliva (MDMA,
= 16; placebo,
= 7). Methylation levels at all 259 CpG sites annotated to three HPA genes (
,
, and
) were assessed in relation to treatment response as measured by the Clinician-Administered PTSD Scale (CAPS-5; Total Severity Score). Second, group (MDMA vs. placebo) differences in methylation change were assessed for sites that predicted treatment response.
Methylation change across groups significantly predicted symptom reduction on 37 of 259 CpG sites tested, with two sites surviving false discovery rate (FDR) correction. Further, the MDMA-treatment group showed more methylation change compared to placebo on one site of the
gene.
The findings of this study suggest that therapy-related PTSD symptom improvements may be related to DNA methylation changes in HPA genes and such changes may be greater in those receiving MDMA-assisted therapy. These findings can be used to generate hypothesis driven analyses for future studies with larger cohorts.
The data were expressed as the relative change in optical density with respect to the male or female control group, considered as 100%. Since samples from male and female animals were analyzed in ...separate blots, sex-dependent effects could not be analyzed for these measurements. (2013) Correction: Sex-Dependent Psychoneuroendocrine Effects of THC and MDMA in an Animal Model of Adolescent Drug Consumption.
Rapid and efficient identification of the precise isomeric form of new psychoactive substances (NPS) by forensic casework laboratories is a relevant challenge in the forensic field. Differences in ...legal status occur for ring-isomeric species of the same class, thus leading to different penalties and judicial control. Portable systems such as near-infrared (NIR) spectroscopy recently emerged as suitable techniques for the on-scene identification of common drugs of abuse such as cocaine, MDMA and amphetamine. This way, the overall forensic process becomes more efficient as relevant information on substance identity becomes available directly at the scene of crime. Currently, no NIR-based applications exist for the rapid, on-scene detection of NPS isomers. Herein, we present the differentiation of cathinone and phenethylamine-type NPS analogues based on their NIR spectrum recorded in 2 seconds on a portable 1350 – 2600 nm spectrometer. A prior developed data analysis model was found suitable for the identification of the methylmethcathinone (MMC) isomers 2-MMC, 3-MMC and 4-MMC. In 51 mixtures and 22 seized casework samples, the correct isomeric form was detected in all cases except for a few mixtures with an active ingredient content of 10 wt%. These results show the feasibility of on-site NPS detection as presumptive test performed directly at the scene of crime with a small size NIR-spectrometer. Additionally, in the illicit drug analysis laboratory the combination of NIR and GC–MS analysis might be suitable for robust identification of NPS isomers and analogues.
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•Drug isomer differentiation by near-infrared (NIR) spectroscopy is possible.•New psychoactive substances (NPS) analogues yield unique NIR-spectra.•Cathinone-isomers were correctly detected in both mixtures and casework samples.•Analysis of samples through their plastic packaging is feasible.•On-scene drug detection by portable NIR may speed-up the forensic process.
Amphetamine-related drugs, such as 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH), are popular recreational psychostimulants. Several preclinical studies have demonstrated that, ...besides having the potential for abuse, amphetamine-related drugs may also elicit neurotoxic and neuroinflammatory effects. The neurotoxic potentials of MDMA and METH to dopaminergic and serotonergic neurons have been clearly demonstrated in both rodents and non-human primates. This review summarizes the species-specific cellular and molecular mechanisms involved in MDMA and METH-mediated neurotoxic and neuroinflammatory effects, along with the most important behavioral changes elicited by these substances in experimental animals and humans. Emphasis is placed on the neuropsychological and neurological consequences associated with the neuronal damage. Moreover, we point out the gap in our knowledge and the need for developing appropriate therapeutic strategies to manage the neurological problems associated with amphetamine-related drug abuse.
Combinations of psychotherapy with antidepressants are gold-standard psychiatric treatments. They operate through complex and interactional mechanisms, not unlike the reemergent paradigm of ...psychedelic-assisted psychotherapy, which promising research suggests may also be highly effective in even challenging populations.
We review the therapeutic mechanisms behind both conventional and psychedelic paradigms, including the evolution of this knowledge and the associated explanatory frameworks. We explore how psychedelics have provided insights about psychiatric illnesses and treatments over the past decades. We discuss limitations to early explanatory models while highlighting and comparing the psychological and biological mechanisms underlying many psychiatric treatments.
A narrative review was conducted based on a search in Medline/Pubmed up to January 1
, 2020, and iterative retrieval of references from recent reviews and clinical trials.
The contextual model of the common factors of psychotherapy provides a powerful perspective on psychotherapy, antidepressants, and psychedelics, as well as 3,4-methylenedioxymethamphetamine (MDMA) and ketamine. It aligns well with key tenets of psychedelic-assisted psychotherapy. Conventional antidepressants and especially psychedelics may improve the efficacy of psychotherapy via neurochemical changes and increased environmental sensitivity. Combined treatments hold significant promise for advancing the knowledge and treatment of many forms of psychopathology.
MDMA-assisted psychotherapy for treatment of PTSD has recently progressed to Phase 3 clinical trials and received Breakthrough Therapy designation by the FDA. MDMA used as an adjunct during ...psychotherapy sessions has demonstrated effectiveness and acceptable safety in reducing PTSD symptoms in Phase 2 trials, with durable remission of PTSD diagnosis in 68% of participants. The underlying psychological and neurological mechanisms for the robust effects in mitigating PTSD are being investigated in animal models and in studies of healthy volunteers. This review explores the potential role of memory reconsolidation and fear extinction during MDMA-assisted psychotherapy. MDMA enhances release of monoamines (serotonin, norepinephrine, dopamine), hormones (oxytocin, cortisol), and other downstream signaling molecules (BDNF) to dynamically modulate emotional memory circuits. By reducing activation in brain regions implicated in the expression of fear- and anxiety-related behaviors, namely the amygdala and insula, and increasing connectivity between the amygdala and hippocampus, MDMA may allow for reprocessing of traumatic memories and emotional engagement with therapeutic processes. Based on the pharmacology of MDMA and the available translational literature of memory reconsolidation, fear learning, and PTSD, this review suggests a neurobiological rationale to explain, at least in part, the large effect sizes demonstrated for MDMA in treating PTSD.
•MDMA-assisted psychotherapy for treatment of posttraumatic stress disorder received Breakthrough Therapy designation by FDA after six Phase 2 trials demonstrated promising safety and efficacy results.•MDMA stimulates release of monoamines, hormones, and signaling molecules that modulate emotional memory circuits engaged in reprocessing of traumatic memories.•Fear extinction and memory reconsolidation could possibly be mechanisms underlying the beneficial outcomes of MDMA-assisted psychotherapy for reducing PTSD symptoms.
3,4-methylenedioxymethamphetamine (MDMA), substance known as "Ecstasy" among the people and used due to entertainment, euphoric and energy booster effect, is one of the famous synthetic stimulants. ...22-year-old man was found as unconscious in the early morning. According to the expressions of his family and friends, it was learned that he drank alcohol until late in the previous evening and took ecstasy besides this before he died. It was reported that he was taken to intensive care unit with temperature of 41oC and death occurred 12 hours later. At autopsy in external examination, petechial and purpuric hemorrhages in purple and red color were detected on body. In internal examination, petechial hemorrhages on the surface of the heart and lungs, subendocardial hemorrhage in the heart, hemorrhage on the mucosal surface of the stomach were seen. In the toxicological analyses of the blood, Paracetamol (4870 ng/ml), MDMA (847 ng/ml), MDA (94,2 ng/ml), Lidocaine (23 ng/ml), Pantoprazole (10,5 ng/ml), Midazolam (1,83 ng/ml) were detected. The death occurred due to coagulopathy related MDMA intoxication. Here, we present a case of autopsy, clinical findings and histopathologic findings, laboratory results in medicolegal literature.
•Overview and evaluation of available literature using WBE to detect illicit drugs .•The WBE approach shows an improvement in quality over the recent years.•High cocaine and methamphetamine ...consumption rates are found in the USA.•Relatively low illicit drug consumption is found in the continent of Asia.
Illicit drug use is complex, hidden and often highly stigmatized behaviour, which brings a vast challenge for drug surveillance systems. Drug consumption can be estimated by measuring human excretion products in untreated wastewater, known as wastewater-based epidemiology (WBE). Over the last decade, the application of wastewater-based epidemiology to monitor illicit drug loads increased and WBE is currently applied on a global scale. Studies from over the globe are evaluated with regard to their sampling method, analytical accuracy and consumption calculation, aiming to further reduce relevant uncertainties in order to make reliable comparisons on a global level. Only a limited number is identified as high-quality studies, so further standardization of the WBE approach for illicit drugs is desired especially with regard to the sampling methodology. Only a fraction of the reviewed papers explicitly reports uncertainty ranges for their consumption data. Studies which had the highest reliability are recently published, indicating an improvement in reporting WBE data. Until now, WBE has not been used in large parts of Africa, nor in the Middle East and Russia. An overview of consumption data across the continents on commonly studied drugs (cocaine, MDMA, amphetamine and methamphetamine) is provided. Overall, high consumption rates are confirmed in the US, especially for cocaine and methamphetamine, while relatively low illicit drug consumption is reported in Asia.
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In vitro human studies show that the metabolism of most amphetamine-like psychostimulants is regulated by the polymorphic cytochrome P450 isozyme CYP2D6. Two compounds, methamphetamine and ...3,4-methylenedioxymethamphetamine (MDMA), were selected as archetypes to discuss the translation and clinical significance of in vitro to in vivo findings. Both compounds were chosen based on their differential interaction with CYP2D6 and their high abuse prevalence in society. Methamphetamine behaves as both a weak substrate and competitive inhibitor of CYP2D6, while MDMA acts as a high affinity substrate and potent mechanism-based inhibitor (MBI) of the enzyme. The MBI behavior of MDMA on CYP2D6 implies that subjects, irrespective of their genotype/phenotype, are phenocopied to the poor metabolizer (PM) phenotype. The fraction of metabolic clearance regulated by CYP2D6 for both drugs is substantially lower than expected from in vitro studies. Other isoenzymes of cytochrome P450 and a relevant contribution of renal excretion play a part in their clearance. These facts tune down the potential contribution of CYP2D6 polymorphism in the clinical outcomes of both substances. Globally, the clinical relevance of CYP2D6 polymorphism is lower than that predicted by in vitro studies.
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