The Future for Psychedelic Agents in the Treatment of Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) treatment options, including the potential use of psychedelic-assisted therapy, are reviewed. Traditional PTSD treatment remains ineffective for many, and includes, trauma focused cognitive behavioral therapy, eye movement desensitization and remodeling, and selective serotonin reuptake inhibitors. Evidence has shown that with further supportive research, psychedelic-assisted therapy may offer an alternative treatment option.

Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSD.

Background: 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, n = 16; placebo, n = 7). Methylation levels at all 259 CpG sites annotated to three HPA genes (CRHR1, FKBP5, and NR3C1) 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. Results: 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 NR3C1 gene. Conclusion: 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.

Wastewater-based monitoring of illicit drugs in Cyprus by UPLC-MS/MS: The impact of the COVID-19 pandemic.

The outbreak and spread of COVID-19 impacted through various ways the lives of millions of humans globally. In this work, wastewater-based epidemiology (WBE) was applied to investigate the effect of the actions taken by the Republic of Cyprus to confine COVID-19 on the use of illicit stimulant drugs. Daily influent samples were collected from the six main wastewater treatment plants (WWTPs) of the country i) before lockdown (3-9 April 2019), ii) during lockdown (21-27 April 2020), iii) during the post-lockdown period (14-20 July 2020), and, iv) during each season of the following year (20-26 April 2021, 19-25 July 2021, 11-17 October 2021, 25 December 2021-2 January 2022), and analyzed for amphetamine, methamphetamine, MDMA and cocaine. In most areas, amphetamine and methamphetamine use was not affected during the confinement period, but as availability of the substances decreased with time, a drop in their use was observed when most restriction measures were eased (up to 9- and 22-fold decrease, respectively). The limitations on social interactions and events during the quarantine period seem to have led to the reduction of MDMA and cocaine and driven a sharp decrease of their use in most areas studied (up to 11 and 6 times lower, respectively). However, the re-opening of activities led to a pronounced consumption increase, reaching maximum daily values of 800 and 2691 mg/1000 inhabitants/day, respectively. In 2021, drug use was re-established to lower levels. The examination of weekly patterns during this year revealed higher weekend use of methamphetamine, MDMA and cocaine. Our results suggest that both the implementation and the easing of COVID-19 related measures affected the availability and the use of drugs. This study also provides the first insight on the consumption of illicit drugs in the Republic of Cyprus during pre-, post- and pandemic times and demonstrates the importance of WBE.

MDMA-Assisted Therapy for Treatment-Resistant Posttraumatic Stress Disorder (PTSD) - One step further toward a patient-centered treatment pathway

Introduction: PTSD is a chronic, debilitating condition with limited treatment efficacy. Accessing traumatic memories often leads to overwhelming distress, impacting treatment process. Current approved pharmacological treatments have exhibited small to moderate effects when compared with placebo. Evidence suggests 3,4,-methylene-dioxymethamphetamine(MDMA)-assisted psychotherapy as a viable option for refractory PTSD. Objective(s): Comprehensive review of early clinical research, proposed mechanisms, safety and emerging therapeutic models. Method(s): Eligible studies will be identified through strategic search of MEDLINE. Result(s): Pre-clinical and imaging studies suggest memory reconsolidation and fear extinction as candidate psychological and neurological mechanisms, involving MDMA's combined effects of increasing serotonergic activity, as well the release of oxytocin and brain-derived neurotrophic factor in key memory and emotional circuits. Resulting reduction in amygdala and insula activation and increasing connectivity between the amygdala and hippocampus may create a tolerance window of neuroplasticity for emotional engagement and reprocessing of traumatic memories during psychotherapy. Early clinical trials report impressive and durable reduction in PTSD symptoms, with a safety profile comparable to that of SSRIs. A recently completed randomized, double-blind, placebocontrolled phase 3 trial reported full remission of PTSD symptoms in 67% of patients at 2 months, with no increase in suicidality, cardiovascular events or abuse behavior. Emerging treatment models underline the importance of unmedicated therapeutic sessions for preparation for the experience and subsequent integration as essential for full benefit and safety of the clinical context. Conclusion(s): The psychological impact associated with the COVID-19 pandemic is an reminder of the emotional and economic burden associated with PTSD. MDMA-assisted therapy may be a breakthrough approach meriting further multidisciplinary investment and clinical research.

Psychoactive Drugs in the Management of Post Traumatic Stress Disorder: A Promising New Horizon.

Post-traumatic stress disorder (PTSD) is an anxiety disorder that often presents after exposure to a traumatic, life-threatening event. Experiencing a traumatic event is not rare, with inciting incidents ranging from being burglarized to politically motivated genocide. While traditional psychopharmacology and psychotherapy are the mainstays of the treatment of PTSD currently, psychoactive drugs (otherwise known as psychedelics) are being explored for their novel role in the treatment of PTSD patients. Psychoactive drugs such as MDMA, ketamine, and psilocybin have been shown to specifically target and decrease fear and anxiety pathways in the brain. These unique properties hold the potential to be utilized in addressing symptoms of trauma in those with refractory or treatment-resistant PTSD. Historically, federal and state laws have restricted research into how psychoactive drugs can be used to treat mental illness due to the widespread belief that these drugs present more harm than benefit. However, the current shift in public opinion on psychedelics has propelled research to look into the benefits of these drugs for patients with mental illness. This article aims to discuss the mechanisms of how MDMA, ketamine, and psilocybin work in the PTSD brain, as well as their beneficial role in treatment.

Changes in illicit drug use and markets with the COVID-19 pandemic and associated restrictions: Findings from the Ecstasy and Related Drugs Reporting System, 2016-20

Aims: To describe (i) self-reported changes in drug use and (ii) trends in price, perceived availability, and perceived purity of illicit drugs, among people who regularly use ecstasy/ 3,4-methylenedioxymethamphetamine (MDMA) and other illicit stimulants in Australia following COVID-19 and associated restrictions. Design: Annual interviews with cross-sectional sentinel samples conducted face-to-face in 2016-19 and via video conferencing or telephone in 2020. Data were collected via an interviewer-administered structured questionnaire. Setting: Australian capital cities. Participants: Australians aged 16 years or older who used ecstasy/MDMA and other illicit stimulants on a monthly or more frequent basis and resided in a capital city, recruited via social media and word-of-mouth (n ~ 800 each year). Measurements: Key outcome measures were self-reported illicit drug market indicators (price, purity and availability) and, in 2020 only, perceived change in drug use (including alcohol and tobacco) since March 2020 and reasons for this change. Findings: For most drugs, participants reported either no change or a reduction in their use since COVID-19 restrictions were introduced. Ecstasy/MDMA was the drug most frequently cited as reduced in use (n = 552, 70% of those reporting recent use), mainly due to reduced opportunities for socialization. While market indicators were largely stable across most drugs, the odds of perceiving MDMA capsules as 'high' in purity decreased compared with 2016-19 [adjusted odds ratio (aOR) = 0.72, 95% confidence interval (CI) = 0.53-0.99], as did perceiving them as 'easy' to obtain (aOR = 0.42, CI = 0.26-0.67). The odds of perceiving cocaine and methamphetamine crystal as 'easy' to obtain also decreased (aOR = 0.67, CI = 0.46-0.96 and aOR = 0.12, CI = 0.04-0.41, respectively). Conclusions: After COVID-19-related restrictions were introduced in Australia, use of ecstasy/MDMA, related stimulants and other licit and illicit drugs mainly appeared to remain stable or decrease, primarily due to impediments to socialization. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

No party, no drugs? Use of stimulants, dissociative drugs, and GHB/GBL during the early COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic is presumably having an impact on the consumption of psychoactive substances. Social distancing and lockdown measures may particularly affect the use of "party drugs" (e.g., stimulants, dissociatives, and GHB/GBL) through the absence of typical use settings. We aimed to analyse the use patterns of those substances and underlying motivations before and during the pandemic. METHODS: A subsample of 1,231 users of stimulants (amphetamine, methamphetamine, MDMA/ecstasy, cocaine), dissociative drugs (ketamine, dextromethorphan, PCP), and GHB/GBL was assessed from 30th April to 4th August 2020 as part of the Corona Drug Survey, a cross-sectional international online survey in five languages that included a total of 5,049 participants. The reported use of distinct substances and the underlying motivations were ascertained before (retrospectively) and during the pandemic. Furthermore, associations between drug use as a coping mechanism, pandemic-related stressors, and substance use were examined. RESULTS: Regarding the reported frequency of use during the pandemic, 48.0-64.8% of the sample ceased or decreased, 11.9-25.5% maintained, and 23.6-29.1% increased their consumption. MDMA/ecstasy showed the strongest decrease and GHB/GBL and dissociatives the highest increase. Participants reported that price, quality, and supply were mostly unaffected by the pandemic. The most common motivations before and during the pandemic were mood-related factors, such as a desire to feel exhilarated, euphoric, high, or buzzed. The relevance of social purposes and mood-related motivators declined during the pandemic, whereas dealing with boredom increased. Overall, 16.4-35.6% perceived drug use as helpful for dealing with pandemic-related stressors, which were associated with an increased consumption frequency. CONCLUSION: The early stage of the COVID-19 pandemic was associated with major changes in the use of "party drugs". Those who increased their level of drug use and perceived it as a coping strategy in particular might be targeted with adaptive preventive and therapeutic measures.

A quantitative analysis of MDMA seized at New South Wales music festivals over the 2019/2020 season: Form, purity, dose and adulterants.

INTRODUCTION: This research aims to understand the content and nature, and to explore the harm potential, of suspected 3,4-methylenedioxymethamphetamine (MDMA) substances circulating at music festivals in New South Wales. METHODS: Across 19 music festivals held between October 2019 and March 2020, 302 substances detected and suspected by police to contain MDMA were selected for quantitative analysis. RESULTS: Five percent of substances contained a drug other than MDMA (n = 13) or no drug (n = 2). The remaining 95.0% (n = 287) contained MDMA. Of this sub-sample, capsule was the commonest form (83.3%), followed by tablet (7.7%), crystal (6.3%) and powder (2.8%). The median MDMA base-purity of non-tablet forms ranged between 73.5% and 75.0%. The median MDMA base-dose per tablet (116 mg) was higher than per capsule (68 mg). The dose range varied substantially for capsules (14-146 mg) and tablets (24-201 mg). A higher dose (130 mg or greater) was found in 3.5% of MDMA tablets or capsules. Adulterants were identified in 14.1% of MDMA substances but only 1.6% contained a psychoactive adulterant and none presented as dangerous due to their nature or low concentration. DISCUSSION AND CONCLUSIONS: Dangerous MDMA adulterants or new psychoactive substances in tablet, capsule, powder or crystal forms (whether misrepresented as MDMA or not) were unlikely to be in circulation during the study period. Harm reduction messaging should inform that a key risk-factor for MDMA-related harm is the high and wide variation of purity and dose across forms. Market changes may have occurred since COVID-19, but continued monitoring will ensure messaging remains current.