Reviewing the Potential of Psychedelics for the Treatment of PTSD.

There are few medications with demonstrated efficacy for the treatment of posttraumatic stress disorder (PTSD). Treatment guidelines have unequivocally designated psychotherapy as a first line treatment for PTSD. Yet, even after psychotherapy, PTSD often remains a chronic illness, with high rates of psychiatric and medical comorbidity. Meanwhile, the search for and development of drugs with new mechanisms of action has stalled. Therefore, there is an urgent need to explore not just novel compounds but novel approaches for the treatment of PTSD. A promising new approach involves the use of psychedelic drugs. Within the past few years, 2 psychedelics have received breakthrough designations for psychiatric indications from the US Food and Drug Administration, and several psychedelics are currently being investigated for the treatment of PTSD. This review discusses 4 types of compounds: 3,4-methylenedioxymethamphetamine, ketamine, classical psychedelics (e.g., psilocybin and lysergic acid diethylamide), and cannabinoids. We describe the therapeutic rationale, the setting in which they are being administered, and their current state of evidence in the treatment of PTSD. Each compound provides unique qualities for the treatment of PTSD, from their use to rapidly target symptoms to their use as adjuncts to facilitate psychotherapeutic treatments. Several questions are formulated that outline an agenda for future research.

From opiates to methamphetamine: building new harm reduction responses in Jakarta, Indonesia.

BACKGROUND: Despite the rise of stimulant use, most harm reduction programs still focus on people who inject opioids, leaving many people who use methamphetamine (PWUM) underserviced. In Asia, especially, where methamphetamine prevalence has overtaken opioids prevalence, harm reduction programs assisting PWUM are rare. The few existing innovative practices focusing on methamphetamine use lie underreported. Understanding how these programs moved their focus from opiates to methamphetamine could help inspire new harm reduction responses. Hence, this paper analyzes a newly implemented outreach program assisting methamphetamine users in Jakarta, Indonesia. It addresses the program's critical learning points when making the transition to respond to stimulant use. METHODS: This case study is part of a more extensive research on good practices of harm reduction for stimulant use. For this case study, data was collected through Indonesian contextual documents and documents from the program, structured questionnaire, in-depth interviews with service staff and service users, a focus group discussion with service users, and in-loco observations of activities. For this paper, data was reinterpreted to focus on the key topics that needed to be addressed when the program transitioned from working with people who use opioids to PWUM. RESULTS: Four key topics were found: (1) getting in touch with different types of PWUM and building trust relationships; (2) adapting safer smoking kits to local circumstances; (3) reframing partnerships while finding ways to address mental health issues; and (4) responding to local law enforcement practices. CONCLUSIONS: The meaningful involvement of PWUM was essential in the development and evaluation of outreach work, the planning, and the adaptation of safer smoking kits to local circumstances. Also, it helped to gain understanding of the broader needs of PWUM, including mental health care and their difficulties related to law enforcement activities. Operating under a broad harm reduction definition and addressing a broad spectrum of individual and social needs are preferable to focusing solely on specific interventions and supplies for safer drug use. Since many PWUM smoke rather than inject, securing funding for harm reduction focused on people who do not inject drugs and/or who do not use opioids is fundamental in keeping programs sustainable.

Patient perspectives and experiences with psilocybin treatment for treatment-resistant depression: a qualitative study.

Psilocybin is the most researched classic psychedelic for Treatment-Resistant Depression (TRD). While optimizing set and setting are considered essential for efficacy and safety, patient perspectives on these aspects have rarely been investigated. To address this knowledge gap, the current paper explored the experiences of 11 TRD patients (8 women, 3 men) participating in a double-blind randomized clinical trial with a single session of oral (1, 10 or 25 mg) psilocybin treatment. After qualitative analysis, three major themes were identified: (1) challenges with trust-building and expectation management; (2) navigating the experience; and (3) the need for a more comprehensive treatment. Subthemes of the first theme include a general distrust in mental healthcare, trust in study therapists, limited time for preparation, and managing expectations. The second theme included the following subthemes: trusting to surrender, profound and overwhelming experiences, and music as a guide. The third theme addressed a desire for multiple psilocybin sessions, and challenges with sensemaking. Patients' perspectives provided important insights into potential optimization of psilocybin treatment of TRD, including individualized preparation, investment in trust-building, offering additional psilocybin sessions, providing access to sustained (psycho)therapy with trusted therapists, and personalizing treatment approaches, which may also enhance real-world adaption of these treatments.

Phenomenology and therapeutic potential of patient experiences during oral esketamine treatment for treatment-resistant depression: an interpretative phenomenological study.

BACKGROUND: Ketamine and its enantiomers are widely researched and increasingly used to treat mental disorders, especially treatment-resistant depression. The phenomenology of ketamine-induced experiences and their relation to its psychotherapeutic potential have not yet been systematically investigated. AIMS: To describe the phenomenology of patient experiences during oral esketamine treatment for treatment-resistant depression (TRD) and to explore the potential therapeutic relevance of these experiences. METHODS: In-depth interviews were conducted with 17 patients after a 6-week, twice-weekly 'off label' generic oral esketamine (0.5-3.0mg/kg) treatment program. Interviews explored participants' perspectives, expectations, and experiences with oral esketamine treatment. Audio interviews were transcribed and analyzed using an Interpretative Phenomenological Analysis (IPA) framework. RESULTS: The effects of ketamine were highly variable, and psychological distress was common in most patients. Key themes included (a) perceptual effects (auditory, visual, proprioceptive), (b) detachment (from body, self, emotions, and the world), (c) stillness and openness, (d) mystical-type effects (transcendence, relativeness, spirituality), and (e) fear and anxiety. Key themes related to post-session reports included (a) feeling hungover and fatigued, and (b) lifting the blanket: neutralizing mood effects. CONCLUSION: Patients reported several esketamine effects with psychotherapeutic potential, such as increased openness, detachment, an interruption of negativity, and mystical-type experiences. These experiences deserve to be explored further to enhance treatment outcomes in patients with TRD. Given the frequency and severity of the perceived distress, we identify a need for additional support in all stages of esketamine treatment.

Holding on or letting go? Patient experiences of control, context, and care in oral esketamine treatment for treatment-resistant depression: A qualitative study.

Background: Ketamine and its enantiomer esketamine represent promising new treatments for treatment-resistant depression (TRD). Esketamine induces acute, transient psychoactive effects. How patients perceive esketamine treatment, and which conditions facilitate optimal outcomes, remains poorly understood. Understanding patient perspectives on these phenomena is important to identify unmet needs, which can be used to improve (es)ketamine treatments. Aims: To explore the perspectives of TRD patients participating in "off label" oral esketamine treatment. Materials and methods: In-depth interviews were conducted with 17 patients (11 women) after a six-week, twice-weekly esketamine treatment program, and subsequently after six months of at-home use. Interviews explored participants' perspectives, expectations, and experiences with esketamine treatment. Audio interviews were transcribed verbatim and analysed following an Interpretative Phenomenological Analysis (IPA) framework. Results: Key themes included overwhelming experiences; inadequate preparation; letting go of control; mood states influencing session experiences; presence and emotional support, and supportive settings. Patients' attempts to let go and give into vs. attempts to maintain control over occasionally overwhelming experiences was a central theme. Multiple factors influenced patients' ability to give into the experience and appeared to impact their mood and anxiety about future sessions, including level of preparation and education, physical and emotional support, and setting during the session. Conclusion: Better preparation beforehand, an optimized treatment setting, and emotional and psychological support during (es)ketamine sessions can help patients to "let go" and may lead to better quality of care and outcomes. Recommendations to improve quality of patient care in (es)ketamine treatment are provided, including suggestions for the training of nurses and other support staff.

Psychedelics for the treatment of depression, anxiety, and existential distress in patients with a terminal illness: a systematic review.

BACKGROUND: Terminally ill patients may experience existential distress, depression, or anxiety, limiting quality of life in the final stage. Existing psychotherapeutic or pharmacological interventions have (time) limited efficacy. Psychedelic treatment may be a safe and effective alternative treatment option. AIM: Systematically review studies on psychedelic treatment with and without psychotherapy for existential distress, depression, and anxiety in terminally ill patients. METHODS: Medline, PsycINFO, and Embase were searched for original-data studies on the treatment of depression, anxiety, and existential distress with classical or a-typical psychedelics in patients with a terminal illness, using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: A total of 1850 records were screened, and 33 articles were included in this review: 14 studies on classical psychedelics (DPT, LSD, and psilocybin) and 19 studies on atypical psychedelics (MDMA and ketamine). Results of early pre-post studies are promising but have serious methodological flaws. Recent (controlled) trials with LSD, psilocybin, ketamine, and MDMA are of higher methodological quality and indicate positive effects on existential and spiritual well-being, quality of life, acceptance, and reduction of anxiety and depression with few adverse and no serious adverse effects. CONCLUSIONS: Both classical and a-typical psychedelics are promising treatment options in patients with terminal illness. To draw final conclusions on effectiveness and safety of psychedelics, we need larger high-quality studies for classical psychedelics and MDMA. Ketamine studies should pay more attention to existential dimensions of well-being and the psychotherapeutic context of the treatment.

Adverse events in clinical treatments with serotonergic psychedelics and MDMA: A mixed-methods systematic review.

INTRODUCTION: Small-scale clinical studies with psychedelic drugs have shown promising results for the treatment of several mental disorders. Before psychedelics become registered medicines, it is important to know the full range of adverse events (AEs) for making balanced treatment decisions. OBJECTIVE: To systematically review the presence of AEs during and after administration of serotonergic psychedelics and 3,4-methyenedioxymethamphetamine (MDMA) in clinical studies. METHODS: We systematically searched PubMed, PsycINFO, Embase, and ClinicalTrials.gov for clinical trials with psychedelics since 2000 describing the results of quantitative and qualitative studies. RESULTS: We included 44 articles (34 quantitative + 10 qualitative), describing treatments with MDMA and serotonergic psychedelics (psilocybin, lysergic acid diethylamide, and ayahuasca) in 598 unique patients. In many studies, AEs were not systematically assessed. Despite this limitation, treatments seemed to be overall well tolerated. Nausea, headaches, and anxiety were commonly reported acute AEs across diagnoses and compounds. Late AEs included headaches (psilocybin, MDMA), fatigue, low mood, and anxiety (MDMA). One serious AE occurred during MDMA administration (increase in premature ventricular contractions requiring brief hospitalization); no other AEs required medical intervention. Qualitative studies suggested that psychologically challenging experiences may also be therapeutically beneficial. Except for ayahuasca, a large proportion of patients had prior experience with psychedelic drugs before entering studies. CONCLUSIONS: AEs are poorly defined in the context of psychedelic treatments and are probably underreported in the literature due to study design (lack of systematic assessment of AEs) and sample selection. Acute challenging experiences may be therapeutically meaningful, but a better understanding of AEs in the context of psychedelic treatments requires systematic and detailed reporting.

Working with Weirdness: A Response to "Moving Past Mysticism in Psychedelic Science".

In response to a recent call to rid psychedelic science of the concept of mystical experience, we argue that acknowledging the varieties and weirdness of psychedelic experiences should be at the heart of any research program on this topic. We highlight the rich tradition and scientific tools for studying mystical-type experiences, their relevance for understanding the therapeutic effects of psychedelics, as well as the need for more diversity in the experiences and participants included in this research.

[Treatment with psilocybin: applications for patients with psychiatric disorders]. / Behandeling met psilocybine.

After a cessation of almost 40 years, there is renewed interest into therapeutic applicationsof the serotonergic psychedelic psilocybin for the treatment of patients with various psychiatric disorders. PubMed was searched for clinical trials into "psilocybin" between 2000 and 2020, complemented by handsearching. Articles were also screened for explanatory models and working mechanisms. Psilocybin has been studied in 9 clinical trials: for the treatment of substance use disorders, depression, end-of-life anxiety, demoralization, and obsessive-compulsive disorder. Results show that psilocybin is well tolerated, with only limited side-effects, while even patients with treatment-resistant disorders sometimes show marked, long-term improvements after one or a few sessions. Initial results are encouraging, but there are several limitations. More research is needed to determine which patient populations can benefit, what role setting and the placebo response play, and how these novel treatments can be optimized.

Developing a new national MDMA policy: Results of a multi-decision multi-criterion decision analysis.

BACKGROUND: Ecstasy (3,4-methylenedioxymethamphetamine (MDMA)) has a relatively low harm and low dependence liability but is scheduled on List I of the Dutch Opium Act ('hard drugs'). Concerns surrounding increasing MDMA-related criminality coupled with the possibly inappropriate scheduling of MDMA initiated a debate to revise the current Dutch ecstasy policy. METHODS: An interdisciplinary group of 18 experts on health, social harms and drug criminality and law enforcement reformulated the science-based Dutch MDMA policy using multi-decision multi-criterion decision analysis (MD-MCDA). The experts collectively formulated policy instruments and rated their effects on 25 outcome criteria, including health, criminality, law enforcement and financial issues, thematically grouped in six clusters. RESULTS: The experts scored the effect of 22 policy instruments, each with between two and seven different mutually exclusive options, on 25 outcome criteria. The optimal policy model was defined by the set of 22 policy instrument options which gave the highest overall score on the 25 outcome criteria. Implementation of the optimal policy model, including regulated MDMA sales, decreases health harms, MDMA-related organised crime and environmental damage, as well as increases state revenues and quality of MDMA products and user information. This model was slightly modified to increase its political feasibility. Sensitivity analyses showed that the outcomes of the current MD-MCDA are robust and independent of variability in weight values. CONCLUSION: The present results provide a feasible and realistic set of policy instrument options to revise the legislation towards a rational MDMA policy that is likely to reduce both adverse (public) health risks and MDMA-related criminal burden.

Psychedelic Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of Patient Experiences in Qualitative Studies.

INTRODUCTION: Interest in the use of psychedelic substances for the treatment of mental disorders is increasing. Processes that may affect therapeutic change are not yet fully understood. Qualitative research methods are increasingly used to examine patient accounts; however, currently, no systematic review exists that synthesizes these findings in relation to the use of psychedelics for the treatment of mental disorders. OBJECTIVE: To provide an overview of salient themes in patient experiences of psychedelic treatments for mental disorders, presenting both common and diverging elements in patients' accounts, and elucidating how these affect the treatment process. METHODS: We systematically searched the PubMed, MEDLINE, PsycINFO, and Embase databases for English-language qualitative literature without time limitations. Inclusion criteria were qualitative research design; peer-reviewed studies; based on verbalized patient utterances; and a level of abstraction or analysis of the results. Thematic synthesis was used to analyze and synthesize results across studies. A critical appraisal of study quality and methodological rigor was conducted using the Critical Appraisal Skills Programme (CASP). RESULTS: Fifteen research articles, comprising 178 patient experiences, were included. Studies exhibited a broad heterogeneity in terms of substance, mental disorder, treatment context, and qualitative methodology. Substances included psilocybin, lysergic acid diethylamide (LSD), ibogaine, ayahuasca, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Disorders included anxiety, depression, eating disorders, post-traumatic stress disorder, and substance use disorders. While the included compounds were heterogeneous in pharmacology and treatment contexts, patients reported largely comparable experiences across disorders, which included phenomenological analogous effects, perspectives on the intervention, therapeutic processes and treatment outcomes. Comparable therapeutic processes included insights, altered self-perception, increased connectedness, transcendental experiences, and an expanded emotional spectrum, which patients reported contributed to clinically and personally relevant responses. CONCLUSIONS: This review demonstrates how qualitative research of psychedelic treatments can contribute to distinguishing specific features of specific substances, and carry otherwise undiscovered implications for the treatment of specific psychiatric disorders.