Psychedelic Therapy Research Articles

5-MeO-DMT for post-traumatic stress disorder: a real-world longitudinal case study

Psychedelic therapy is, arguably, the next frontier in psychiatry. It offers a radical alternative to longstanding, mainstays of treatment, while exciting a paradigm shift in translational science and drug discovery. There is particular interest in 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)—a serotonergic psychedelic—as a novel, fast-acting therapeutic. Yet, few studies have directly examined 5-MeO-DMT for trauma- or stress-related psychopathology, including post-traumatic stress disorder (PTSD). Herein, we present the first longitudinal case study on 5-MeO-DMT for chronic refractory PTSD, in a 23-year-old female. A single dose of vaporized bufotoxin of the Sonoran Desert Toad (Incilius alvarius), containing an estimated 10−15 mg of 5-MeO-DMT, led to clinically significant improvements in PTSD, with next-day effects. This was accompanied by marked reductions in hopelessness and related suicide risk. Improvements, across all constructs, were sustained at 1-, 3-, 6-, and 12-months follow-up, as monitored by a supporting clinician. The subject further endorsed a complete mystical experience, hypothesized to underly 5-MeO-DMT’s therapeutic activity. No drug-related, serious adverse events occurred. Together, results showed that 5-MeO-DMT was generally tolerable, safe to administer, and effective for PTSD; however, this was not without risk. The subject reported acute nausea, overwhelming subjective effects, and late onset of night terrors. Further research is warranted to replicate and extend these findings, which are inherently limited, non-generalizable, and rely on methods not clinically accepted.

Psychedelia: The interplay of music and psychedelics.

Music and psychedelics have been intertwined throughout the existence of Homo sapiens, from the early shamanic rituals of the Americas and Africa to the modern use of psychedelic-assisted therapy for a variety of mental health conditions. Across such settings, music has been highly prized for its ability to guide the psychedelic experience. Here, we examine the interplay between music and psychedelics, starting by describing their association with the brain's functional hierarchy that is relied upon for music perception and its psychedelic-induced manipulation, as well as an exploration of the limited research on their mechanistic neural overlap. We explore music's role in Western psychedelic therapy and the use of music in indigenous psychedelic rituals, with a specific focus on ayahuasca and the Santo Daime Church. Furthermore, we explore work relating to the evolution and onset of music and psychedelic use. Finally, we consider music's potential to lead to altered states of consciousness in the absence of psychedelics as well as the development of psychedelic music. Here, we provide an overview of several perspectives on the interaction between psychedelic use and music-a topic with growing interest given increasing excitement relating to the therapeutic efficacy of psychedelic interventions.

Assessment of the acute subjective psychedelic experience: A review of patient-reported outcome measures in clinical research on classical psychedelics.

The classical psychedelics psilocybin, peyote, ayahuasca/ N, N-dimethyltryptamine, and lysergic acid diethylamide can temporarily produce altered states of consciousness, characterized by changes in sensory perception, thought, mood, and the sense of self-reality and meaning. It is important to have reliable instruments for quantifying these altered states in trials, due to a plausible link between the acute subjective experience and treatment outcome. We conducted a review of outcome measures applied in research on classical psychedelics to assess one or more dimensions of the acute subjective psychedelic experience. Three relevant databases were searched electronically. Two reviewers independently conducted article selection and data extraction regarding the instruments, dimensions, geography, population, and psychedelic substance investigated in the included studies. We identified the five most utilized instruments for the most recent 6 years, as well as the five most utilized instruments for each psychedelic. We included 93 papers, which reported on 93 unique trials and utilized 17 different rating scales. Of these, the most utilized were the Five-Dimensional Altered States of Consciousness Questionnaire, visual analog or Likert scales specially developed for the trials, the Hallucinogen Rating Scale, the States of Consciousness Questionnaire, and the Abnormer Psychischer Zustand. Considerable variability was found in the instruments utilized in clinical trials on classical psychedelics. We advise and encourage the development of a core outcome set for psychedelic research to enable altered state comparisons across compounds, participants, and settings. We further advise that instruments be designed to assess the "setting" of a psychedelic experience.

When the Trial Ends: The Case for Post-Trial Provisions in Clinical Psychedelic Research

The ethical value—and to some scholars, necessity—of providing trial patients with post-trial access (PTA) to an investigational drug has been subject to significant attention in the field of research ethics. Although no consensus has emerged, it seems clear that, in some trial contexts, various factors make PTA particularly appropriate. We outline the atypical aspects of psychedelic clinical trials that support the case for introducing the provision of PTA within research in this field, including the broader legal status of psychedelics, the nature of the researcher-therapist/participant relationship, and the extended time-frame of the full therapeutic process. As is increasingly understood, the efficacy of psychedelic-assisted psychotherapy is driven as much by extrapharmacological elements and the cultural therapeutic container as by the drug itself. As such, we also advocate for a refocusing of attention from post-trial access to a broader concept encompassing other elements of post-trial care. We provide an overview of some of the potential post-trial care provisions that may be appropriate in psychedelic clinical trials. Although the World Medical Association’s Declaration of Helsinki calls on researchers, sponsors, and governments to make provisions for post-trial access, such provision may feel impracticable or out-of-reach within psychedelic trials that are already constrained by a high resource demand and significant bureaucratic burden. We show how conceiving of post-trial provision as an integral site of the research process, and an appropriate destination for research funding, will serve to develop the infrastructure necessary for the post-legalisation psychedelic medicine ecosystem.

The Bad Seed: Mystical Experience and Time Travel in the Treatment of Psychopathy

ABSTRACT Psychopathy has long been considered untreatable. The purpose of this paper is to provide a report from the field on therapeutic gains made in the case of a psychopathic personality and to outline what appear to be the most effective aspects of the treatment, as well as to help integrate current psychedelic research and theory with psychoanalytic theory. These therapeutic factors include: tactful acknowledgment and confrontation of the patient’s behavior and the disclosure to him of the diagnosis of psychopathy; a focus on his resentment toward existence itself; the cultivation of a relationship between the patient and his future self through the engagement of his imagination using mental time travel; the patient’s psilocybin-induced mystical experience which occurred several months into treatment; and finally, the impact of the analyst’s spiritual work that shaped the countertransference. The patient made dramatic improvements subsequent to his mystical experience, and was able to make use of the psychoanalytic work done during the “pre-mystical experience” period of his treatment. This case is an addition to the accumulating evidence for the efficacy of psychedelic-induced mystical experiences, and provides guidance on the provision of psychoanalytic treatment prior to treatment with psychedelic medication.

Psychedelic Crystals in Cinema: Opening Virtual Dimensions and Potential Healing

This article proposes a different aesthetic state of Gilles Deleuze’s crystal-image defined as ‘psychedelic crystal’, a formation of the crystalline regime in light of the contemporary revival of scientific research exploring the healing potentialities of hallucinogenic drugs. The proposition of the psychedelic crystal occurs between Deleuze’s crystals of time, the therapeutic dimension of psychedelics, and Siegfried Kracauer’s concept of redemption (as salvation) through the cinematic medium. What lies in the middle of this encounter is a shared understanding of media – films as media; drugs as media – as holding a curative influence: to resume an affirmative potentiality for life and to restore a belief in the (physical and psychical) world. The film-philosophical dimension of the psychedelic crystal, developed specifically through an engagement with Jan Kounen’s Blueberry (2004) as case study, sees cinema with the potential to reanimate our mental and physical reality, especially when in relation to traumatically repressed, dissociated or repeated memory formations – thus looking at certain film aesthetics as a mind-revealing, mind-expanding and mind-healing technology which can be considered as intrinsically entangled with the current revival of therapeutic practices of psychoactive substances. As a proposition, the psychedelic crystal discloses a potential dimension of the psychedelic frontier of healing which transversally embraces the transdisciplinary gamut of film-philosophy, film theory and psychedelic research.

Psychedelic and nutraceutical interventions as therapeutic strategies for military-related mild traumatic brain injuries

LAY SUMMARY Concussion is a type of acquired brain injury that is common in the military, as well as among civilians and contact sport athletes, and is defined by a transient impairment in mental function. Nevertheless, concussion presents a considerable health burden, and a small minority of people suffer from continued impairment. Repetitive sub-concussive head injury is a known risk factor for neurodegenerative disease, including dementias. Concussions are difficult to treat because symptom profiles vary, but psychedelic therapies may help address some of the neurological issues that occur after brain injury. Classic psychedelics show promise as an emerging pharmacological intervention because they appear to help the brain to rewire, and they have anti-inflammatory effects. Nutraceutical interventions are widely available, cost-effective, and well tolerated, and they could also support recovery when combined with psychedelic compounds. Here, studies presenting classical psychedelics and nutraceuticals that may be combined with psychedelics as therapeutic strategies for the treatment of concussions and persistent symptoms are discussed.

Extended difficulties following the use of psychedelic drugs: A mixed methods study.

Long-term adverse experiences following psychedelic use can persist for weeks, months, or even years, and are relatively unexplored in psychedelic research. Our convergent mixed-method study gained quantitative and qualitative data from 608 participants who reported extended difficulties following psychedelic experiences. Data was gathered on the context of use, the nature and duration of the challenges they experienced (including a written description of these), plus a range of possible risk factors and perceived causes. The most common forms of extended difficulty were feelings of anxiety and fear, existential struggle, social disconnection, depersonalization and derealization. For approximately one-third of the participants, problems persisted for over a year, and for a sixth, they endured for more than three years. It was found that a shorter duration of difficulties was predicted by knowledge of dose, drug type and lower levels of difficulty reported during the psychoactive experience, while a narrower range of difficulties was predicted by taking the drug in a guided setting. Implications for psychedelic harm reduction are discussed.

Methodological concerns in psychedelic research: The issues of nonequivalent psychological support and generalizability

Methodological concerns in psychedelic research: The issues of nonequivalent psychological support and generalizability

Psychedelic Research and Therapeutic Practices: Embracing Communities, Groups, and Traditional Knowledge

ABSTRACTThe global prevalence of substance abuse and mental disorders continues to challenge healthcare systems, with one in eight individuals affected. The therapeutic potential of psychedelics is recognized not only for treating mental disorders but also for enhancing well-being and promoting pro-social behaviors. Conventional biomedical research models fall short in addressing the broader health needs of populations and poorly suited for overcoming barriers to service delivery. This special issue includes six articles that explore alternative approaches to psychedelic research and practice, emphasizing collaboration with diverse actors, including indigenous communities, and incorporating traditional knowledge systems into contemporary psychedelic research. They underscore the need for innovative research methods that engage multidisciplinary approaches while promoting culturally relevant outcome measures. They emphasize the importance of shifting from punitive drug policies to those grounded in public health and human rights, allowing for multi-country studies and the development of evidence-based care models for community mental health. Incorporating traditional knowledge and community-based methodologies into psychedelic science is vital for its evolution beyond biomedical research for widespread dissemination, offering new avenues for improved health outcomes and promotion of human flourishing.

The Key Role of Intracellular 5-HT2A Receptors: A Turning Point in Psychedelic Research?

Psychedelics could have revolutionary potential in psychiatry, although, until recently, the pharmacodynamic properties of such compounds have not seemed to differ much from those of serotonin, whose levels are raised by Serotonin Reuptake Inhibitors (SSRI). The cardinal point is that serotonergic compounds, such as antidepressive drugs, do not have the potential to induce long-lasting neuroplasticity as psychedelics do. Therefore, the biological underpinnings of the peculiar effect of such compounds had not been fully understood until new astonishing molecular findings came out this year to shed new light on them. Specifically, the phenomena of neuroplasticity are triggered by the stimulation of a peculiar type of receptors: the intracellular 5-HT2A receptors. Interestingly, psychedelics can reach this pool of intracellular receptors due to their lipophilic properties, as they can cross the lipophilic neuronal membrane while serotonin cannot. The importance of such a discovery should not be underestimated as the specific mechanisms involved have not yet been elucidated and a better understanding of them could pave the way to the development of new drugs (and/or new tailored therapeutic strategies) able to sustain neuroplasticity while minimizing side effects.

The ego in psychedelic drug action - ego defenses, ego boundaries, and the therapeutic role of regression.

The ego is one of the most central psychological constructs in psychedelic research and a key factor in psychotherapy, including psychedelic-assisted forms of psychotherapy. Despite its centrality, the ego-construct remains ambiguous in the psychedelic literature. Therefore, we here review the theoretical background of the ego-construct with focus on its psychodynamic conceptualization. We discuss major functions of the ego including ego boundaries, defenses, and synthesis, and evaluate the role of the ego in psychedelic drug action. According to the psycholytic paradigm, psychedelics are capable of inducing regressed states of the ego that are less protected by the ego's usual defensive apparatus. In such states, core early life conflicts may emerge that have led to maladaptive ego patterns. We use the psychodynamic term character in this paper as a potential site of change and rearrangement; character being the chronic and habitual patterns the ego utilizes to adapt to the everyday challenges of life, including a preferred set of defenses. We argue that in order for psychedelic-assisted therapy to successfully induce lasting changes to the ego's habitual patterns, it must psycholytically permeate the characterological core of the habits. The primary working principle of psycholytic therapy therefore is not the state of transient ego regression alone, but rather the regressively favored emotional integration of those early life events that have shaped the foundation, development, and/or rigidification of a person's character - including his or her defense apparatus. Aiming for increased flexibility of habitual ego patterns, the psycholytic approach is generally compatible with other forms of psychedelic-assisted therapy, such as third wave cognitive behavioral approaches.

Intellectual Property of Psychedelics for Addiction Treatment: Enabling Access and Protecting Innovation Opportunities Through Preserving the Public Domain.

Recent research has shown potential for psychedelic therapeutics as addiction treatments; however, some academic institutions, commercial entities, and individuals are attempting to monopolize psychedelic compounds through exploiting the patent process. This Perspective article describes efforts that have been devised to mitigate exclusionary patent practices pertinent to psychedelic therapeutics for addiction. The nonprofit Porta Sophia has identified 170 patent documents focused on treating addiction through psychedelics, and many of these patents could threaten to privatize public domain knowledge and severely limit or increase the cost of research if granted. Patent examiners who determine if a patent application should be granted must negate false claims to innovation. Yet, given the unique history of psychedelics, prior knowledge can be difficult to find. As a result, overreaching patents may be granted, causing dramatic shifts in access to addiction-focused psychedelic research, treatments, and funding. As the field of psychedelics approaches this crucial inflection point of U.S. Food and Drug Administration decisions, it is imperative for all stakeholders--including university investigators, academic and commercial patent seekers, and policymakers--to use available tools for determining prior knowledge. Maintaining an informed awareness of legal patent eligibility and limitations is crucial for establishing an ethical patent landscape and ensuring subsequent access to these potential life-altering psychedelic therapeutics for addiction.

Bedside to bench: the outlook for psychedelic research.

There has recently been a resurgence of interest in psychedelic compounds based on studies demonstrating their potential therapeutic applications in treating post-traumatic stress disorder, substance abuse disorders, and treatment-resistant depression. Despite promising efficacy observed in some clinical trials, the full range of biological effects and mechanism(s) of action of these compounds have yet to be fully established. Indeed, most studies to date have focused on assessing the psychological mechanisms of psychedelics, often neglecting the non-psychological modes of action. However, it is important to understand that psychedelics may mediate their therapeutic effects through multi-faceted mechanisms, such as the modulation of brain network activity, neuronal plasticity, neuroendocrine function, glial cell regulation, epigenetic processes, and the gut-brain axis. This review provides a framework supporting the implementation of a multi-faceted approach, incorporating in silico, in vitro and in vivo modeling, to aid in the comprehensive understanding of the physiological effects of psychedelics and their potential for clinical application beyond the treatment of psychiatric disorders. We also provide an overview of the literature supporting the potential utility of psychedelics for the treatment of brain injury (e.g., stroke and traumatic brain injury), neurodegenerative diseases (e.g., Parkinson's and Alzheimer's diseases), and gut-brain axis dysfunction associated with psychiatric disorders (e.g., generalized anxiety disorder and major depressive disorder). To move the field forward, we outline advantageous experimental frameworks to explore these and other novel applications for psychedelics.

Predicting the Intensity of Psychedelic-Induced Mystical and Challenging Experience in a Healthy Population: An Exploratory Post-Hoc Analysis.

In psychedelic therapy, mystical as well as challenging experience may influence therapeutic outcome. However, predictors of such experience have not been sufficiently established. Determining predictors of their intensity is, therefore, potentially beneficial in targeting psilocybin therapy for depression. In a post hoc data analysis of a Phase 1, randomised, double-blind, placebo-controlled, between-groups clinical trial, dosage, personality traits, affect, and individual data were analysed as possible clinical predictors. Eighty-nine healthy volunteers were randomised to receive a single dose of placebo, 10 mg of psilocybin, or 25 mg of psilocybin. ANOVA was used to analyse the relationship between dosage and mystical and/or challenging experience, and correlation analysis for all other variables. The intensity of both mystical and challenging experience was strongly associated with higher dosage. Age was negatively correlated with intensity of challenging experience. Correlation between identified personality traits and either mystical or challenging experience was minimal, with the exception of positive correlation between neuroticism and challenging experience at higher dose. Neither positive nor negative affect indicated correlation with the intensity of either type of experience. A limitation of this study is its post hoc, exploratory design; recommendations for further research are provided.

How psychedelic-assisted therapy works for depression: expert views and practical implications from an exploratory Delphi study.

As investigations into the efficacy of psychedelic-assisted psychotherapy to treat depression continue, there is a need to study the possible mechanisms of action that may contribute to the treatment's antidepressant effects. Through a two-round Delphi design, the current study investigated experts' opinions on the psychological mechanisms of action associated with the antidepressant effects of psychedelic-assisted psychotherapy and the ways such mechanisms may be promoted through the preparation, dosing, and integration components of treatment. Fourteen and fifteen experts, including both clinical psychedelic researchers and therapists, participated in Round 1 and Round 2 of the study, respectively. Thematic analysis identified nine important or promising 'mechanistic themes' from Round 1 responses: psychological flexibility, self-compassion, mystical experiences, self-transcendence, meaning enhancement, cognitive reframing, awe, memory reconsolidation and ego dissolution. These mechanisms were presented back to experts in Round 2, where they rated 'psychological flexibility' and 'self-compassion' to be the most important psychological mechanisms in psychedelic-assisted psychotherapy for depression. Strategies or interventions recommended to promote identified mechanisms during the preparation, dosing, and integration components of treatment were nonspecific to the endorsed mechanism. The findings from this study provide direction for future confirmatory mechanistic research as well as provisional ideas for how to support these possible therapeutic mechanisms.

Perceptions of psychedelic-assisted therapy among Black Americans

The present study investigated differences in perceptions of psychedelic-assisted therapy between Black and White Americans, as well as factors that may influence these perceptions. A final sample of 294 adults (42% female, 44% Black/African American or Mixed Race (of Black/African ancestry), 56% White American; Mage = 36.3 years) completed an online survey which assessed baseline knowledge and views of psychedelic-assisted therapy. Participants were then provided brief psychoeducation related to MDMA and psilocybin-assisted therapy. After psychoeducation, participants were queried on their perceptions of psychedelic-assisted therapy and factors potentially influencing these perceptions, including trauma history, current depressive and PTSD symptoms, perceived stress, and perceived barriers to psychological treatments. Psychoeducation had a positive impact on both level of interest and positivity of views of psychedelic-assisted therapy across groups. Black American participants reported more positive views of psychedelic-assisted therapy than White participants following psychoeducation. Greater depression and PTSD symptom severity was associated with greater baseline interest in Black and White Americans and there was significant interactions in predicting baseline view and interest, such that Black participants who reported greater depression symptom severity were more interested and had more positive views of PAT. Despite historical exclusion from psychedelic clinical trials and experiences of unethical treatment in research, Black Americans demonstrate more positive views of psychedelic therapy, and Black Americans more in need of novel mental health care demonstrate more interest and more positive views. Our findings demonstrate that the onus for diversification of psychedelic research samples is on research groups. These findings also provide an impetus for the psychedelic research community to rebuild trust in psychedelic research among Black Americans, conduct outreach, and provide culturally attuned psychedelic-assisted interventions that are accessible to Black Americans.

Indigenous Voices in Psychedelic Therapy: Experiential Learnings from a Community-Based Group Psychedelic Therapy Program

ABSTRACTNovel and traditional psychedelic medicines are attracting interest as potential treatments of mental illness. Before psychedelic therapies can be made available in culturally safe and effective ways to diverse peoples, the field must grapple with the complex legacies of colonialism and ongoing clashes between biomedical and Indigenous Ways of Knowing. This article presents results of a pilot program offering group-based therapy augmented by three sessions of ketamine at a psychedelic dose, for a group of Indigenous participants. This unique project was undertaken in partnership between Roots to Thrive and the Snuneymuxw First Nation to assess this approach’s effectiveness and safety for Indigenous peoples. Thematic analysis of qualitative interviews and anonymous feedback received throughout the program from eight participants and two Elders provided rich information on participant motivations, perceived barriers, appreciated and beneficial aspects of the program, and the psychedelic experiences, as well as important directions for further improvement. In addition to challenges, participants attributed significant benefits to the program while highlighting the importance of the involvement of Indigenous team members, the incorporation of traditional approaches to healing, and the cultivation of open and authentic relationships between group participants and facilitators. We discuss important lessons learned and the essential work of reconciliation in, and beyond, psychedelic therapies.

Lifeboat ethics, risk, and therapeutic opportunity: an appeal for equitable psychedelic therapy access in the "high-risk" addiction patient.

Psychedelic-assisted treatment (PAT) for mental health is in renaissance. Psilocybin and MDMA stand near FDA approval, and US cities and states are decriminalizing or regulating the non-clinical use of psilocybin. However, neither FDA indications nor a regulated use model sufficiently address the complex needs and opportunities for an improved treatment of addiction. When paired with disability and social dispossession, addiction increasingly burdens informal care networks, public safety, and particularly healthcare systems. Stigma and mistreatment alienate people from opportunities for care and multiply the costs of providing care. This dynamic worsens socially determined resource limitations, enforcing stark ethical choices and perpetuating socioeconomic inequities, isolation, mental illness, medical illness, overdose, suicide, and violence. In order for psychedelic treatments to achieve their greatest utility to population health, we must intentionally develop regulatory, clinical, and payment systems supporting clinical research, rigorous safety monitoring, and implementation to address these immense needs and reduce the barriers to engagement for those who now bear the costs, including those who work at the front lines of addiction care. To achieve full fruition, I advocate for a collaborative approach, built from within networks of mutual social support but linked and accountable to public institutions charged with the equitable dissemination of these therapies for the greatest social and health equities. Rather than relegating PAT to the needs of the commercially insured or wellness markets, this is the moment to learn from ancient traditions of ritualized sacramental use, organized around faith in our mutual dependency and accountability, and to capture an opportunity to improve population health and equity. To miss this opportunity is to accept the status quo in the midst of a growing emergency, for lack of moral vision and intention to change our habits.

The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression.

Subanesthetic ketamine has accumulated meta-analytic evidence for rapid antidepressant effects in treatment-resistant depression (TRD), resulting in both excitement and debate. Many unanswered questions surround ketamine's mechanisms of action and its integration into real-world psychiatric care, resulting in diverse utilizations that variously resemble electroconvulsive therapy, conventional antidepressants, or serotonergic psychedelics. There is thus an unmet need for clinical approaches to ketamine that are tailored to its unique therapeutic properties. This article presents the Montreal model, a comprehensive biopsychosocial approach to ketamine for severe TRD refined over 6 years in public healthcare settings. To contextualize its development, we review the evidence for ketamine as a biomedical and as a psychedelic treatment of depression, emphasizing each perspectives' strengths, weaknesses, and distinct methods of utilization. We then describe the key clinical experiences and research findings that shaped the model's various components, which are presented in detail. The Montreal model, as implemented in a recent randomized clinical trial, aims to synergistically pair ketamine infusions with conventional and psychedelic biopsychosocial care. Ketamine is broadly conceptualized as a brief intervention that can produce windows of opportunity for enhanced psychiatric care, as well as powerful occasions for psychological growth. The model combines structured psychiatric care and concomitant psychotherapy with six ketamine infusions, administered with psychedelic-inspired nonpharmacological adjuncts including rolling preparative and integrative psychological support. Our integrative model aims to bridge the biomedical-psychedelic divide to offer a feasible, flexible, and standardized approach to ketamine for TRD. Our learnings from developing and implementing this psychedelic-inspired model for severe, real-world patients in two academic hospitals may offer valuable insights for the ongoing roll-out of a range of psychedelic therapies. Further research is needed to assess the Montreal model's effectiveness and hypothesized psychological mechanisms.