Beyond the numbers: reimagining healing with psychedelics for eating disorders.

Psychedelic medicine is currently being evaluated for numerous mental health indications, and there is significant interest in applying these models of care to eating disorders (EDs) given the limited efficacy of available treatment models, especially for those living with anorexia nervosa. Preliminary findings across a number of studies suggest promise. In this commentary, researchers with experience in psychedelics and EDs present a rationale and considerations for the application of psychedelic medicine, including psychedelic-assisted therapy (PAT) for EDs. These contributions are informed by those with lived experience as well as the authors' experiences in the field. By addressing underlying psychological and transpersonal factors and improving treatment engagement, psychedelic medicine, though not without risks, may offer a valuable adjunct to existing treatments, enhancing overall outcomes for some living with an ED. This commentary also aims to provide a multi-dimensional perspective to inform the field, including with respect to the etiology of these illnesses, as psychedelic medicine becomes more accessible in naturalistic, research and clinical settings.

Impact of psilocybin on cognitive function: A systematic review.

Psilocybin is a classic psychedelic with demonstrated preliminary clinical efficacy in a range of psychiatric disorders. Evaluating the impact of psilocybin on cognitive function is essential to unravel its potential benefits and risks. In this systematic review, we assessed psilocybin's effect on cognitive function through a comprehensive search of electronic databases from inception to January 2024, identifying 20 articles involving 2,959 participants. While 85% of studies were conducted in healthy volunteers, most of these studies (85%) used macrodoses, ranging from 45 µg/kg to 30 mg/70 kg. Various cognitive aspects were evaluated and yielded mixed results. Global cognitive function, and processing speed remained mostly unchanged in healthy individuals; However, a limited number of studies reported improvements in certain areas such as sustained attention, working memory, and executive function especially in patients with treatment-resistant depression (TRD). Emotional processing was positively modified, particularly in TRD patients. Psilocybin was observed to enhance emotional empathy without significantly altering cognitive empathy and social cognition. Cognitive flexibility and creative cognition were noted to initially decline but could potentially improve over time. Additionally, with respect to learning and memory skills, psilocybin showed promise in improving specific memory types such as semantic associations and associative learning, while its effects on episodic and verbal memory have been less pronounced compared to other cognitive enhancers. The observed mixed findings underscore the complexity of psilocybin's cognitive influence. Further research is essential to provide a clearer understanding of psilocybin's impact on cognitive domains and to guide the development of safe and effective interventions.

A Cross-Sectional Survey Investigating Maori and Non-Maori Cancer Patients' Views on Psychedelic-Assisted Therapy in Aotearoa New Zealand.

People with cancer experience higher rates of psychological dysfunction than the general population, with extreme inequity among indigenous people. Psychedelic-assisted therapy (PAT) is a reemerging area with promising evidence as a treatment for mental health difficulties. The current study aimed to investigate the perceptions of PAT in indigenous (Maori) and non-indigenous cancer patients in Aotearoa, New Zealand. Eighty-five cancer patients (Maori n = 32, non-Maori n = 53) completed a brief anonymous survey assessing demographics, psychological factors, and awareness and perceptions of PAT. Participants were recruited online (via social media and cancer support e-mail lists) and in person at Auckland City Hospital. Maori had significantly poorer psychological well-being than non-Maori. All participants had low awareness of this novel treatment and held largely neutral attitudes. Regression analyses revealed that predictors of more favorable attitudes toward PAT included greater awareness of psychedelics, advanced cancer stage, younger age, poorer holistic well-being, greater demoralization, and prioritizing treatment effectiveness over possible risks and uncertainty. The current study provides a foundational step in exploring perceptions toward PAT in indigenous and non-indigenous groups. These results have the potential to shape future research trials investigating PAT and further highlight the importance of indigenous involvement in the psychedelic research space.

Multimodal creativity assessments following acute and sustained microdosing of lysergic acid diethylamide.

INTRODUCTION: Enhanced creativity is often cited as an effect of microdosing (taking repeated low doses of a psychedelic drug). There have been recent efforts to validate the reported effects of microdosing, however creativity remains a difficult construct to quantify. OBJECTIVES: The current study aimed to assess microdosing's effects on creativity using a multimodal battery of tests as part of a randomised controlled trial of microdosing lysergic acid diethylamide (LSD). METHODS: Eighty healthy adult males were given 10 µg doses of LSD or placebo every third day for six weeks (14 total doses). Creativity tasks were administered at a drug-free baseline session, at a first dosing session during the acute phase of the drug's effects, and in a drug-free final session following the six-week microdosing regimen. Creativity tasks were the Alternate Uses Test (AUT), Remote Associates Task (RAT), Consensual Assessment Technique (CAT), and an Everyday Problem-Solving Questionnaire (EPSQ). RESULTS: No effect of drug by time was found on the AUT, RAT, CAT, or EPSQ. Baseline vocabulary skill had a significant effect on AUT and RAT scores. CONCLUSIONS: Despite participants reporting feeling more creative on dose days, objective measurement found no acute or durable effects of the microdosing protocol on creativity. Possible explanations of these null findings are that laboratory testing conditions may negatively affect ability to detect naturalistic differences in creative performance, the tests available do not capture the facets of creativity that are anecdotally affected by microdosing, or that reported enhancements of creativity are placebo effects.

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.

Psychedelics as a tool for a more connected and sustainable world? Considering the importance of rituals, boundaries, and commitment.

Despite the surge of interest in psychedelic research in the past decade, largely due to the promise of psychedelics for improving mental health outcomes, there has been comparatively little discussion about the social and environmental consequences of psychedelic drug use. While there is growing evidence to suggest psychedelics could foster a greater connection to the natural world and improve social relationships, such positive repercussions are far from guaranteed. In this commentary, we focus on LSD, psilocybin and especially MDMA, and outline three insights we came to see as crucial to creating beneficial outcomes: 1) the importance of setting and rituals, 2) the establishment of boundaries, and 3) understanding the long-term commitment required. These insights are grounded in the history of psychedelics, which is intimately intertwined with ritualised use, yet the process of commercialisation of these substances threatens to strip away important contextual factors. Creating boundaries around when, how and with whom psychedelics are used have been found to protect recreational users from harm and could also be instrumental in steering commercial interests to align with socio-environmental goals. Finally, far from being a 'quick fix' for social or environmental problems, the use of psychedelics requires sustained engagement to integrate the insights obtained. Whereas we remain optimistic about the transformative potential of psychedelics for social relationships and the environment, we also emphasise the need for a more cautious, considered approach if we are to harness the benefits and minimise the challenges of psychedelic drug use.

Psychoactive substances for the treatment of neuropsychiatric disorders.

In the contemporary landscape of psychiatric medicine, critical advancements have been noted in the utilization of psychoactive substances such as hallucinogens, 3,4-methylenedioxymethamphetamine (MDMA), and ketamine for the treatment of severe mental health disorders. This review provides a detailed evaluation of these substances, focusing on their mechanisms of action and the profound clinical outcomes observed in controlled environments. Hallucinogens like lysergic acid diethylamide and psilocybin primarily target the 5-HT2A receptor agonist-2 (5-HT2AR), inducing substantial perceptual and cognitive shifts that facilitate deep psychological introspection and significant therapeutic advances, particularly in patients suffering from depression and anxiety disorders. MDMA, influencing multiple neurotransmitter systems including 5-Hydroxytryptamine (5-HT), dopamine, and norepinephrine, has been demonstrated to effectively alleviate symptoms of post-traumatic stress disorder, enhancing patients' emotional engagement and resilience during psychotherapy. Meanwhile, ketamine, a glutamate receptor antagonist, rapidly alleviates depressive symptoms, offering a lifeline for individuals with treatment-resistant depression through its fast-acting antidepressant properties. The integration of these substances into psychiatric practice has shown promising results, fundamentally changing the therapeutic landscape for patients unresponsive to traditional treatment modalities. However, the potent effects of these agents also necessitate a cautious approach in clinical application, ensuring careful dosage control, monitoring, and risk management to prevent potential abuse and mitigate adverse effects.

Antidepressant and anxiolytic effects of activating 5HT2A receptors in the anterior cingulate cortex and the theoretical mechanisms underlying them - A scoping review of available literature.

Psychedelic drugs that activate the 5HT2A receptor have long been the target of extensive clinical research, particularly in models of psychiatric illness. The aim of this literature review was to investigate the therapeutic effects of 5HT2A receptor activation in the anterior cingulate cortex (ACC) and the respective mechanisms that underlie them. Based on the available research, I suggest that 5HT2A receptors in the ACC exert profound changes in excitatory neurotransmission and brain network connectivity in a way that reduces anxious preoccupation and obsessional thoughts, as well as promoting cognitive flexibility and long-lasting mood improvements in anhedonia. This is possibly due to a complex interplay with glutamate and gamma-butyric acid neurotransmission, particularly 5HT2A activation enhances α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor signalling, thus altering the ratio of AMPA to N-methyl-D-Aspartate (NMDA) activity in the ACC, which can dismantle previously established neuronal connections and aid the formation of new ones, an effect that may be beneficial for fear extinction and reversal learning. Psychedelics potentially change intra- and internetwork connectivity, strengthening connectivity from the dorsal ACC / Salience Network to the Default Mode Network (DMN) and Central Executive Network (CEN), which correlates with improvements in attentional shifting and anti-anhedonic effects. Additionally, they may decrease inhibitory influence of the DMN over the CEN which may reduce overevaluation of internal states and ameliorate cognitive deficits. Activation of ACC 5HT2A receptors also has important downstream effects on subcortical areas, including reducing amygdala reactivity to threatening stimuli and enhancing mesolimbic dopamine, respectively improving anxiety and the experience of natural rewards.

Neurobiological research on N,N-dimethyltryptamine (DMT) and its potentiation by monoamine oxidase (MAO) inhibition: from ayahuasca to synthetic combinations of DMT and MAO inhibitors.

The potent hallucinogen N,N-dimethyltryptamine (DMT) has garnered significant interest in recent years due to its profound effects on consciousness and its therapeutic psychopotential. DMT is an integral (but not exclusive) psychoactive alkaloid in the Amazonian plant-based brew ayahuasca, in which admixture of several ß-carboline monoamine oxidase A (MAO-A) inhibitors potentiate the activity of oral DMT, while possibly contributing in other respects to the complex psychopharmacology of ayahuasca. Irrespective of the route of administration, DMT alters perception, mood, and cognition, presumably through agonism at serotonin (5-HT) 1A/2A/2C receptors in brain, with additional actions at other receptor types possibly contributing to its overall psychoactive effects. Due to rapid first pass metabolism, DMT is nearly inactive orally, but co-administration with ß-carbolines or synthetic MAO-A inhibitors (MAOIs) greatly increase its bioavailability and duration of action. The synergistic effects of DMT and MAOIs in ayahuasca or synthetic formulations may promote neuroplasticity, which presumably underlies their promising therapeutic efficacy in clinical trials for neuropsychiatric disorders, including depression, addiction, and post-traumatic stress disorder. Advances in neuroimaging techniques are elucidating the neural correlates of DMT-induced altered states of consciousness, revealing alterations in brain activity, functional connectivity, and network dynamics. In this comprehensive narrative review, we present a synthesis of current knowledge on the pharmacology and neuroscience of DMT, ß-carbolines, and ayahuasca, which should inform future research aiming to harness their full therapeutic potential.

A bibliometric analysis of research on psychedelics for depression treatment.

Psychedelics, as a class of potent psychoactive substances, significantly alter sensory perception and mood, thereby profoundly impacting cognition. Increasing evidence indicates that psychedelics can facilitate individual social function and rapidly and sustainably improve symptoms of moderate and severe depression. The growing interest in psychedelics as potential treatments for depression has led to a substantial increase in related publications; however, the overall quantity and quality of these works remain unclear. To address this issue, we conducted a bibliometric analysis of literature on psychedelic drugs for depression published between 2004 and October 2023. Our study meticulously collected 710 publications, allowing for a comprehensive analysis of bibliographic elements such as annual publication trends, authorship, country of origin, institutional affiliations, journals, and keywords. By visualizing trends, emerging frontiers, popular topics, author collaborations, and influential factors in the field of psychedelics for depression, we have enhanced our understanding of advancements in this area. On this basis, we assert that the regulation of psychedelic drugs is necessary, but it should not hinder the scientific research progress.

Single-dose 1cp-LSD administration for canine anxiety: a pilot study.

Anxiety affects 14-20% of dogs. Pharmacological treatments often fail. Psychedelics have shown to be useful for anxiety and depression in humans, but their veterinary use remains unexplored. We aimed to determine the effects of low-dose 1-cyclopropionyl-d-lysergic acid diethylamide (1cp-LSD) administered in a single dose to a dog, to observe the effect and establish the safety of the substance. The patient was a 13-year-old female dog, weighing 13 kg, mixed breed, and spayed. A total of 5 µg was administered orally, equivalent to 0.38 µg/kg. The animal has had a history of separation related behavioral problems throughout her life. To objectively assess the degree of anxiety in the dog, a validated scale was utilized. The trial was scheduled at the house where the animal lives. The owner was present throughout the experience. Informed consent was obtained prior to the assay. The trial began at 12:15 p.m. on January 10, 2024, lasting for 5 and a half hours. The response to anxiety-inducing stimuli was equally anxious during the first two hours. From that point onwards, a significant change in the animal's behavior was observed, with no signs/mild signs of anxiety. The trial concluded without any adverse effects on the animal. The patient did not show signs of having a psychedelic experience. This is the first time that a study of this nature has been conducted and reported in the canine species. 1cp-LSD proved to be safe and exerted the desired effect on the animal's behavior, significantly reducing the patient's anxiety.

Psychedelic mushroom-containing chocolate exposures: Case series.

INTRODUCTION: The recreational use of psilocybin or psilocin-containing products, a chemical found naturally in certain mushroom species, is on the rise across the United States. Several cases of serious clinical effects related to mushroom-containing products have recently been reported to the Food and Drug Administration (FDA). The emergence of these new products and their health consequences are not yet well understood. This case series aims to characterize exposures to mushroom-containing chocolate products, including patient characteristics, clinical effects, treatment(s), and clinical outcome severity, reported to a poison center network. MATERIAL AND METHODS: This was a retrospective case series conducted in patients exposed to mushroom-containing chocolate products across three poison centers between January 2023 to August 2024. Patients were identified via a database search of ToxSentry®. Patients were included if they were exposed to a mushroom-containing chocolate product. Patients were excluded if they ingested an unrelated product or if there was insufficient information documented within ToxSentry®. The primary endpoint was to describe clinical outcome severity after exposure to mushroom-containing chocolate products. RESULTS: A query of ToxSentry® identified 164 cases; 36 cases met study criteria. The median age of patients in this case series was 17 years old. For most patients (23, 64 %), the reason for the exposure was intentional, with 20 reporting intentional abuse or misuse of the product. Common clinical effects reported included mental status changes (26, 76 %), paranoia/hallucinations (10, 28 %), dysrhythmias (7, 19 %) and gastrointestinal discomfort (6, 17 %). There was one report of seizure. Most clinical effects lasted between 3 and 24 h after ingestion (29, 81 %). Intravenous fluids (18, 50 %) and benzodiazepines (7, 19 %) were the most common treatments given. No fatalities were reported. DISCUSSION: While most patients in this series experienced minor clinical effects, some developed serious effects after ingestion of a mushroom-containing chocolate product. Findings from this study further characterize the limited patient demographics, clinical effects, and outcomes published thus far. Further characterization in a larger cohort of patients could expand on our initial findings and is needed to better identify factors that may influence clinical outcomes.

Less is more? A review of psilocybin microdosing.

BACKGROUND: The applications of psilocybin, derived from 'magic mushrooms,' are vast, including a burgeoning practice known as microdosing, which refers to the administration of sub-hallucinogenic doses of psychedelic substances to obtain benefits without experiencing significant cognitive and perceptual distortion. However, current research is fairly new with several limitations and gaps that hinder adequate conclusions on its efficacy. AIMS: This semi-structured review aimed to identify and highlight research gaps in the field of psilocybin microdosing for future research. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses based strategy was employed, utilizing a chain of keywords and key phrases across multiple databases, augmented by a cross-sectional Google search for relevant grey literature in the form of the top 10 search results. A total of 40 studies and 8 unique websites were identified, summarized and tabulated into four distinct categories, namely non-clinical, clinical, observational and anecdotal evidence. RESULTS: The majority of available evidence originates from observational studies, while non-clinical and clinical study findings remain comparatively sparse and inconsistent. Web-based findings were consistent with current research findings. Key research gaps were highlighted: the imperative for more randomized placebo-controlled trials, exploration of dose-response ranges, psychological and personality testing of participants, utilization of active placebos, greater diversity in study populations, an increase in psilocybin-exclusive microdosing studies and the refinement of animal models. CONCLUSION: Definitive conclusions regarding the efficacy of psilocybin microdosing remain elusive, emphasizing the need for further study. Numerous research gaps necessitate consideration for future investigations.

Lost in translation? Qualitative interviews with Australian psychedelic-assisted therapy trial clinicians.

BACKGROUND: Policy changes in Australia mean that psychedelic-assisted therapy (PAT) is now available to consumers outside of clinical trials. Yet, the regulatory frameworks guiding the practice of PAT are underdeveloped, and the evidence base for guiding clinical practice is diverse and emerging, resulting in anticipated challenges in translation to community practice. Mental health clinicians who have experience delivering PAT in clinical trials are likely to be at the forefront of community practice and training, and influential in discussions about implementation. Yet little is known of their perspectives, preferences, and practices associated with the implementation of PAT. METHOD: Interviews with 11 clinicians working on clinical trials of PAT were thematically analysed. RESULTS: Four themes were identified, describing the therapeutic frames that interviewees used to understand PAT and shaped their views on its interface with the mental health system: (1) therapeutic eclecticism, (2) enhanced reflexivity for PAT providers, (3) legitimisation of extra-medical perspectives in mental health, and (4) what might be lost in translation? CONCLUSION: We argue that clinicians' perspectives on PAT are reflective of existing tensions between a medical model of mental health care and other psychosocial, relational models. Therapists' ideals for the delivery of PAT can be conceptualised as a sort of 'enhanced care' approach, but workforce development and economic constraints are likely to challenge the accessible and impactful translation of this vision.

Can Psychedelic Use Benefit Meditation Practice? Examining Individual, Psychedelic, and Meditation-Related Factors.

Introduction: Meditation practice and psychedelic use have attracted increasing attention in the public sphere and scientific research. Both methods induce non-ordinary states of consciousness that may have significant therapeutic benefits. Thus, there is growing scientific interest in potential synergies between psychedelic use and meditation practice with some research suggesting that psychedelics may benefit meditation practice. The present study examined individual, psychedelic-related, and meditation-related factors to determine under what conditions meditators perceive psychedelic use as beneficial for their meditation practice. Method: Participants (N = 863) who had reported psychedelic use and a regular meditation practice (at least 3 times per week during the last 12 months) were included in the study. To accommodate a large number of variables, machine learning (i.e., elastic net, random forest) was used to analyze the data. Results: Most participants (n = 634, 73.5%) found psychedelic use to have a positive influence on their quality of meditation. Twenty-eight variables showed significant zero-order associations with perceived benefits even following a correction. Elastic net had the best performance (R2 = .266) and was used to identify the most important features. Across 53 variables, the model found that greater use of psychedelics, intention setting during psychedelic use, agreeableness, and exposure to N,N-Dimethyltryptamine (N,N-DMT) were most likely to be associated with the perception that psychedelics benefit meditation practice. The results were consistent across several different approaches used to identify the most important variables (i.e., Shapley values, feature ablation). Discussion: Results suggest that most meditators found psychedelic use to have a positive influence on their meditation practice, with: 1) regularity of psychedelic use, 2) the setting of intentions for psychedelic use, 3) having an agreeable personality, and 4) reported use of N,N-DMT being the most likely predictors of perceiving psychedelic use as beneficial. Longitudinal designs and randomized trials manipulating psychedelic use are needed to establish causality.

Refractory CRPS pain treated with psilocybin: A case report.

Psilocybin shows promise as a treatment for CRPS, offering significant pain relief and functional improvement in a patient with refractory symptoms. This case highlights the need for further research into psilocybin's efficacy and optimal dosing for chronic pain management.

MDMA for treatment of PTSD and neurorehabilitation in military populations.

BACKGROUND: Neurorehabilitation in military populations is complicated by higher rates of PTSD and unique characteristics of military institutions. These factors can adversely impact the patient-therapist therapeutic alliance and engagement with the rehabilitation process leading to poorer outcomes. MDMA is a non-classical psychedelic with pro-social and fear regulating properties. MDMA-assisted therapy is being explored as a novel treatment for PTSD that potentially offers rapid symptom improvement and enhances therapeutic alliance. OBJECTIVE: A review of MDMA-assisted therapy for PTSD is provided in the context of neurorehabilitation in military populations. The molecular mechanism of MDMA is outlined and a novel application of MDMA for neurorehabilitation is proposed. METHODS: This is an expert review and synthesis of the literature. RESULTS: Results from late-stage clinical trials suggest MDMA-assisted therapy for PTSD would be of particular benefit for military populations with PTSD. The unique pro-social properties of MDMA could be leveraged to enhance the therapeutic alliance and patient engagement during neurorehabilitation. CONCLUSION: The unique qualities and benefits of MDMA and MDMA-assisted therapy for PTSD suggest relevant application in military personnel undergoing neurorehabilitation. There are many similarities in patient-therapist dynamics in PTSD treatment and neurorehabilitation. The properties of MDMA which enhance therapeutic alliance, downregulate fear, and increase cognitive flexibility would potentially benefit both military personnel with and without PTSD undergoing neurorehabilitation.

Validation of the imperial psychedelic predictor scale.

BACKGROUND: Access to psychedelic drugs is liberalizing, yet responses are highly unpredictable. It is therefore imperative that we improve our ability to predict the nature of the acute psychedelic experience to improve safety and optimize potential therapeutic outcomes. This study sought to validate the 'Imperial Psychedelic Predictor Scale' (IPPS), a short, widely applicable, prospective measure intended to be predictive of salient dimensions of the psychedelic experience. METHODS: Using four independent datasets in which the IPPS was completed prospectively - two online surveys of 'naturalistic' use (N = 741, N = 836) and two controlled administration datasets (N = 30, N = 28) - we conducted factor analysis, regression, and correlation analyses to assess the construct, predictive, and convergent validity of the IPPS. RESULTS: Our approach produced a 9-item scale with good internal consistency (Cronbach's α = 0.8) containing three factors: set, rapport, and intention. The IPPS was significantly predictive of 'mystical', 'challenging', and 'emotional breakthrough' experiences. In a controlled administration dataset (N = 28), multiple regression found set and rapport explaining 40% of variance in mystical experience, and simple regression found set explained 16% of variance in challenging experience. In another (N = 30), rapport was related to emotional breakthrough explaining 9% of variance. CONCLUSIONS: Together, these data suggest that the IPPS is predictive of relevant acute features of the psychedelic experience in a broad range of contexts. We hope that this brief 9-item scale will be widely adopted for improved knowledge of psychedelic preparedness in controlled settings and beyond.

Single-dose psilocybin for U.S. military Veterans with severe treatment-resistant depression - A first-in-kind open-label pilot study.

BACKGROUND: The enduring and severe depression often suffered by Veterans causes immense suffering and is associated with high rates of suicide and disability. This is the first study to evaluate the efficacy and safety of psilocybin in Veterans with severe treatment-resistant depression (TRD). METHODS: 15 Veterans with severe TRD (major depressive episode failing to respond to ≥5 treatments, or lasting >2 years) received 25 mg of psilocybin. Primary outcome was change in Montgomery-Åsberg Depression Rating scale (MADRS) at 3 weeks posttreatment. Response was defined s ≥ 50 % reduction in MADRS, and remission as ≤10 MADRS score. Psychedelic experience was assessed using the Five-Dimensional Altered States of Consciousness scale (5D-ASC). Safety measures included assessment of suicidality and adverse events. Participants on antidepressants were tapered to avoid drug interactions. RESULTS: Of 15 participants, 60 % met response and 53 % met remission criteria at Week 3. At 12 weeks, 47 % maintained response, and 40 % remission. Co-morbid PTSD did not significantly influence study outcomes. The psychedelic experience reported in 5D-ASC did not correlate with response. Participants judged to need antidepressants were restarted and considered non-responders from that timepoint (n = 4). No unexpected adverse events occurred. LIMITATIONS: Limitations include the small sample size, and the uncontrolled and unblinded nature of the study. CONCLUSIONS: In this first study on psilocybin for Veterans with severe TRD, a surprising response and remission was seen. Many Veterans had PTSD though no moderating impact of response was observed. The degree of psychedelic experience did not correlate with depression changes. Further study is warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04433858.