Psychedelic research at a crossroads.

There is an urgent need to develop better treatments for mental health conditions that affect one in every eight people in the world. To combat this concern, psychedelic drugs have been combined with psychotherapy and studied in clinical trials in the United States and Europe. Psychedelics are hallucinogenic drugs that alter brain activity and facilitate altered states of consciousness. The proposed benefits of psychedelic-assisted therapy (PAT) include relatively short treatment times and stronger effects compared to other treatments. Although results of trials using MDMA for trauma or psilocybin for depression are promising, PAT is controversial because many questions about its safety and effectiveness are unanswered. This is evident in the recent ruling by the US Food and Drug Administration against the approval of MDMA therapy for post-traumatic stress disorder and the retraction of several papers about MDMA trials owing to unethical conduct by study therapists and data integrity, among other concerns. This field is at a crossroads, and the research community must address several obstacles to transition from exploratory trials to established, evidence-based treatments while avoiding pitfalls that can hinder advancement.

Efficacy, Safety, and Tolerability of Psychedelics in Treatment-Resistant Depression (TRD).

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, associated with substantial burden and large economical costs. Notwithstanding various conventional antidepressant treatment options, a large portion of depressed people (ca. 30%) fails to respond to first-line treatment, resulting in treatment-resistant depression (TRD). Although non-response to multiple antidepressant interventions is a common outcome, a consensus definition of TRD is not yet available. In practice, TRD is applied when two or more successive treatments with different antidepressants are not working. The last decade's intense research into new medicines for TRD has led to two developments, using typical or serotonergic (psilocybin, ayahuasca) and atypical (glutamatergic) psychedelics (ketamine, esketamine). Both approaches, although via different entrance mechanism, exhibit a fast onset but also long-lasting antidepressant effect far beyond the biological presence of the drug in the body, strongly indicating that downstream mechanisms activated by signaling cascades in the brain are involved. The present chapter describes the clinical development of psilocybin and esketamine for TRD and discusses the problems involved in the use of a proper placebo because of the psychotomimetic (psilocybin) or dissociative (ketamine) effects that interfere with performing "blind" studies. Nevertheless, intranasal esketamine was developed and approved for TRD, whereas psilocybin has shown positive results. Adverse effects and tolerability of both drugs in the dose ranges used are generally acceptable. The emergence of anti-TRD medicines for treatment of a very severe disease is a breakthrough in psychiatry.

Examining the influence of team-based learning on medical students' comprehension and attitudes regarding psychedelic therapies.

INTRODUCTION: This study evaluates the impact of a two-hour team-based learning (TBL) curriculum on medical students' knowledge, comprehension, ethical understanding, and attitudes towards psychedelic therapies. METHODS: Sixty-three pre-surveys and fifty post-surveys assessed students' perceived knowledge and attitudes using Likert scales. Forty-eight matched pre/post-knowledge tests with multiple-choice questions quantified changes in comprehension. The TBL approach featured independent learning, team readiness assessments, and application exercises. RESULTS: Post-curriculum, students demonstrated significantly improved test scores (mean 41.4% increase, p < 0.0001) and more positive attitudes across 16 of 18 items (p ≤ 0.0495). Overall attitude scores increased 23% (p < 0.0001). Qualitative feedback reflected enhanced comfort discussing psychedelics clinically. While some students expressed support for psychedelic-assisted therapy, others cited reservations. DISCUSSION: This innovative curriculum bridged an important education gap given the increasing relevance of psychedelic medicine. Findings suggest TBL enhances medical student preparedness in this emerging field. Continued curricular development is warranted to ensure proper psychedelic education aligns with patient needs and legislative policies. As psychedelic research progresses, maintaining instructional excellence is crucial for future healthcare professionals.

Jung, the Rebirth Motif and Psychedelics I: Documenting Jung's Contact with the British Pioneers.

C. G. Jung wrote very little about psychedelic drugs and he took a sceptical view of them. However, he was sufficiently impressed by Aldous Huxley's 1954 account of taking mescaline, The Doors of Perception, to invite Huxley to visit him in Switzerland. Huxley declined Jung's invitation but Huxley's collaborator Humphry Osmond met Jung instead. This paper documents Jung's contact with the British pioneers of psychedelics research and presents the scant material illuminating his views about these drugs. It also determines the efforts of British psychiatrist Ronald Sandison, who was the first to develop an "explicitly Jungian approach" to psychedelic-assisted psychotherapy (Hill, 2013), and it highlights a connection between Sandison's initiative and the Society of Analytical Psychology (SAP) through the involvement of two SAP members: Margot Cutner, Sandison's colleague, and Michael Fordham, who supervised a trainee working with one of Sandison's former patients. Despite Jung's objections to the use of psychedelics, Sandison and Cutner developed ground-breaking protocols during the 1950s and they were among the first to document the phenomenon of "spiritual rebirth symbolized in the birth experience known to many LSD therapists" (Sandison, 2001). In two companion papers, I consider Jung's treatment of the rebirth motif in his commentary on The Tibetan Book of the Dead, which later became a central text in the psychedelic movement, and I chart the evolution in psychedelics research from an association with schizophrenia during the 1950s to the mystical paradigms of the 1960s and beyond.

C.G. Jung a très peu écrit sur les drogues psychédéliques et il avait à leur égard une attitude sceptique. Cependant il fut suffisamment impressionné par le récit d'Aldous Huxley de son expérience avec la mescaline en 1954, Les Portes de la Perception, pour inviter Huxley à lui rendre visite en Suisse. Huxley déclina l'invitation de Jung mais son collaborateur Humphry Osmond rencontra Jung à sa place. Cet article rend compte des contacts de Jung avec les recherches des pionniers britanniques en matière de drogues psychédéliques. Il présente aussi le peu de matériel qui illustre ses opinions concernant ces drogues. L'article explore les efforts du psychiatre britannique Ronald Sandison ­ qui fut le premier à développer une « approche spécifiquement jungienne ¼ à la psychothérapie assistée par des drogues psychédéliques ­ et il souligne un lien entre l'initiative de Sandison et The Society of Analytical Psychology (SAP) par l'implication de deux de ses membres : Margot Cutner, collègue de Sandison, et Michael Fordham, qui supervisa un candidat sur son travail avec un des anciens patients de Sandison. Malgré les objections de Jung sur l'utilisation des drogues psychédéliques, Sandison et Cutner ont développé des protocoles très innovants durant les années 1950 et furent parmi les premiers à documenter le phénomène de la « renaissance spirituelle symbolisée par l'expérience de naissance, bien connue par la plupart des thérapeutes utilisant le L.S.D. ¼ (Sandison, 2001). Dans deux articles apparentés j'examine la manière dont Jung a traité le motif de la renaissance dans son commentaire sur Le Livre des Morts Tibétain, qui devint par la suite un texte central dans le mouvement psychédélique, et je retrace l'évolution dans la recherche sur les drogues psychédéliques à partir d'une association avec la schizophrénie dans les années 1950 et jusqu'aux paradigmes mystiques des années 1960 et au­delà.

C. G. Jung escribió muy poco sobre las drogas psicodélicas y adoptó una postura escéptica hacia ellas. Sin embargo, quedó lo suficientemente impresionado por el relato, Las Puertas de la Percepción, que Aldous Huxley hizo en 1954 en referencia a su consumo de mescalina, como para invitar a Huxley a visitarle en Suiza. Huxley declinó la invitación, pero en su lugar Jung se reunió con Humphry Osmond, colaborador de Huxley. Este artículo documenta el contacto de Jung con los pioneros británicos en investigación psicodélica y presenta el escaso material que da cuenta de las opiniones de estos, sobre dichas drogas. También determina los esfuerzos del psiquiatra británico Ronald Sandison, que fue el primero en desarrollar un "enfoque explícitamente Junguiano" de la psicoterapia asistida por psicodélicos (Hill, 2013), y destaca una conexión entre la iniciativa de Sandison y la Sociedad de Psicología Analítica (SAP) a través de la participación de dos miembros de la SAP: Margot Cutner, colega de Sandison, y Michael Fordham, quien supervisaba a un candidato a analista que trabajaba con uno de los antiguos pacientes de Sandison. A pesar de las objeciones de Jung al uso de psicodélicos, Sandison y Cutner desarrollaron innovadores protocolos durante la década de 1950 y fueron los primeros en documentar el fenómeno del "renacimiento espiritual simbolizado en la experiencia del nacimiento conocida por muchos terapeutas del LSD" (Sandison, 2001). En dos artículos complementarios, considero el tratamiento que Jung da al motivo del renacimiento en su comentario sobre El Libro Tibetano de los Muertos, que más tarde se convirtió en un texto central del movimiento psicodélico, y trazo la evolución de la investigación sobre psicodélicos desde su asociación con la esquizofrenia durante la década de 1950 hasta los paradigmas místicos de la década de 1960 y posteriores.

[Psychedelic and dissociative agents in psychiatry: challenges in the treatment]. / Psychedelika und Dissoziativa in der Psychiatrie: Herausforderungen in der Behandlung.

With the discovery of the antidepressive effects of ketamine and the increasing withdrawal of the pharmaceutical industry from the development of new psychotropic drugs, the psychiatric research into the clinical application of hallucinogens in psychiatry has literally blossomed in the last two decades. Promising results for various treatment approaches with psychedelic agents, such lysergic acid diethylamide (LSD) and psilocybin, and dissociative agents, such as ketamine and esketamine, have raised great hopes among researchers, clinicians and patients in recent years, so that there was already talk of a new era in psychiatry. As one of the first of these substances, in December 2019 intranasal esketamine was approved in the USA and the EU for the treatment of treatment-resistant depression and Switzerland followed in 2020. Recently, psilocybin was approved in Australia, Canada and Switzerland for compassionate use in exceptional cases for the treatment of depression, while large approval studies with various psychedelic agents are currently ongoing worldwide. The medical application of psychedelic agents and ketamine/esketamine is considered to be safe; however, as with all new forms of treatment it is of crucial importance that, in addition to the hopes, the specific challenges of these new treatment approaches must also be carefully considered and assessed. Excessive expectations and an insufficient risk-benefit estimation are detrimental to the patients and the reputation of the treating physician. Although a possible paradigm shift in the care of mental health is already being discussed, this review article consciously concentrates on the possible risks of treatment and the methodological weaknesses of the studies carried out so far.

Classic psychedelics and the treatment for alcoholism.

Alcohol is a harmful drug, and reducing its consumption is a significant challenge for users. Furthermore, alcohol dependence is often treatment-resistant, and no completely effective treatment model is available for chemical dependence. Classic psychedelics, such as LSD, psilocybin, and ayahuasca have been used in different clinical and pre-clinical trials, demonstrating promising pharmacotherapeutic effects in the treatment of treatment-resistant psychopathological conditions, such as addiction, especially related to alcohol dependence. In this work, we conducted a narrative review of the emerging research regarding the potential of psychedelics for alcohol use disorder treatment. Psychedelic substances have demonstrated potential for treating drug addiction, especially AUD, mostly by modulating neuroplasticity in the brain. Given that serotonergic psychedelics do not produce physical dependence or withdrawal symptoms with repeated use, they may be considered promising treatment options for managing drug use disorders. However, certain limitations could be found. Although many participants achieve positive results with only one treatment dose in clinical studies, great inter-individual variability exists in the duration of these effects. Therefore, further studies using different doses and experimental protocols should be conducted to enhance evidence about psychedelic substances.

Psilocybin in pharmacotherapy of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a chronic mental disease that affects approximately 2% of the population. Obsessions and compulsions are troublesome for patients and may disturb their everyday activities. The pathogenesis of this disease is still not fully elucidated, but dysfunctions of serotonin-, dopamine- and glutamate-mediated neurotransmission together with early maladaptive schemas seem of importance. Pharmacological treatment includes drugs affecting the serotoninergic, dopaminergic, and glutamatergic systems, such as selective serotonin reuptake inhibitors (SSRIs). Providing that up to 40% of patients with OCD are resistant to the currently available medications, there is a need for novel and effective therapies. Recent discoveries suggest that psilocybin, a non-physically addictive psychoactive substance, may ameliorate disease symptoms. When used in appropriate doses and under strict clinical control, psilocybin appears as a valuable treatment for OCD. This narrative article provides a thorough overview of OCD's etiology, current treatment options, and the emerging evidence supporting psilocybin's efficacy in managing OCD symptoms.

Comparative oral monotherapy of psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, ayahuasca, and escitalopram for depressive symptoms: systematic review and Bayesian network meta-analysis.

OBJECTIVE: To evaluate the comparative effectiveness and acceptability of oral monotherapy using psychedelics and escitalopram in patients with depressive symptoms, considering the potential for overestimated effectiveness due to unsuccessful blinding. DESIGN: Systematic review and Bayesian network meta-analysis. DATA SOURCES: Medline, Cochrane Central Register of Controlled Trials, Embase, PsycINFO, ClinicalTrial.gov, and World Health Organization's International Clinical Trials Registry Platform from database inception to 12 October 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials on psychedelics or escitalopram in adults with depressive symptoms. Eligible randomised controlled trials of psychedelics (3,4-methylenedioxymethamphetamine (known as MDMA), lysergic acid diethylamide (known as LSD), psilocybin, or ayahuasca) required oral monotherapy with no concomitant use of antidepressants. DATA EXTRACTION AND SYNTHESIS: The primary outcome was change in depression, measured by the 17-item Hamilton depression rating scale. The secondary outcomes were all cause discontinuation and severe adverse events. Severe adverse events were those resulting in any of a list of negative health outcomes including, death, admission to hospital, significant or persistent incapacity, congenital birth defect or abnormality, and suicide attempt. Data were pooled using a random effects model within a Bayesian framework. To avoid estimation bias, placebo responses were distinguished between psychedelic and antidepressant trials. RESULTS: Placebo response in psychedelic trials was lower than that in antidepression trials of escitalopram (mean difference -3.90 (95% credible interval -7.10 to -0.96)). Although most psychedelics were better than placebo in psychedelic trials, only high dose psilocybin was better than placebo in antidepression trials of escitalopram (mean difference 6.45 (3.19 to 9.41)). However, the effect size (standardised mean difference) of high dose psilocybin decreased from large (0.88) to small (0.31) when the reference arm changed from placebo response in the psychedelic trials to antidepressant trials. The relative effect of high dose psilocybin was larger than escitalopram at 10 mg (4.66 (95% credible interval 1.36 to 7.74)) and 20 mg (4.69 (1.64 to 7.54)). None of the interventions was associated with higher all cause discontinuation or severe adverse events than the placebo. CONCLUSIONS: Of the available psychedelic treatments for depressive symptoms, patients treated with high dose psilocybin showed better responses than those treated with placebo in the antidepressant trials, but the effect size was small. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42023469014.

"This is you teaching you:" Exploring providers' perspectives on experiential learning and enhancing patient safety and outcomes in ketamine-assisted therapy.

OBJECTIVES: This study explores therapists' perspectives on experiential learning, competencies, and training in ketamine-assisted therapy (KAT), a form of psychedelic-assisted therapy (PAT). We aim to understand how therapists' personal psychedelic experiences influence their self-perceived competency and therapeutic relationships regarding KAT. METHODS: Licensed therapists from Numinus Wellness clinics in Canada and the USA who were trained in KAT were invited to participate in the study. Participation included a 60-90-minute semi-structured interview conducted remotely via secure videoconferencing. The interviews focused on the professional and personal impacts of providing KAT, its mechanisms, and the role of therapists' personal psychedelic experiences in delivering KAT. Data analysis utilized Interpretative Phenomenological Analysis (IPA) and a mix of deductive and inductive coding with Nvivo software. RESULTS: Eight therapists (62.5% female, 37.5% male) were interviewed. All had formal training in KAT, with many also trained in other forms of PAT. All respondents endorsed the value of personal psychedelic experience for deepening understanding of clients' experiences and strengthening the therapeutic alliance. They all also expressed a desire for formal experiential training in KAT, which they viewed as a missing element in their training. Additional themes identified included the importance of relational safety and the therapeutic container, KAT's impact on professional development, competency, and purpose, and navigating risks and challenges in KAT, particularly with complex trauma clients. CONCLUSIONS: Our findings highlight the need for enhanced therapist training and evidence-based standardization of PAT programs that incorporate experiential learning. Such training has the potential to optimize safety and therapeutic outcomes.

Attitudes of European psychiatrists on psychedelics: a cross-sectional survey study.

Research and public interest in psychedelic-assisted psychotherapy (PAP) are growing. This study investigated attitudes toward psychedelics among a diverse and multinational sample of psychiatrists currently working in Europe. We conducted an anonymous, web-based survey consisting of demographic information, a test of basic knowledge on psychedelics, and the previously validated 20-item Attitudes on Psychedelics Questionnaire (APQ), which was validated for the first time in English within this sample. We included N = 419 participants from 33 countries in the study. One-third of participants (34%) reported past use of psychedelics. The APQ sub-scale with the highest score was Openness to Psychedelics, while Risk Assessment of Psychedelics was rated lowest. Regression modelling, explaining 31.3% of variance in APQ scores, showed that younger male psychiatrists who identified as spiritual, were better at recognizing and classifying substances as psychedelics and had previously used psychedelics had more positive attitudes on psychedelics. No professional variables besides self-reported previous experience with PAP or psychedelic research predicted APQ scores. European psychiatrists, therefore, show a general openness to psychedelics and PAP, but are concerned by the potential risks associated with them. Our findings overall suggest that psychedelics are a subject where it is difficult to remain impartial. Protocol registration: The study was pre-registered at the Open Science Framework (available online at https://osf.io/upkv3 ).

Expert opinions on implementation of MDMA-assisted therapy in Europe: critical appraisal towards training, clinical practice, and regulation.

Introduction: The positive results of MDMA from Phase 2 and 3 clinical trials in MDMA-assisted therapy (MDMA-AT) for the treatment of post-traumatic stress disorder (PTSD) call for a critical evaluation of its regulatory status within the European mental healthcare system. This is driven by the recent submission of MDMA-AT for FDA approval in the United States. Unless coordinated efforts in the European regulatory landscape start, there may be potential divergences in national regulatory strategies. Gaining insights from researchers and clinicians involved in the application of MDMA-AT may be useful in guiding the discussion of factors involved in its implementation.Method: A comprehensive invitation-only survey was sent to researchers and clinicians involved in MDMA-AT clinical trials and contributors to the scientific literature on MDMA-AT from around the globe. This study aimed to collect opinions on clinical practices, training, and regulation worldwide, examining the global best practices and pitfalls to outline strategies for possible European implementation of MDMA-AT.Results: The survey, which included responses from 68 experts, yielded a range of opinions where a large majority endorsed the need for training and standardization, emphasizing equity and access, stressing impediments in the national approval processes, and reflecting critically on anticipated spill-over effects of MDMA-AT in clinical settings.Conclusion: The experts highlight the need for science-informed policy development, active regulatory involvement, and international cooperation to incorporate MDMA-AT into the European mental healthcare system in general and the treatment of PTSD in particular. The study emphasizes the importance of ongoing research, open professional discourse, and collaborative engagement to facilitate MDMA-AT's ethical and effective implementation.

Positive clinical trials of therapy using MDMA for treating post-traumatic stress disorder (PTSD) call for a thorough review of its regulatory status in Europe, especially following its submission for approval in the United States.A global survey of 68 researchers and clinicians underscores the necessity for standardized training, equitable access, and streamlined national approval processes for MDMA therapy, highlighting potential clinical benefits and challenges.Experts emphasize the importance of science-based policies, international cooperation, and continuous research to effectively integrate MDMA therapy into European mental healthcare for PTSD treatment.

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.

Psychotropic Drugs Reemerging as Headache Medicines.

Scientific and public attention on the therapeutic effects of psychedelics and other psychoactive compounds in headache disorders has recently grown. The use and reported therapeutic effects of such treatments have long been reported, though formal clinical trials are only recently taking place. When considering how these substances might be further studied and eventually applied, it is important to consider the specific headache disorder, the particular drug, and the mode of use. No singular protocol will be applicable across all headache disorders and drugs. In this leading article, the nuance required to consider the value of classic psychedelics, ketamine, and cannabinoids as headache medicines is presented.

Interrupting the Psychedelic Experience Through Contextual Manipulation to Study Experience Efficacy.

This quality improvement study investigates the association of interruptions during psychedelic therapy with ratings of intensity of experience.

New and emerging treatments for major depressive disorder.

Major depressive disorder (MDD) affects a substantial portion of the population; however, much is still unknown about the pathophysiology of this disorder. Treatment resistance highlights the heterogeneous nature of MDD and the need for treatments to target more than monoamine neurotransmission. This review summarizes research into the new and emerging targets of MDD. These include drugs such as psychedelics, antibiotics, opioid modulators, neuropeptides, and onabotulinumtoxin. Neuromodulatory treatments such as light based therapies and neuromodulation involving either magnetic or electrical stimulation are also discussed. Almost all interventions, pharmacological and neuromodulation, were trialed as adjunctive treatments to an antidepressant. Most research has been conducted on psychedelics, with trials suggesting rapid antidepressant and anti-suicidal effects. Trial findings, tolerability, study design limitations and quality of research have been considered throughout this review. There remains challenges in forming recommendations with the current research at present. With there being considerable interest into the research of new and emerging treatments-in particular, psychedelics-there may be scope in the future to form more robust recommendations.

Psilocybin fungi microdose treatment in major depressive disorder: a case report / Tratamiento con microdosis de hongos con psilocibina en trastorno depresivo mayor: reporte de un caso.

Major depression disorder is an entity with high prevalence and worldwide impact. Current treatments present a non-response rate of 15-30%, and certain adverse effects are seen like apathy syndrome and lack of emotional response. It is stated that the treatment with psilocybin fungi allows the possibility of dose reduction and suspension of classic psychotropic drugs and entails changes on an emotional and behavioral level that result benefic in patients with major depressive syndrome. We present a case of a 19 years old patient with major depressive syndrome diagnosis. Accompaniment and patient advice was made appealing to the right of autonomy, on the psilocybin microdose self-administration process, aiming to reducing health risks and potentiate probable beneficial effects, with weekly evaluations, for a period of 7 months; using clinical anamnesis, laboratory tests and the Hamilton depression scale. As a result of this intervention, a symptomatic complete remission was proven, alongside with the suspension of conventional pharmacological treatment without discontinuation symptoms and improvements at the communicational level, social interaction and general well-being. These findings support the idea that psilocybin microdose treatments are promising tools in depression treatments. Scientific studies are needed in order to certify these findings.

La depresión mayor es una enfermedad de gran prevalencia e impacto mundial. Los tratamientos actuales presentan una tasa de no respuesta del 15 al 30 %, mientras que en casos de eficacia se suelen observar efectos adversos como el síndrome de apatía y la falta de respuesta emocional. Se postula que el tratamiento con hongos psilocibios genera la posibilidad de reducción de dosis y suspensión de psicofármacos clásicos y ocasiona cambios a nivel emocional y comportamental benéficos en pacientes con trastorno depresivo mayor. Este es un caso de un paciente no binario de 19 años de edad con diagnóstico de trastorno depresivo mayor. Se realizó unacompañamiento y asesoramiento del paciente apelando al derecho de autonomía, en el proceso de autoadministración de microdosis de psilocibina, para disminución de riesgos en salud y potenciar efectos benéficos probables, con evaluación semanal, durante un periodo de 7 meses; utilizando la anamnesis clínica, análisis de laboratorio y la escala validada de depresión de Hamilton. Como resultado de esta intervención se evidenció una remisión completa sintomática, la suspensión del tratamiento farmacológico convencional, sin síntomas de discontinuación y mejorías a nivel comunicacional, de interacción social y bienestar general. Estos hallazgos apoyan la idea de que los tratamientos con microdosis de psilocibina son una herramienta prometedora en los tratamientos de depresión. Se necesitan más estudios que aporten evidencia científica para comprobar dichos hallazgos.