MDMA as a Probe and Treatment for Social Behaviors.

MDMA, better known as the recreational drug "ecstasy," is well known for stimulating a feeling of closeness and empathy in its users. We advocate that exploring its mechanism of action could lead to new treatments for psychiatric conditions characterized by impairments in social behavior.

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.

Ethical considerations for psychedelic-assisted therapy in military clinical settings.

Psychedelic treatments, particularly 3,4-methylenedioxymethamphetamine (MDMA)-assisted and psilocybin-assisted therapies, have recently seen renewed interest in their clinical potential to treat various mental health conditions. Clinical trials for both MDMA-assisted and psilocybin-assisted therapies have shown to be highly efficacious for post-traumatic stress disorder and major depression. Recent research trials for psychedelic-assisted therapies (PAT) have demonstrated that although they are resource-intensive, their effects are rapid-acting, durable and cost-effective. These results have generated enthusiasm among researchers seeking to investigate psychedelic therapies in active-duty service members of the US military, particularly those with treatment refractory mental health conditions. At the same time, psychedelics remain in early stages of clinical investigation, have not yet achieved regulatory approval for general clinical use and may confer unique psychological and neurobiological effects that could raise novel ethical considerations when treating active-duty service members. Should psychedelics achieve regulatory approval, military relevant considerations may include issues of access to these treatments, appropriate procedures for informed consent, confidentiality standards, and possible unanticipated mental health risks and other psychological sequelae. A service member's deployability, as well as their ability to return to full military duty following PAT, may also be of unique concern. The authors argue that MDMA-assisted therapy currently represents a promising treatment that should be more rapidly investigated as a clinical therapy for service members while still taking a measured approach that accounts for the many military-specific uncertainties that remain.

Psychedelics: From Cave Art to 21st-Century Medicine for Addiction.

BACKGROUND: Psychedelic substance use in ritualistic and ceremonial settings dates back as early as 8,500 BCE. Only in recent years, from the mid-20th century, we have seen the re-emergence of psychedelics in a therapeutic setting and more specifically for the treatment of addiction. This article aims to review research over the past 40 years using classic (psilocybin, lysergic acid diethylamide [LSD], dimethyltryptamine [DMT], mescaline) and atypical (ketamine, ibogaine, 5-MeO-DMT, 3,4-methylenedioxymethamphetamine) psychedelics for the treatment of addiction. SUMMARY: We will start with an overview of the pharmacology and physiological and psychological properties of psychedelic substances from pre-clinical and clinical research. We will then provide an overview of evidence gathered by studies conducted in controlled research environments and naturalistic and ceremonial settings, while we identify the proposed therapeutic mechanisms of each psychedelic substance. KEY MESSAGES: Classic and atypical psychedelics show promise as therapeutic alternatives for the treatment of addiction, through the improvement of psychological and physiological symptoms of dependence. A more comprehensive understanding of the ancient and present-day knowledge of the therapeutic potential of psychedelics can facilitate hope for psychedelic therapeutics in the treatment of addiction, especially for individuals who have failed other conventional treatment methods.

Psychedelic-Assisted Therapy in Military and Veterans Healthcare Systems: Clinical, Legal, and Implementation Considerations.

PURPOSE OF REVIEW: This review discusses the current and projected landscape of psychedelic-assisted therapy (PAT), with a focus on clinical, legal, and implementation considerations in Department of Defense (DoD) and Department of Veterans Affairs (VA) healthcare systems. RECENT FINDINGS: 3,4-Methylenedioxymethamphetamine (MDMA)- and psilocybin-assisted therapy have shown promising outcomes in efficacy, safety, tolerability, and durability for PTSD and depression, respectively. MDMA-assisted therapy is already approved by the Food and Drug Administration (FDA) on an Expanded Access ("compassionate use") basis for PTSD, with full approval projected for 2024. Psilocybin-assisted therapy is projected to be FDA-approved for depression soon thereafter. Other psychedelics are in earlier stages of development. The VA is currently conducting PAT clinical trials. Although there are clear legal pathways for the VA and DoD to conduct PAT trials, a number of implementation barriers exist, such as the very high number of clinical hours necessary to treat each patient, resource requirements to support treatment infrastructure, military-specific considerations, and the high level of evidence necessary for PAT to be recommended in clinical practice guidelines. Ongoing considerations are whether and how PAT will be made available to VA and DoD beneficiaries, feasibility and cost-effectiveness, and ethical safeguards that must be implemented to prioritize access to PAT given the likelihood of extremely limited initial availability. However, with imminent FDA approval of PATs and considerable national interest in these treatments, DoD and VA policymakers must be prepared with clearly delineated policies and plans for how these healthcare systems will approach PAT.

MDMA-assisted psychotherapy for post-traumatic stress disorder: The devil is in the detail.

Recent years have seen escalating media, public and scientific interest in psychedelic medicine. Australia and New Zealand have been late to this research; however, in the past 2 years, rapid developments suggest that this is changing. Here, we argue for the need to critically review existing evidence in this field to guide future directions. We focus on (±)3,4-methylenedioxymethamphetamine-assisted psychotherapy for post-traumatic stress disorder, currently the most advanced area of clinical psychedelic research. Food and Drug Administration approval of this approach is likely in 2023, based on a series of promising findings. We provide a detailed overview of Phase 2 and 3 studies published to date. We identify several concerns related to this body of evidence, including methodological/design limitations and broader factors - such as robust involvement of advocacy groups in research and reliance on non-government financing leading to simplistic public messaging - that compound the methodological issues identified. We propose steps for future improvement, including the need for large, high-quality, independent efficacy trials with design enhancements, effectiveness trials and for researchers to consider their own engagement with media and public messaging around these modalities. We argue that, notwithstanding promising findings to date, rigorous and dispassionate science is needed to move the field forward and safeguard the welfare of participants.

Concomitant Drug Use among Opioid-Dependent Patients with and without Attention Deficit Hyperactivity Disorder: Does Methylphenidate Merit a Trial?

INTRODUCTION: Concomitant drug use is common among opioid-dependent patients in maintenance therapy. Attention deficit hyperactivity disorder (ADHD), a common comorbidity among opioid users, is associated with a higher risk of concomitant drug use. Earlier studies showed that methylphenidate (MPH) can reduce cocaine consumption among patients with ADHD. The use of MPH as an agonist-replacement or maintenance therapy in cocaine-dependent patients without ADHD is also common in Switzerland, despite a lack of supporting evidence. The aim of this study was to assess concomitant cocaine, amphetamine, MDMA, MPH, and heroin use among patients in opioid maintenance therapy either with or without comorbid ADHD. We expected stimulant consumption to be higher in patients with cocaine dependence and comorbid ADHD and that use of MPH would not lead to a reduction in cocaine consumption in patients without ADHD. We therefore evaluated correlations between use of MPH and cocaine consumption and between MPH consumption and cocaine craving within the two groups. METHODS: This cross-sectional study included 94 opioid-dependent patients in maintenance therapy in an outpatient department of the Psychiatric Hospital of Zurich. The patients were divided into two groups based on comorbid ADHD; a group with ADHD (N = 27) and a group without ADHD (N = 67). Drug use was assessed using 3-month hair analysis. RESULTS: We did not find significant differences in the number of patients using cocaine, amphetamine, MDMA, or heroin between groups with or without ADHD. With respect to cocaine use, 85.2 percent of patients in the ADHD group and 73.1 percent in the non-ADHD group were users. The non-ADHD group showed a significant positive correlation between the concentration of MPH and cocaine in hair samples (p < 0.05), and a positive correlation between cocaine craving and the concentration of MPH in hair samples (p = 0.065). These two trends were not evident in the ADHD group. CONCLUSION: Among patients without ADHD, use of MPH correlates with higher cocaine consumption and craving. Conversely, no significant correlation was found between MPH and cocaine use in patients with ADHD. Our study adds to the evidence that MPH confers negative effects in cocaine users without ADHD and should thus have no place in the treatment of these patients.

The Emerging Field of Psychedelic Psychotherapy.

PURPOSE OF REVIEW: Few treatments are available for patients with mood disorders or post-traumatic stress disorder (PTSD) who have already failed multiple interventions. After several decades when research into psychedelics was effectively halted by federal legislation, the past several years have shown the re-emergence of thoughtful investigations studying the utility of compounds such as 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin. RECENT FINDINGS: Several studies have coupled the safe administration of psychedelic compounds in a controlled environment after several hours of preparation of study participants and followed by multiple sessions to integrate the psychedelic experience. The improvement participants experience appear related to the often profound perspective changes experienced and seem unlike the improvements seen in the currently available care paradigms. Studies cited include treatment resistant depression, end of life despair, and PTSD. Psychedelic psychotherapy, a unique remarriage of biological therapy and psychotherapy, has the potential to transform mental health care.

Potential processes of change in MDMA-Assisted therapy for social anxiety disorder: Enhanced memory reconsolidation, self-transcendence, and therapeutic relationships.

OBJECTIVE: Researchers have suggested that psychotherapy may be enhanced by the addition of 3,4-methylenedioxymethamphetamine (MDMA), particularly in the treatment of disorders wherein interpersonal dysfunction is central, such as social anxiety disorder. We review literature pertaining to three potential processes of change that may be instigated during sessions involving MDMA administration in the treatment of social anxiety disorder. DESIGN: This is a narrative review that integrates research on the etiology and maintenance of social anxiety disorder and mechanisms of action of MDMA to examine how MDMA may enhance psychotherapy outcomes. RESULTS: We first outline how MDMA may enhance memory reconsolidation in social anxiety disorder. We then discuss how MDMA may induce experiences of self-transcendence and self-transcendent emotions such as compassion, love, and awe; and how these experiences may be therapeutic in the context of social anxiety disorder. We subsequently discuss the possibility that MDMA may enhance the strength and effectiveness of the therapeutic relationship which is a robust predictor of outcomes across many disorders as well as a potential key ingredient in treating disorders where shame and social disconnection are central factors. CONCLUSION: We discuss how processes of change may extend beyond the MDMA dosing sessions themselves.

Assessing the quality of publicly available videos on MDMA-assisted psychotherapy for PTSD.

BACKGROUND AND OBJECTIVES: Patients increasingly rely on the Internet for healthcare information. This study aimed to evaluate the quality of videos on 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder (PTSD) on YouTube™. METHODS: YouTube™ was searched for the terms "MDMA" and "PTSD." The 100 most viewed videos were analyzed using three standard quality measures: Global Quality Scores (GQS), JAMA benchmark, and DISCERN. Viewer engagement features and source of upload, video duration, inclusion of patient narrative and/or MD/DO/PhD, the mention of lack of Food and Drug Administration (FDA) approval, side effects, potential for abuse, and use in conjunction with psychotherapy were recorded. RESULTS: The videos were of poor quality (mean GQS: 2.26 ± 0.94/5, JAMA: 1.96 ± 0.45/4, and DISCERN: 29.5 ± 8.2/80). A significant positive association was found between video quality and duration (GQS: r = .5857, p < .0001, JAMA: r = .279, p = .0409, DISCERN: r = .5783, p < .0001). Videos including an MD/DO/PhD had the highest scores (GQS: 2.87/5 [1.22], p = .006, DISCERN: 38.35/80 [13.32], p < .0003). A minority of videos were uploaded by academic institutions (1%); most were from professional organizations (29%). No correlation was found between quality and viewer engagement features-number of views, subscribers, likes/dislikes, or comments. A majority mentioned that MDMA must be used in conjunction with psychotherapy (85%) and is not FDA-approved (82%) for PTSD. Only 32% of videos mentioned risks or potential for abuse. CONCLUSIONS: These findings highlight the need for better quality of online health material and an opportunity for involvement of healthcare professionals in the dissemination of accurate health information via content creation. SCIENTIFIC SIGNIFICANCE: This is the first study to examine publicly available information on the use of MDMA for PTSD.

Sleep Quality Improvements After MDMA-Assisted Psychotherapy for the Treatment of Posttraumatic Stress Disorder.

Sleep disturbances (SDs) are among the most distressing and commonly reported symptoms in posttraumatic stress disorder (PTSD). Despite increased attention on sleep in clinical PTSD research, SDs remain difficult to treat. In Phase 2 trials, 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy has been shown to greatly improve PTSD symptoms. We hypothesized that MDMA-assisted psychotherapy would improve self-reported sleep quality (SQ) in individuals with PTSD and be associated with declining PTSD symptoms. Participants in four studies (n = 63) were randomized to receive 2-3 sessions of active MDMA (75-125 mg; n = 47) or placebo/control MDMA (0-40 mg, n = 16) during all-day psychotherapy sessions. The PSQI was used to assess change in SQ from baseline to the primary endpoint, 1-2 months after the blinded sessions. Additionally, PSQI scores were measured at treatment exit (TE) and 12-month follow-up. Symptoms of PTSD were measured using the CAPS-IV. At the primary endpoint, CAPS-IV total severity scores dropped more after active MDMA than after placebo/control (-34.0 vs. -12.4), p = .003. Participants in the active dose group showed more improvement in SQ compared to those in the control group (PSQI total score ΔM = -3.5 vs. 0.6), p = .003. Compared to baseline, SQ had improved at TE, p < .001, with further significant gains reported at 12-month follow-up (TE to 12-months ΔM = -1.0), p = .030. Data from these randomized controlled double-blind studies provide evidence for the beneficial effects of MDMA-assisted psychotherapy in treating SDs in individuals with PTSD.

Psilocybin and MDMA for the treatment of trauma-related psychopathology.

This review examines the role of trauma in psychiatric morbidity and analogous psychoneurobiological changes. Trauma is a necessary criterion for Post-Traumatic Stress Disorder (PTSD), however, trauma history is highly correlated with a variety of psychiatric conditions. Some evidence suggests that Major Depressive Disorder (MDD) is the most common psychiatric condition that arises following trauma. Approximately 50% of PTSD cases present with co-morbid MDD. Overlapping symptomatology and neurobiology between these conditions underlie the debate over whether these phenomena result from problematic nosology or whether comorbid MDD + PTSD is a distinct phenotype of trauma-related psychopathology. Regardless, similar treatment approaches have been employed historically, with varying success. The drug-assisted psychotherapy treatment model, which combines pharmacological and psychotherapeutic approaches, is currently being trialled as a novel treatment approach in psychiatry. Both psilocybin- and 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy have received Food and Drug Administration 'breakthrough therapy' designation for the treatment of resistant MDD and PTSD, respectively. This paper reviews the therapeutic rationale of both psilocybin and MDMA for treating both trauma-related MDD and PTSD.

Compassionate use of psychedelics.

In the present paper, we discuss the ethics of compassionate psychedelic psychotherapy and argue that it can be morally permissible. When talking about psychedelics, we mean specifically two substances: psilocybin and MDMA. When administered under supportive conditions and in conjunction with psychotherapy, therapies assisted by these substances show promising results. However, given the publicly controversial nature of psychedelics, compassionate psychedelic psychotherapy calls for ethical justification. We thus review the safety and efficacy of psilocybin- and MDMA-assisted therapies and claim that it can be rational for some patients to try psychedelic therapy. We think it can be rational despite the uncertainty of outcomes associated with compassionate use as an unproven treatment regime, as the expected value of psychedelic psychotherapy can be assessed and can outweigh the expected value of routine care, palliative care, or no care at all. Furthermore, we respond to the objection that psychedelic psychotherapy is morally impermissible because it is epistemically harmful. We argue that given the current level of understanding of psychedelics, this objection is unsubstantiated for a number of reasons, but mainly because there is no experimental evidence to suggest that epistemic harm actually takes place.

Psychedelic Therapy Scrutinized by FDA Advisory Committee?

This Viewpoint analyzes the Psychopharmacologic Drugs Advisory Committee's decisions regarding 3,4-methylenedioxymethamphetamine­assisted therapy and what they mean for psychedelic research.