The Interdisciplinary Annotated Psychedelic Research Bibliography of 2024

Produced by Michael Haichin, PharmD

Introduction

Welcome to the second edition of the Interdisciplinary Annotated Psychedelic Research Bibliography!

For the past several years, with the help of the Psychedelic Alpha team, I have closely followed all the academic papers published about or related to psychedelics and compiled an annual list of the most intriguing ones.

Last year’s inaugural Annotated Bibliography was born from said list, with generous input from an invited interdisciplinary pool of academic authors and critics providing context and commentary to enrich our understanding of psychedelic research. Building on that foundation, this edition continues to explore the rapidly evolving research landscape and offers valuable perspectives from experts across the field.

In reflecting on the notable psychedelic moments of 2024, I found myself going back to Shayla Love’s 2022 Year in Review op-ed, which quoted Jack Kornfield, “After the Ecstasy, The Laundry”. The laundry symbolizes the challenges of integrating psychedelics into broader society and the maturation that must come with it.

It’s safe to say that last year was a challenging one for the field of psychedelics, where the metaphorical laundry certainly piled up. However, amidst these hurdles, the field has continued to grow, demonstrating resilience and a commitment to advancing our understanding of psychedelics. It is my hope that the 2024 edition of the bibliography captures the essence of this growth.

The number of psychedelic science publications flourished, and this project required narrowing a list of over 2,000 papers published online in 2024¹, to a more manageable ~500, before being sent to invited researchers. It was a true labour of love (and a test of my patience), but ultimately was a small fraction of the time spent considering and evolving the ideas that end up in these scientific publications that deserve engaging with.

The development of this list was far from scientific in process, in that I included what I found most interesting or what I thought might be most pertinent to the various disciplines in the field at Large (including the many I am less than qualified in). To further simplify the task, case reports, individual chapters or whole academic textbooks, and dissertations/theses were not included².

This biased methodology undoubtedly resulted in the exclusion of very deserving papers, which I attempted to offset by asking participating researchers to nominate any excluded paper(s).

A few more notes about the list before moving on to the annotated bibliography:

• Let’s remember that this list is neither exhaustive nor definitive. Not all papers were read in full and thus their inclusion is not necessarily an endorsement.
• Similar to last year, despite some objection from certain invited researchers³, papers about MDMA, ketamine, and related entactogens and dissociatives were included under the “psychedelic” umbrella.
• The references are listed in alphabetical order and divided into the following categories: Reviews, Clinical Trials, Discovery & Preclinical, Editorials/Commentary, Miscellaneous, and Preprints.

I hope this is a valuable addition to researchers and anyone who doesn’t have time to read everything they’d like to (so, everybody), and inspires collaboration in hopes of folding some more laundry.

Lastly, thank you to those who commented on literature included in this year’s bibliography: Alex Kwan, Samuli Kangaslampi, Matteo Malgaroli, CJ Healy, Gretchen Shaub, Jacob Aday, Hailey Gilmore, Alaina Jaster, Rebecca Ehrenkranz, Lucie Berkovitch, Lauren Lepow, S. Parker Singleton, David Mathai, Sharday Mosurinjohn, Maia Mallvays, Vince Polito, Matthew Baggott, Helena Aicher, Bente Vissel, Lauri Elsilä, Juliet Meccia, Chloé Pronovost-Morgan, Zoë Dubus, Eddie Jacobs, Meghan DellaCrosse, Gregory Yates, Harriet Phelan, Evan Lewis-Healey, Marc Duque Ramirez, and George Blackburne.

Are you a researcher interested in participating in the 2025 Annotated Bibliography? Please contact michael@psychedelicalpha.com.

A Brief Overview

While we received comments on a broad array of 2024’s publications, one of the papers that received the most attention was Aday et al.’s review, Psychedelic-assisted psychotherapy: Where is the psychotherapy research?”

Indeed, 2024 saw a continuation of the debate around the role of psychotherapy in psychedelic-based treatments, which was intensified by a 2023 publication from Compass Pathways Chief Medical Officer Guy Goodwin and co. that drew commentary in last year’s Bibliography. That 2023 article has since been responded to by a salvo from the likes of Alpert et al., Bogenschutz, Schenberg et al., O’Donnell et al., Earleywine et al., and the late Deckel et al., which attracted comments in this Bibliography, including from CJ Healy who described it as a “diverse series of thoughtful and often impassioned arguments against active efforts to minimize or excise entirely…the psychosocial component…of psychedelic therapy.” The question was also raised by Weintraub and Miklowitz, who asked: How should psychotherapy proceed when adjoined with psychedelics?

In her review of several psychotherapy-related articles, Gretchen Shaub suggests that some of the animosity around this topic is due to a lack of consensus terminology in the field. That, she says, “has resulted in the role of psychotherapy being an increasingly contentious issue for many stakeholders”.

Aday et al.’s review proposes ways in which we might make this debate more productive or empirical, such as through the publication of treatment manuals. Efforts to standardise the therapy element could benefit from mainstream psychotherapy research, the authors suggest, a view that Samuli Kangaslampi endorsed in his commentary on the article.

Others, including CJ Healy, appear to agree: “Psychedelic therapy is psychotherapy that involves the use of drugs, and so psychedelic therapy research ought to look methodologically and conceptually just as much like psychotherapy research as like drug research (if not more so!).”

On the topic of more practical suggestions for psychedelic researchers, Barnett et al.’s contribution in Psychopharmacology offers a blueprint for establishing psychedelic research programs, including a focus on “[u]nusual situations arising in psychedelic research”, which Jacob Aday said he found “highly interesting and underscores the wide spectrum of challenges one can expect to encounter in this field of research.”

Another publication that could have implications for the practice of psychedelic trials, and the interpretation of their findings, is Roseman et al.’s investigation of how “brief and relatively minor demands on attention during a psychedelic experience”, in the words of CJ Healy’s comments on the article, “prove to be significant enough distractions from subjective immersion in the experience that they compromise not only the acute phenomenological effects but also the long-term therapeutic benefits of the experience.”

Helena Aicher found the study “particularly noteworthy as it reinforces the long-standing understanding that contextual factors shape psychedelic experiences”, adding that “the findings also imply that results from prior studies involving acute assessments or experimental tasks during the psychedelic state may have been influenced by those very interventions.” She also warned that, in addition to differing doses and drugs, the design of studies should be considered when comparing effects across studies.

As might be clear already, many of those people researching psychedelics are well over the hype curve, instead increasingly focused on highlighting—and overcoming—challenges in psychedelic research and potential roll-out. Lauri Elsilä welcomes more critical perspectives, like Lemarchand et al.’s commentary in BMJ, but said that some of the issues identified in psychedelic studies should be addressed in clinical (psycho)pharmacological studies writ large.

The broad array of contributions, and commentary on said contributions submitted as part of this process, continues to impress. Here are just a handful of other topics discussed:

• McGovern et al.’s integrated theory of false insights and beliefs under psychedelics stirred discussion, with S. Parker Singleton describing it as “probably my favorite read of 2024”.
• Bartlett et al.’s review looked at queer representation in psychedelic research, while Bouchet et al. surveyed the inclusion (or lack thereof) of older adults in such work.
• Aepfelbacher et al.’s article on the role of awe and music in ketamine’s antidepressant effects made Maia Mallvays wonder: “Could deliberately enhancing awe during ketamine sessions…enhance and prolong its therapeutic efficacy?” Greenway et al.’s study on music as an intervention to mitigate blood pressure increases on patients receiving IV ketamine for depression, meanwhile, interested University of Zurich researcher and psychotherapist Helena Aicher. She said that this is a line of research that might be worth extending to other psychoactive substances, like classical psychedelics or empathogens, which “could help understand the broader role of music and sensory environment for the physiological responses and subjective experiences across different pharmacological interventions.”
• Alex Kwan said that Braun et al.’s zebrafish behavioural assay “may be a promising approach for high throughput screens with live animals.” Lauri Elsilä, meanwhile, appreciated University of Bristol researchers’ efforts (Hinchcliffe et al.) in “developing rodent models that have better translational validity”.
• On the access side of the equation, McInnes et al.’s contribution explored ways of achieving insurance coverage for ketamine using real-world evidence. In reviewing the publication, Hailey Gilmore said that a “public benefit approach when pharma profit isn’t possible presents ripe conditions for transforming innovative treatment option access for the world’s 3rd leading cause of disability.”
• Breeksema et al.’s qualitative study of patient perspectives and experiences with psilocybin for treatment-resistant depression (TRD) was well-received when it was published last February. Here, Meghan DellaCrosse describes it as “a valuable contribution to the psychedelic literature as it centers on patient narratives”.
• Researchers at University Hospital Basel (Straumann et al.) published findings on the acute effects of MDMA and its two enantiomers in healthy subjects (N=24). In a detailed comment, Tactogen co-founder Matthew Baggott said it was a welcome addition to the literature, even if it does not initially replicate findings from mice studies in humans. Baggott also pointed out challenges in selecting comparable doses between the enantiomers, given a dearth of data. “Disappointingly”, he continued, “the enantiomers did not have dramatically different qualitative pharmacological profiles”, Baggott said, but added the “[p]roponents of the potential value of the R-enantiomer might point out that there were no measures that would be analogous to the improved fear extinction seen in mice”, referencing those preclinical studies. “[E]ven if the study proved disappointing for those of us hoping to improve on racemic MDMA, the study nonetheless provides a wealth of careful pharmacokinetics and dynamics information.”
• A paper by Myran et al. on emergency department visits involving hallucinogen use and risk of schizophrenia spectrum disorder caused quite the stir late last year. Here, Gregory Yates and Harriet Phelan describe it as “helpful for our work in the emergency department”, but suggest that the findings be taken “with a pinch of salt.” ‘Hallucinogens’ include PCP and amphetamines, they note (a matter they also noted in reviewing Simon et al.’s review of over fifty-four thousand medical cases), and they further suggest that there could be a ‘third variable’ at play. Lucie Berkovitch, meanwhile, described the findings as “alarming” and said that they “underscore the need for proactive follow-up and preventive strategies for this high-risk group.”

Aday, J. S., Horton, D., Fernandes-Osterhold, G., O’Donovan, A., Bradley, E. R., Rosen, R. C., & Woolley, J. D. (2024). Psychedelic-assisted psychotherapy: Where is the psychotherapy research? Psychopharmacology, 241(8), 1517–1526. https://doi.org/10.1007/s00213-024-06620-x

“For a long time, research on psychedelic-assisted (psycho)therapy was strangely divorced from the more mainstream psychotherapy research that had been going on for decades. This meant that little attention was paid to things like the common factors of psychotherapy and transdiagnostic mechanisms of change previous research had uncovered, or to research designs best suited for comparing (elements) of psychotherapeutic approaches. In recent years, this has begun to change, but as Aday and colleagues write in this paper, “there is much the field has yet to leverage from decades of non-psychedelic psychotherapy research to optimize the psychotherapeutic aspect of treatment”. Here, the authors do a particularly good job of presenting a number of apt suggestions on what psychedelic-assisted psychotherapy could and should learn from mainstream psychotherapy research and how we should move forward to better understand and optimize the psychotherapy in psychedelic-assisted psychotherapy.” – Samuli Kangaslampi

“This critical review highlights a significant gap in psychedelic research: despite the term “psychedelic-assisted psychotherapy,” there has been remarkably little empirical investigation into the actual psychotherapy component. The authors identify how researchers have manipulated drug variables while neglecting to systematically study the accompanying psychological support, creating ambiguity about best practices. The authors correctly suggest to leverage established psychotherapy research methods — including standardizing protocols, identifying mechanisms of change, and using dismantling studies for advancing the field.” – Matteo Malgaroli

“Psychedelic therapy is psychotherapy that involves the use of drugs, and so psychedelic therapy research ought to look methodologically and conceptually just as much like psychotherapy research as like drug research (if not more so!).” – CJ Healy

“PAT, PAP, PT…there is yet to be consensus on language for psychedelic treatments in development. This lack of alignment has resulted in the role of psychotherapy being an increasingly contentious issue for many stakeholders. Valid arguments have been made regarding the role of psychotherapy in potentially FDA-approved psychedelic treatments. No one company, organization, or stakeholder group should be responsible for establishing best practices – a coordinated approach is required to support the entire industry. The opportunity is ripe for psychology to enter the chat. As experts continue to make valid and at times conflicting arguments, perhaps the conversation should evolve to identify who might “own” the psychotherapy of it all. There are highly qualified therapists with hundreds and thousands of hours of experience in psychedelic clinical trials confused about what their roles in real-world settings will be should products come to market. Isn’t everyone in this space confused about what their roles will be in the future? After all, this has never been done at commercial scale in the U.S. medical system. In an incipient and diverse industry might the current debate be missing the forest for the trees?

In December 2024 The American Psychiatric Association (APA) published updated practice guidelines on the treatment of Borderline Personality Disorder (BPD). The APA recommendation is tiered to include both psychosocial interventions and pharmacotherapy treatments. Importantly, they suggest that patients with BPD treated with “any psychotropic medication be time-limited, aimed at addressing a specific measurable target symptom, and adjunctive to psychotherapy.”  Of note for emerging psychedelic treatments the APA does not distinguish between the numerous types of psychosocial interventions available; rather, the APA calls for a structured approach to psychotherapy, recognizing that many effective evidence-based options exist. Other examples of treatment models involving psychosocial interventions provide additional food for thought e.g. – SUD, HIV, bariatric surgery, dialysis, etc.

If the ultimate goal for those pursuing FDA approval is to provide treatment options that are safe and more effective than those presently available, shouldn’t the through line be meeting patients’ needs? Are we asking what patients want and incorporating that into decision-making or are we leaning into biased assumptions? All of the papers focused on this topic have provided space for healthy and much needed reflection and research.” – Gretchen Shaub (also responding to Weintraub et al. and Alpert et al., below.

Barnett, B. S., Vest, M. F., Delatte, M. S., King IV, F., Mauney, E. E., Coulson, A. J., Nayak, S. M., Hendricks, P. S., Greer, G. R., & Murnane, K. S. (2024). Practical considerations in the establishment of psychedelic research programs. Psychopharmacology, 242(1), 27–43. https://doi.org/10.1007/s00213-024-06722-6

“This paper is an incredibly useful blueprint for how to go about establishing a psychedelic research program. The section “Unusual situations arising in psychedelic research”, in particular, is a highly interesting read and underscores the wide spectrum of challenges one can expect to encounter in this field of research.” – Jacob Aday

This important manuscript advising investigators new to psychedelic trials is a comprehensive review (perhaps it should be added to the “Resources” section of any psychedelic company’s IIT program page). It highlights the longer timelines than expected due to additional regulation of scheduled substances over standard drug trials. From the outset, there is a need to begin building interdisciplinary relationships and support as soon as feasible, ranging from administration to community.

For most sites, there is a learning curve on conducting compliant FDA and DEA regulated research, given the pace of innovation in the mental health space over the last few decades. What’s more, psychedelic trials present unique challenges for trial design, managing selection/expectancy/evaluation biases, and also how to ethically conduct truly informed consent to ineffable experiences. Logistically, there are few clinical grade suppliers, and a duplicative system of state licensing for managing controlled substance inventory on site. Competent core staff are key, including in data management, recruitment, and laboratory processes – and yet, having such robust staffing expertise is challenging when funding for such work is limited.

Once more for the people in the back (of DOGE): funding remains the most substantial challenge in this space, and also the thing that would move the needle the most.” – Hailey Gilmore

Bartlett, A., Christ, C., Martins, B., Saxberg, K., & Ching, T. H. W. (2024). The library is open: A scoping review on queer representation in psychedelic research. Frontiers in Public Health, 12, 1472559. https://doi.org/10.3389/fpubh.2024.1472559

“Reviews like this are so important. Representation is so important. This review brought up a lot of good connections between psychedelics and queerness, specifically highlighting that psychedelic use has been a part of fluid conceptions of gender in several societies, and even the fungal kingdom of which psilocybin is a part of has thousands of distinct sexual identities. My favorite part of the review was about who is being studied in the psychedelic studies, and unfortunately out of the studies screened only five reported a breakdown of participants’ genders outside of the gender binary and no studies focused specifically on queer women. Another point this review makes that I appreciated was that many studies were excluded from their analysis due to historical pathologizing of psychedelic use within the queer community. I would love to see more work focused on the queer experience.” – Alaina Jaster

Bouchet, L., Sager, Z., Yrondi, A., Nigam, K. B., Anderson, B. T., Ross, S., Petridis, P. D., & Beaussant, Y. (2024). Older adults in psychedelic-assisted therapy trials: A systematic review. Journal of psychopharmacology (Oxford, England), 38(1), 33–48. https://doi.org/10.1177/02698811231215420

“This article points out the critical public health importance of including older adults in psychedelic clinical trials. The key impact of this paper is highlighting the dearth of representation of older adults in psychedelic trials – the authors find that less than 1.4% of participants in included psychedelic trials are age 65 or older. While there may be concerns about excess risk for experiencing adverse events in older populations, this paper did not find anything atypical for psychedelic studies (i.e., no serious adverse events were reported and both medical and psychiatric adverse events were transient). This study provides helpful insight into the potential risk-benefit profile of psychedelics in older adults, and includes initial recommendations for monitoring adverse events that may be more likely to occur in this population. These findings will hopefully pave the way for more inclusion of older adults in future psychedelic clinical trials.” – Rebecca Ehrenkranz

Calder, A. E., Hase, A., & Hasler, G. (2024). Effects of psychoplastogens on blood levels of brain-derived neurotrophic factor (BDNF) in humans: A systematic review and meta-analysis. Molecular Psychiatry, 30(2), 763–776. https://doi.org/10.1038/s41380-024-02830-z

“Given the widely held theory that plasticity is behind the therapeutic effects of psychedelics and/or psychoplastogens, this systematic review and meta-analysis is quite interesting. One of the large issues within the field is the translational validity of animal studies to human studies, specifically as it relates to measures of plasticity. It’s extremely difficult to measure plasticity in humans and many people have been working on figuring out better measures, which include measuring the circulating levels of brain derived neurotrophic factor (BDNF) in blood. While this analysis of 29 studies found no changes in peripheral BDNF levels following psychoplastogen administration, it is a good first step in identifying gaps in the literature and what can be done to improve measures.” – Alaina Jaster

Glennon, R. A., & Dukat, M. (2024). 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents – A Review. ACS Pharmacology & Translational Science, 7(6), 1722–1745. https://doi.org/10.1021/acsptsci.4c00157

“I thought this review was pretty timely given the U.S. Drug Enforcement’s Agency’s attempt to schedule DOI and it’s DOx family member, DOC, this past year. Dr. Glennon is one of the foremost experts on psychedelic action at the serotonin 2A receptor, and one of the first to discover psychedelics activate the 2A receptor, making him the go-to guy on the subject. He provides a great overview of the chemistry, pharmacology and behavioral effects of DOI in this review. I believe it is a “must read” for anyone interested in psychedelic research.” – Alaina Jaster

Hinkle, J. T., Graziosi, M., Nayak, S. M., & Yaden, D. B. (2024). Adverse Events in Studies of Classic Psychedelics: A Systematic Review and Meta-Analysis. JAMA Psychiatry, 81(12), 1225. https://doi.org/10.1001/jamapsychiatry.2024.2546

“The occurrence of adverse events (AEs) in the medical use of psychedelics is a critical consideration for potential future marketing authorization. In this work, Hinkle et al. show that serious AEs are rare in clinical and research settings, although a systematic approach to AE assessment is lacking in many clinical trials. Overall, this study offers reassuring evidence about the safety profile of psychedelics when used in controlled environments.” – Lucie Berkovitch

Mathai, D. S. (2024). Learning how to make use of dissociative therapies. International Review of Psychiatry, 1–13. https://doi.org/10.1080/09540261.2024.2406329

“This article reframes dissociative therapies by highlighting their unique therapeutic potential, especially the often-overlooked role of subjective drug experiences like those with ketamine. It advances the field by calling for a more nuanced understanding of “dissociation,” distinguishing it from pathological constructs and highlighting its potential adaptive and meaning-making capacities, which could be intentionally harnessed in therapeutic contexts. The discussion opens new directions for integrating meaning-making and context into psychedelic and ketamine-assisted therapies.” – Lauren Lepow

McGovern, H. T., Grimmer, H. J., Doss, M. K., Hutchinson, B. T., Timmermann, C., Lyon, A., Corlett, P. R., & Laukkonen, R. E. (2024). An Integrated theory of false insights and beliefs under psychedelics. Communications Psychology, 2(1), 69. https://doi.org/10.1038/s44271-024-00120-6

“This was probably my favorite read of 2024. Psychedelics reliably produce the feeling of insight – that feeling (often strong) leads individuals to believe these insights are true. These insights (whether false or true) are to some degree a mechanism through which lasting behavioral and attitude changes occur following psychedelic administration (whether positive or negative). There tends to be a reverence around psychedelics leading to newcomers being told things like “trust the medicine”. With psychedelic use on the rise both in clinical and non-clinical settings, it feels extremely important to raise awareness around the possibility of false insights. McGovern et al provide a very readable review on this literature and some parameters through which insights can be evaluated post-acutely. This is a good one to send to your friends.” – S. Parker Singleton

Neitzke-Spruill, L., Devenot, N., Sisti, D., Averill, L. A., & McGuire, A. L. (2024). Bio-Psycho-Spiritual Perspectives on Psychedelics: Clinical and Ethical Implications. Perspectives in Biology and Medicine, 67(1), 117–142. https://doi.org/10.1353/pbm.2024.a919715

“Given the tremendous challenge of achieving a successful drug development program, psychedelic science is today at risk of losing its longstanding ties to psychological and historical perspectives. In this timely piece, Logan Neitze-Spruill and colleagues argue for the value of diverse frameworks when conceptualizing psychedelic effects and for avoiding the pitfalls of biomedical reductionism. The authors ultimately highlight that this critical work will require interdisciplinary training for researchers and interprofessional collaboration. Our field will be better off if we can make room for different ways of knowing, learning, and being.” – David Mathai

Sabé, M., Sulstarova, A., Glangetas, A., De Pieri, M., Mallet, L., Curtis, L., Richard-Lepouriel, H., Penzenstadler, L., Seragnoli, F., Thorens, G., Zullino, D., Preller, K., Böge, K., Leucht, S., Correll, C. U., Solmi, M., Kaiser, S., & Kirschner, M. (2024). Reconsidering evidence for psychedelic-induced psychosis: An overview of reviews, a systematic review, and meta-analysis of human studies. Molecular Psychiatry. https://doi.org/10.1038/s41380-024-02800-5

“Administering psychedelics to patients with schizophrenia intuitively seems at risk for triggering or exacerbating psychotic symptoms. However, empirical data on this topic is limited. Sabé et al. found that 3.8% of patients with schizophrenia experienced psychotic symptoms after psychedelic intake. By contrast, the incidence of psychedelic-induced psychosis in healthy controls and of prolonged psychosis was anecdotal. Psychedelic-induced psychotic disorders showed a high risk of converting to schizophrenia in 13.1% of the cases. These results call for a balanced risk-benefit assessment when considering psychedelics for patients with depression and co-occurring schizophrenia or psychotic history.” – Lucie Berkovitch

Schmid, Y., & Bershad, A. K. (2024). Altered States and Social Bonds: Effects of MDMA and Serotonergic Psychedelics on Social Behavior as a Mechanism Underlying Substance-Assisted Therapy. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 9(5), 490–499. https://doi.org/10.1016/j.bpsc.2024.02.001

“An implication of the findings discussed in this review is that the effects of psychedelics on self-processing/self-experience, emotional processing/emotional experience, and social processing/social experience are closely related and likely fundamentally inseparable both conceptually and mechanistically.” – CJ Healy

Shinozuka, K., Jerotic, K., Mediano, P., Zhao, A. T., Preller, K. H., Carhart-Harris, R., & Kringelbach, M. L. (2024). Synergistic, multi-level understanding of psychedelics: Three systematic reviews and meta-analyses of their pharmacology, neuroimaging and phenomenology. Translational Psychiatry, 14(1), 485. https://doi.org/10.1038/s41398-024-03187-1

“Shinozuka et al present an impressive dissertation on psychedelic literature, extensively covering their effects on pharmacology, neuroimaging, and phenomenology. They provide extensive coverage on a broad spectrum of literature. Additionally, they perform 3 meta-analyses – using creative approaches in the case of neuroimaging, which has been a notoriously difficult literature to synthesize in psychedelics. Lastly, they relate the results of each level (pharma, imaging, experience) to neural fingerprints (relation to 7 a priori resting-state networks) in an effort to uniquely unify these three levels of understanding. A truly massive effort.” – S. Parker Singleton

Solaja, I., Haldane, K., Mason, N., Weiss, B., Xu, X., Xu, M., Nikolin, S., Jayasena, T., Millard, M., Brett, J., Bayes, A., Loo, C. K., & Martin, D. M. (2024). Who are you after psychedelics? A systematic review and a meta-analysis of the magnitude of long-term effects of serotonergic psychedelics on cognition/creativity, emotional processing and personality. Neuroscience & Biobehavioral Reviews, 158, 105570. https://doi.org/10.1016/j.neubiorev.2024.105570

“Much has been made of how psychedelic experiences can change a person, especially of potential changes in personality (sometimes erroneously claimed to be fully stable in adulthood otherwise). Here, Ivana Solaja and colleagues looked systematically at the evidence up to July 2022 for long-term (minimum one week) changes in cognition/creativity, emotional processing, and personality after serotonergic psychedelics. Mostly the review shows that there is little evidence from controlled studies for such changes and that, as always, more research is needed. The only significant effects that did emerge were for faster reaction times for disgust and sadness, interestingly. While it sometimes feels the ratio of reviews to empirical research papers is unreasonably high in psychedelic research, careful systematic reviews like this are important to temper dramatic claims about things like changes in personality. Clearly, some individual people experience radical changes after taking a psychedelic, but for now at least, there is no solid evidence to suggest that on average they change people’s personality or enhance their creativity.” – Samuli Kangaslampi

Yaden, D. B., Goldy, S. P., Weiss, B., & Griffiths, R. R. (2024). Clinically relevant acute subjective effects of psychedelics beyond mystical experience. Nature Reviews Psychology, 3(9), 606–621. https://doi.org/10.1038/s44159-024-00345-6

“This paper rehearses the past psychedelic mysticism story in order to attempt to go beyond it to other experiences people may have with psychedelics that can either help or hinder their healing and growth. In this story we can see the kernel of how psychedelic science research has mismatched some of its methods to its questions, which Yaden et al. go some way toward acknowledging when they caution researchers that quantitative approaches neglect to probe crucial components of construct validity. They advocate qualitative, iterative and evidence-based approaches to item development that use meta-surveys and interviews to probe sources of construct-irrelevant variance. Yet, what this call should prompt researchers to do, above all, is zoom out to conduct a rigorous self-inquiry into why they desire to find out in the first place, and for what purpose, using these methods. The science of psychedelic subjective experience that Yaden et al. track here and elsewhere begins with William James, who distilled his discussion of mystical experience from richly detailed cases of how such experiences functioned in particular lives, through specific practices (ritual technologies, social frameworks of traditions, etc.), oriented toward specific spiritual purposes articulated through and iteratively informing an anthropology, a metaphysics, and an ontology. Walter Stace then explicitly shed this detail in order to provide the phenomenological typology of mysticism as the basis of the comparison – mysticism becomes a state devoid of any enabling constraints (tradition, context) or purpose guiding practice. The MEQ then formulated by Walter Pahnke was motivated by trying to show a certain effect happened, rather than understand the skills people were using to work with the experience, for what purposes, and how they formulated those purposes in relation to a lifeway and a worldview. By operationalizing mysticism as an artificial grade bar, the MEQ pushed the study of psychedelics’ acute subjective effects deeply into the abstract. Pahnke’s dissertation reported that “three or four of the ten psilocybin subjects reached the 60% to 70% level of completeness,” neglecting to explain what it is to have a “partial” mystical experience, or what the purpose of such an experience is for the subjects’ pastoral or theological practice. The methodological wager that a survey method would yield epistemological precision by virtue of being amenable to quantitative analysis, has continued to shape studies whose methods similarly obscure what happened in the experiment and limit how it could be interpreted.  In rightly pointing out that psychedelic science has often neglected to incorporate insights from psychological science that has already long studied processes such as emotions or self-identity, Yaden et al.’s paper also raises the issue that in these literatures, too, states are often likewise studied so abstractly as to produce tautological discussions. The science of awe, which they highlight as particularly relevant to acute psychedelic experience, is a good example here, with studies often designed to show participants visuals that they predict will elicit awe, and then finding neural or other physiological markers that are interpreted to be consonant with the phenomenological elements that the experimenters and or subjects associate with awe. Additionally, the research on meditation, conceived of as simultaneously a state and an active process, should be instructive here in the push to enhance methodological rigour on acute psychedelic subjective experience. The meditation research has made clear that a state, such as “mystical” or “awe” guarantees nothing – in fact, there is no state separable from the skills one has to be in that state and the role of a practice path around those skills and those states throughout a lifecourse. The therapeutic course after a psychedelic experience – whether and how someone’s wellbeing increases or decreases over time – involves a conative process of using skills to model their phenomenological, emotional, cognitive, etc. experiences, their interrelationships, and the relationship of their subjectivity to everything they exist in relation to. As an acute subjective experience, awe or other supposedly beneficial psychedelic experiences may be conducive to having the motivation and fortitude not to dissociate, and therefore to be integrated enough to do this modelling. The greatest analytical traction will come as the mixed-methods research Yaden et al. call for begins zooming out to account in its study conceptualization and design for the diachronic, contextual, and practical reality in which phenomenological moments have their meaning.” – Sharday Mosurinjohn

Aaronson, S. T., Van Der Vaart, A., Miller, T., LaPratt, J., Swartz, K., Shoultz, A., Lauterbach, M., Suppes, T., & Sackeim, H. A. (2024). Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial. American Journal of Psychiatry, 182(1), 104–113. https://doi.org/10.1176/appi.ajp.20231063

“In this study, Aaronson et al. investigated the safety and efficacy of psilocybin in patients with severe and comorbid treatment-resistant depression. They evidence positive efficacy and safety results sustained at 12 weeks. Despite the small sample size and open-label design, these findings lay important groundwork for future research and care, as these patients are typically the most challenging to treat in real-life clinical practice.” – Lucie Berkovitch

Aepfelbacher, J., Panny, B., & Price, R. B. (2024). Experiences of Awe Mediate Ketamine’s Antidepressant Effects: Findings From a Randomized Controlled Trial in Treatment-Resistant Depression. Biological Psychiatry Global Open Science, 4(4), 100316. https://doi.org/10.1016/j.bpsgos.2024.100316

“Unlike classic psychedelics, the role of ketamine’s acute subjective experiences in its therapeutic efficacy remains underexplored. This randomized, placebo-controlled trial advances the field by specifically examining the role of awe. Results show that experiences of awe during a single ketamine infusion, rather than dissociation,  statistically mediated reductions in depression. Remarkably, these mediation effects persisted up to 30 days post-infusion, suggesting that stronger experiences of awe may allow for more sustained antidepressant effects. Could deliberately enhancing awe during ketamine sessions – through guided reflection, imagery, or music – enhance and prolong its therapeutic efficacy? Further research is warranted to better understand ketamine-induced awe and its underlying mechanisms.” – Maia Mallvays

Allen, N., Jeremiah, A., Murphy, R., Sumner, R., Forsyth, A., Hoeh, N., Menkes, D. B., Evans, W., Muthukumaraswamy, S., Sundram, F., & Roop, P. (2024). LSD increases sleep duration the night after microdosing. Translational Psychiatry, 14(1), 191. https://doi.org/10.1038/s41398-024-02900-4

“This paper reports that participants in a 10ug LSD microdosing condition slept about 20 minutes longer the night after microdosing, compared to people in the control condition. I found this to be a very intriguing demonstration of a clinically meaningful microdosing outcome that is unlikely to be due to placebo. There’s virtually no scientific data on the effectiveness of different microdosing schedules but the delayed effect reported here supports the idea that it may be important to space out dosing days.” – Vince Polito

Atila, C., Straumann, I., Vizeli, P., Beck, J., Monnerat, S., Holze, F., Liechti, M. E., & Christ-Crain, M. (2024). Oxytocin and the Role of Fluid Restriction in MDMA-Induced Hyponatremia: A Secondary Analysis of 4 Randomized Clinical Trials. JAMA Network Open, 7(11), e2445278. https://doi.org/10.1001/jamanetworkopen.2024.45278

“Acute hyponatremia (low sodium in the blood) is an apparently dose-independent adverse effect of MDMA that, when symptomatic, is associated with high risk of morbidity or even mortality. MDMA-related hyponatremia can be particularly bedeviling because it has nonspecific symptoms, including headache, nausea, and lethargy, that may be naively (and dangerously) interpreted as evidence of dehydration. Early studies suggested MDMA-related hyponatremia might be caused by drug-induced release of the antidiuretic hormone vasopressin, possibly in combination with excessive fluid consumption. Subsequent studies administering MDMA to healthy participants supported a role for fluid consumption but did not find evidence that vasopressin was contributing to MDMA-related hyponatremia. The current manuscript conducted a pooled analysis of four MDMA administration studies with healthy participants and found that mild MDMA-related hyponatremia was common despite the clinical setting. Moreover, hyponatremia was associated with plasma oxytocin rather than vasopressin. This suggests oxytocin may be cross-binding to receptors for the structurally similar vasopressin. Given that oxytocin is theorized to contribute to the therapeutic effects of MDMA, hyponatremia may be an inherent risk with MDMA. Happily, this risk appears to be manageable as no cases of hyponatremia occurred in a subset of 15 participants in a protocol with restricted fluid intake. All in all, this paper provides more evidence that both experimental and therapeutic use of MDMA should acutely limit intake of solute free fluids.” – Matthew Baggott

Back, A. L., Freeman-Young, T. K., Morgan, L., Sethi, T., Baker, K. K., Myers, S., McGregor, B. A., Harvey, K., Tai, M., Kollefrath, A., Thomas, B. J., Sorta, D., Kaelen, M., Kelmendi, B., & Gooley, T. A. (2024). Psilocybin Therapy for Clinicians With Symptoms of Depression From Frontline Care During the COVID-19 Pandemic: A Randomized Clinical Trial. JAMA Network Open, 7(12), e2449026. https://doi.org/10.1001/jamanetworkopen.2024.49026

“This was a really interesting clinical trial in a targeted patient population. My favorite thing about it though is the reporting on the methods and results is absolutely top-tier and fully transparent. I hope this sets a standard for trials going forward as having access to results in many forms is key to our ability to robustly synthesize evidence across the field.” – S. Parker Singleton

Deco, G., Sanz Perl, Y., Johnson, S., Bourke, N., Carhart-Harris, R. L., & Kringelbach, M. L. (2024). Different hierarchical reconfigurations in the brain by psilocybin and escitalopram for depression. Nature Mental Health, 2(9), 1096–1110. https://doi.org/10.1038/s44220-024-00298-y

“This study by Deco et al. delves into the brain mechanisms underlying antidepressant effects of psilocybin and escitalopram. They confirmed that both substances significantly changed hierarchical brain organization, but, interestingly, in opposite directions. Moreover, the patterns of reconfiguration varied between responders and non-responders, within and across treatment groups. Overall, these results illustrate how different antidepressants rebalance pathological brain dynamics in depression and offers a valuable framework for understanding individualized responses to treatment.” – Lucie Berkovitch

Glue, P., Loo, C., Fam, J., Lane, H.-Y., Young, A. H., Surman, P., BEDROC study investigators, Glozier, N., Fitzgerald, P., Liu, D., Sharma, S., Grunfeld, J., Barton, D., Hopwood, M., Miles, W., Williams, M., Carson, S., Fam, J., Tor, P.-C., … Huang, Y.-J. (2024). Extended-release ketamine tablets for treatment-resistant depression: A randomized placebo-controlled phase 2 trial. Nature Medicine, 30(7), 2004–2009. https://doi.org/10.1038/s41591-024-03063-x

“In this interesting study, Glue et al., evaluated the efficacy and the safety of an oral extended-release form of ketamine (R-107) in treatment-resistant depression. Following an open-labeled enrichment phase consisting in administering 120 mg of R-107 daily, responders were randomized to receive double-blind doses (30-180 mg) or a placebo for 12 weeks. A sustained dose-dependent response was observed, particularly in the 180 mg group, with a favorable safety profile. These results position extended-release oral ketamine as a promising alternative to existing intranasal and intravenous formulations.” – Lucie Berkovitch

Greenway, K. T., Garel, N., Dinh-Williams, L.-A. L., Beaulieu, S., Turecki, G., Rej, S., & Richard-Devantoy, S. (2024). Music as an Intervention to Improve the Hemodynamic Response of Ketamine in Depression: A Randomized Clinical Trial. JAMA Network Open, 7(2), e2354719. https://doi.org/10.1001/jamanetworkopen.2023.54719

“This randomized clinical trial by Greenway and colleagues investigates whether music can mitigate ketamine-induced hemodynamic changes in patients receiving intravenous ketamine for treatment-resistant depression. The authors highlight that ketamine’s stimulatory effects on blood pressure can require pharmacological intervention in a significant subset of patients. They tested whether curated music during ketamine infusions could reduce these effects, finding that music significantly attenuated increases in systolic blood pressure but had no effect on diastolic pressure. The study underscores how environmental factors, such as auditory stimuli, might modulate ketamine’s physiological and psychoactive effects. While the trial is limited by its modest sample size (N=32), the results suggest music as a nonpharmacological adjunct to improve the safety profile of ketamine therapy. The authors call for future research with larger samples to confirm these findings and explore the broader clinical implications of integrating music into ketamine therapy.

What remains unaddressed, however, is whether different styles of music might elicit differential effects on ketamine-induced hemodynamic responses. Given prior research demonstrating that musical elements (rhythm, tempo, mode, genre, consonant vs dissonant, lyrics, etc.) can influence physiological and psychological parameters (blood pressure, heart rate, respiration, mood, arousal, etc.) (see for example Koelsch & Jäncke, 2015), it is plausible that these factors could also play a role when combined with pharmacological interventions.

A deeper investigation into the nuances of musical selection could offer valuable insights into how auditory stimuli may optimize safety and therapeutic efficacy of ketamine-assisted treatments. Additionally, extending this line of research to other psychoactive substances (e.g., classical psychedelics or empathogens) could help understand the broader role of music and sensory environment for the physiological responses and subjective experiences across different pharmacological interventions.” – Helena Aicher

Haggarty, C., Molla, H., Glazer, J., Tare, I., Rains, A., De Wit, H., & Lee, R. (2024). Low-Dose LSD Alters Early and Late Event-Related Potentials to Emotional Faces. Psychedelic Medicine, 2(4), 210–220. https://doi.org/10.1089/psymed.2024.0005

“I found this paper to be quite interesting due to its use of EEG to understand emotional processing in the brain. So many studies with psychedelics are specifically focused on using these substances as a treatment for mood-based disorders, and even more recently there has been an interest in subthreshold doses of psychedelics to improve mood in healthy people. Despite the heightened interest in psychedelics’ prosocial effects at low doses, a lot is unknown about how different doses of psychedelics directly alter emotional processing. The authors found that low dose LSD reduced amplitude of event-related potential (ERP) elicited in the part of the brain responsible for visuospatial processing in response to neutral faces, but not angry or happy faces. Further, they found that LSD reduced the amplitude of ERPs elicited in brain regions responsible for emotional processing and decision-making in response to neutral and happy faces, but not angry faces. This study provides key insights into how different brain regions are involved in LSD’s differential effects on social and emotional information processing, suggesting that LSD dampens emotional responses in general and isn’t necessarily “prosocial” as many hypothesize.” – Alaina Jaster

Jungwirth, J., Von Rotz, R., Dziobek, I., Vollenweider, F. X., & Preller, K. H. (2024). Psilocybin increases emotional empathy in patients with major depression. Molecular Psychiatry. https://doi.org/10.1038/s41380-024-02875-0

“A variety of acute and post-acute subjective effects of psychedelics (e.g., mystical experience, positive affect) have been repeatedly investigated – but this study addresses a less-explored component of social relationships and therapeutic processes that may be affected by psychedelics: empathy. This study was a randomized, double blind, placebo-controlled trial of 51 participants with depression. Key findings are that psilocybin is associated with emotional empathy, but not implicit or cognitive empathy, and that there were no correlations between increased empathy and reduced depression symptoms. Given the strong theoretical basis for the study and role of empathy in healthy social relationships, it was perhaps unexpected to find that psilocybin only had lasting effects on emotional empathy and that empathy does not seem to be a mechanism through which psilocybin may improve depression. The authors appropriately note limitations of the study (e.g., relatively short follow up period, expectancy bias) and provide interesting preliminary evidence that would support future work on the effects of psilocybin on empathy.” – Rebecca Ehrenkranz

Levin, A. W., Lancelotta, R., Sepeda, N. D., Gukasyan, N., Nayak, S., Wagener, T. L., Barrett, F. S., Griffiths, R. R., & Davis, A. K. (2024). The therapeutic alliance between study participants and intervention facilitators is associated with acute effects and clinical outcomes in a psilocybin-assisted therapy trial for major depressive disorder. PLOS ONE, 19(3), e0300501. https://doi.org/10.1371/journal.pone.0300501

“Psychotherapy is a social situation, and the findings of this study reinforce that the fact that therapists are people with whom patients are in relationship and not nameless professionals performing impersonal interventions is not just relevant to our understanding of mechanisms of therapeutic action but in fact of critical and central consequence.” – CJ Healy

Maples-Keller, J. L., Hyatt, C. S., Phillips, N. L., Sharpe, B. M., Sherrill, A., Yasinski, C., Reiff, C., Rakofsky, J., Rauch, S. A. M., Dunlop, B. W., & Rothbaum, B. O. (2024). Rapid Effects of MDMA Administration on Self-Reported Personality Traits and Affect State: A Randomized, Placebo-Controlled Trial in Healthy Adults. Journal of Psychoactive Drugs, 1–9. https://doi.org/10.1080/02791072.2024.2420044

“Illicit use of MDMA has been associated with both improved mood (“afterglow”) and lowered mood (“midweek lows”) in the days after use. In contrast, MDMA administration in controlled settings has been mainly associated with modest sub-acute side effects such as difficulty concentrating (22% of 166 study participants in Vizeli and Liechti 2017) and lack of energy (30%). This study finds evidence supporting an afterglow-like condition at 48 hours after 100 mg MDMA (or placebo) was administered to healthy MDMA-experienced participants. This was detected with both an instrument designed to measure self-reported personality (IPIP-NEO-60, which detected a medium effect-size increase in Openness) and another designed to measure affect (PANAS-X, which saw a smaller effect-size increase in Positive Affect). Because participants were MDMA-experienced, it’s a little unclear how prevalent this afterglow experience might be among the general population or specific patient populations. Nonetheless, the study provides evidence that MDMA can subacutely improve mood outside of therapeutic contexts. MDMA is not normally considered a fast acting antidepressant. Still, it has been reported to potently increase neuroplasticity in the same assays that shows effects for ketamine and other fast acting antidepressants. If antidepressant-like mood effects are measurable in the days after drug exposure, perhaps MDMA and other entactogens can also produce an enhanced capacity for change and growth in the same time window? If so, it would seem important to study how this can be made reliable and used to support therapeutic outcomes.” – Matthew Baggott

Mehtani, N. J., Johnson, M. O., Hendricks, P. S., Mitchell, J., & Anderson, B. T. (2024). Psilocybin-assisted therapy and HIV-related shame. Scientific Reports, 14(1), 17919. https://doi.org/10.1038/s41598-024-68908-4

“This study suggests the tremendous potential for psilocybin-assisted therapy to reduce shame in people with HIV who may struggle with significant barriers to wellbeing. More broadly, this research considers the value of moving beyond psychiatric diagnosis and conventional symptom reduction as targets for psychedelic interventions and further considering targets like psychological functioning and self-identity as key health-related outcomes. One notable finding from this trial was that, while most people benefited, sexual abuse-related shame increased in two participants after psilocybin – suggesting that psychedelic therapy may not always be straightforward, and that careful support might be needed in vulnerable populations.” – David Mathai

Mortaheb, S., Fort, L. D., Mason, N. L., Mallaroni, P., Ramaekers, J. G., & Demertzi, A. (2024). Dynamic Functional Hyperconnectivity After Psilocybin Intake Is Primarily Associated With Oceanic Boundlessness. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 9(7), 681–692. https://doi.org/10.1016/j.bpsc.2024.04.001

“Mortaheb et al. reanalyzed resting-state fMRI data from 49 healthy individuals who received either psilocybin or placebo. They used sliding-window dynamic functional connectivity to track the temporal evolution of discrete connectivity states. Psilocybin led to widespread increases in static functional connectivity, alongside a heightened occurrence of a recurrent hyperconnected pattern which correlated with subjective experience. Notably, this pattern was linked to low BOLD signal amplitude, which has been associated with heightened cortical arousal and increased vigilance. Global BOLD signal remains a debated topic in psychedelic neuroimaging, as its treatment (preserving vs. regressing) can influence findings. Indeed, when Mortaheb et al. applied global signal regression, the hyperconnected pattern disappeared, leading them to advocate for preserving global signal in dynamic analyses. This aligns with their previous work on mind blanking, which also identified a hyperconnected state—though one marked by increased signal amplitude.” – S. Parker Singleton

Murphy, R. J., Sumner, R. L., Godfrey, K., Mabidikama, A., Roberts, R. P., Sundram, F., & Muthukumaraswamy, S. (2024). Multimodal creativity assessments following acute and sustained microdosing of lysergic acid diethylamide. Psychopharmacology, 242(2), 337–351. https://doi.org/10.1007/s00213-024-06680-z

“Murphy et al. conducted a rigorous and exhaustive evaluation of the impact of LSD microdosing on creativity. They uncover a striking contrast: participants subjectively reported feeling more creative on dose days, yet objective creativity measures showed no significant difference compared to placebo. These results add to growing evidence that microdosing’s perceived benefits may stem from subjective experience rather than measurable cognitive enhancements.” – Lucie Berkovitch

Nicholas, C. R., Banks, M. I., Lennertz, R. C., Wenthur, C. J., Krause, B. M., Riedner, B. A., Smith, R. F., Hutson, P. R., Sauder, C. J., Dunne, J. D., Roseman, L., & Raison, C. L. (2024). Co-administration of midazolam and psilocybin: Differential effects on subjective quality versus memory of the psychedelic experience. Translational Psychiatry, 14(1), 372. https://doi.org/10.1038/s41398-024-03059-8

“A creative approach to understand how recollection and quality of the psychedelic experience relates to outcomes.” – S. Parker Singleton

Raja, S. M., Guptill, J. T., Mack, M., Peterson, M., Byard, S., Twieg, R., Jordan, L., Rich, N., Castledine, R., Bourne, S., Wilmshurst, M., Oxendine, S., Avula, S. G. C., Zuleta, H., Quigley, P., Lawson, S., McQuaker, S. J., Ahmadkhaniha, R., Appelbaum, L. G., … Thomas, C. J. (2024). A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2 R ,6 R )‐Hydroxynorketamine in Healthy Volunteers. Clinical Pharmacology & Therapeutics, 116(5), 1314–1324. https://doi.org/10.1002/cpt.3391

“I liked this paper because one of the first psychedelic research experiences I had was giving hydroxynorketamine (HNK) to cortical neurons in a dish during my undergraduate research course. It’s really great to see this line of research still being explored. This phase 1 assessment, while an obvious important step into developing HNK as a pharmacotherapy, is a great example of the amount of work and effort that goes into the understanding of the safety and tolerability of a drug. Ketamine has been shown to have positive outcomes for people with depression but not without some risks of dependence. It would be amazing to develop HNK as an alternative for those at risk of developing a substance use disorder that still are suffering from depression, and this study is a great first step in that direction.” – Alaina Jaster

Roseman, L., Erritzoe, D., Nutt, D., Carhart-Harris, R., & Timmermann, C. (2024). Interrupting the Psychedelic Experience Through Contextual Manipulation to Study Experience Efficacy. JAMA Network Open, 7(7), e2422181. https://doi.org/10.1001/jamanetworkopen.2024.22181

“This brilliant little paper reports the finding that brief and relatively minor demands on attention during a psychedelic experience prove to be significant enough distractions from subjective immersion in the experience that they compromise not only the acute phenomenological effects but also the long-term therapeutic benefits of the experience. (Interestingly, 2 days later by publication dates, this finding was independently replicated — here in terms of compromised acute brain effects rather than subjective effects — by Siegel et al., Psilocybin desynchronizes the human brain.)” – CJ Healy

“This quality improvement analysis by Roseman and colleagues explores the concept of “experience efficacy” in psychedelic interventions by investigating whether cognitive interruptions can modulate the subjective experience of N,N-dimethyltryptamine (DMT) and also effects of the intervention on depression scores. Using a secondary analysis of a previous study, the authors examined how asking participants to rate their subjective experiences during DMT altered the intensity and therapeutic impact of the experience. They found that these cognitive interruptions significantly diminished key aspects of the psychedelic state, including feelings of unity, insightfulness, and spiritual experience; factors previously associated with positive mental health outcomes. Participants who were not interrupted exhibited greater reductions in depressive symptoms two weeks later. While the study is limited by a small sample size (N=20) and the relatively mild nature of the interruption, it suggests that contextual manipulation can be a useful tool for studying therapeutic mechanisms of psychedelics and more specifically the relevance of the subjective experience. The authors propose that future research should explore more demanding cognitive interruptions to further elucidate the role of experience in psychedelic-assisted therapy.

In my view, this study is particularly noteworthy as it reinforces the long-standing understanding that contextual factors significantly shape psychedelic experiences and extends this by highlighting the relevance of the experience itself in determining therapeutic outcomes – a topic currently under active discussion in the field (e.g., Olson, 2021; Yaden & Griffiths, 2021). Importantly, the findings also imply that results from prior studies involving acute assessments or experimental tasks during the psychedelic state may have been influenced by those very interventions. This underscores the need for caution when comparing drug effects across studies: Not only should differences in substances and dosages be considered, but also the design of the study protocol including the presence, timing, and modality of any in-session assessments or tasks (e.g., computer-based, verbal, written).

The study affirms that there is no singular or fixed “drug effect,” but rather a highly dynamic and context-sensitive state shaped by both pharmacological and extrapharmacological variables. As previously proposed (e.g., Langlitz, 2024; Roseman et al., 2022), future research should more systematically examine how variations in setting affect the acute subjective experience and downstream clinical outcomes.” – Helena Aicher

Sajid, S., Galfalvy, H. C., Keilp, J. G., Burke, A. K., Mann, J. J., & Grunebaum, M. F. (2024). Acute Dissociation and Ketamine’s Antidepressant and Anti-Suicidal Ideation Effects in a Midazolam-Controlled Trial. International Journal of Neuropsychopharmacology, 27(4), pyae017. https://doi.org/10.1093/ijnp/pyae017

“Sajid et al. contribute an insightful exploratory analysis addressing conflicting results from previous clinical trials: Is dissociation during ketamine administration an active mechanism responsible for the antidepressant effects or is it a (possibly undesirable) side effect? Using a post-hoc design in participants with depression and suicidal ideation, they found no correlation between dissociation and clinical improvements, suggesting that dissociation is not an active mechanism of ketamine’s therapeutic effects. The study also explores the potential role of ketamine metabolites in producing dissociation, shedding light on how ketamine’s pharmacokinetics may influence its side effects and therapeutic potential.” – Bente Vissel

Siegel, J. S., Subramanian, S., Perry, D., Kay, B. P., Gordon, E. M., Laumann, T. O., Reneau, T. R., Metcalf, N. V., Chacko, R. V., Gratton, C., Horan, C., Krimmel, S. R., Shimony, J. S., Schweiger, J. A., Wong, D. F., Bender, D. A., Scheidter, K. M., Whiting, F. I., Padawer-Curry, J. A., … Dosenbach, N. U. F. (2024). Psilocybin desynchronizes the human brain. Nature, 632(8023), 131–138. https://doi.org/10.1038/s41586-024-07624-5

“High powered precision functional mapping meets psychedelic science. Six healthy adults were scanned multiple times (roughly 18 fMRI visits per subject with rest and task scans at each visit) before, during and for three weeks after high-dose psilocybin and methylphenidate (ritalin). The combination of multiple repeated scanning visits during each period and the use of a stimulant control allowed the authors to study both psilocybin’s acute effects with respect to a heightened arousal state, and psilocybin’s enduring post-acute effects with respect to normal sampling variability. Persistent effects of psilocybin were isolated to an uncoupling of anterior-hippocampal-cortical functional connectivity in the three weeks post-psilocybin that returned to baseline by 6-12 month follow-up visits. Super cool and robust study, plus a Huxley-inspired mage on the cover of Nature magazine.” – S. Parker Singleton

Sloshower, J., Zeifman, R. J., Guss, J., Krause, R., Safi-Aghdam, H., Pathania, S., Pittman, B., & D’Souza, D. C. (2024). Psychological flexibility as a mechanism of change in psilocybin-assisted therapy for major depression: Results from an exploratory placebo-controlled trial. Scientific Reports, 14(1), 8833. https://doi.org/10.1038/s41598-024-58318-x

“How do we build a rigorous psychotherapy framework for psychedelic-assisted therapy? Jordan Sloshower and colleagues have been leaders in this space with their long standing focus on Acceptance and Commitment Therapy (ACT) as a well-suited pairing for psychedelics. Their report lends further empirical support for ACT as an evidence-based therapy that can engage psychological flexibility and facilitate drug-specific mechanisms of action for psilocybin.” – David Mathai

Straumann, I., Avedisian, I., Klaiber, A., Varghese, N., Eckert, A., Rudin, D., Luethi, D., & Liechti, M. E. (2024). Acute effects of R-MDMA, S-MDMA, and racemic MDMA in a randomized double-blind cross-over trial in healthy participants. Neuropsychopharmacology, 50(2), 362–371. https://doi.org/10.1038/s41386-024-01972-6

“MDMA is a racemic substance that contains equal amounts of the enantiomers S- and R- MDMA. The effects of these enantiomers in humans were qualitatively studied by Dave Nichols, Sasha Shulgin, and their colleagues in the late 1970s after Nichols developed a method of synthesizing the pure enantiomers. These researchers were generally unimpressed by up to 200 mg of the clearly less potent R-enantiomer of MDMA. When methods advanced enough to profile R-MDMA’s effects at monoamine transporters, it appeared to have a profile reminiscent of a less potent MDAI, a compound that the US federal government never bothered to schedule. This all made it somewhat surprising when R- but not S- MDMA was reported to facilitate in mice the extinction of conditioned fear behavior, an animal model with good face validity for studying exposure therapy and recovery from trauma. Interestingly, while R-MDMA improved extinction testing the next day, it did not acutely reduce fear behavior (freezing) during the fear extinction training session. S-MDMA was the opposite: acutely reducing conditioned fear behavior during extinction training, but not helping the next day. Setting aside the fact that mice are an outlier species with respect to MDMA effects, this seemed to set up the possibility that both enantiomers might play distinct and complementary roles in the therapeutic effects of MDMA. And given the known greater chronic monoamine lowering effects of the S-enantiomer, this also seemed to justify exploration of R-heavy mixtures or even pure R-MDMA as a therapeutic adjunct. (Weighing somewhat against this approach is an early finding that R- was equipotent to S- MDMA in acutely lowering tryptophan hydroxylase, a putative marker of oxidative stress. Because R has the lower potency and thus requires higher doses, this raises questions how much higher oxidative stress might be with effective doses of R.)

Against this background, the current MDMA-administration study from Staumann et al. is a much needed investigation of the acute pharmacology of MDMA’s enantiomers in 24 healthy participants. The five dosing conditions – placebo, 125 mg of racemic MDMA, 125 mg of S-MDMA, 125 and 250 mg of R-MDMA – were selected to facilitate comparisons between the enantiomers. However, 125 mg S-MDMA appeared distinctly more active than the 250 mg dose of R, suggesting the selected doses were not quite comparable. (It’s not obvious how to best select doses of different drugs for the purposes of comparing them, especially without any pharmacokinetics, but it would seem reasonable to ask that psychoactive drugs be comparable on self-reported ‘any drug effect’ or similar.) Disappointingly, the enantiomers did not have dramatically different qualitative pharmacological profiles, at least not given the current study’s measures. Proponents of the potential value of the R-enantiomer might point out that there were no measures that would be analogous to the improved fear extinction seen in mice. Thus, it remains to be seen if R-MDMA might have clearer value when, for example, paired with some type of exposure therapy. Still, even if the study proved disappointing for those of us hoping to improve on racemic MDMA, the study nonetheless provides a wealth of careful pharmacokinetics and dynamics information. Having a clean measure of the elimination half-lives of the enantiomers, independent from their competition when given together, is valuable. The shortened half-life of S-MDMA given alone compared to when given as part of racemic MDMA suggests that part of the appeal of racemic MDMA might be that the presence of the R-MDMA is extending exposure to the more active S-MDMA. It is additionally intriguing that the S-enantiomer was the only treatment to significantly lower mood ratings in the days after administration, providing hints to the potential mechanism of this elusive phenomenon.” – Matthew Baggott

Szigeti, B., Weiss, B., Rosas, F. E., Erritzoe, D., Nutt, D., & Carhart-Harris, R. (2024). Assessing expectancy and suggestibility in a trial of escitalopram v. Psilocybin for depression. Psychological Medicine, 54(8), 1717–1724. https://doi.org/10.1017/S0033291723003653

“Compelling evidence against the notion that the therapeutic benefits of psychedelics are largely or entirely driven by placebo effects.” – CJ Healy

Alberto‐Silva, A. S., Hemmer, S., Bock, H. A., Da Silva, L. A., Scott, K. R., Kastner, N., Bhatt, M., Niello, M., Jäntsch, K., Kudlacek, O., Bossi, E., Stockner, T., Meyer, M. R., McCorvy, J. D., Brandt, S. D., Kavanagh, P., & Sitte, H. H. (2024). Bioisosteric analogs of MDMA: Improving the pharmacological profile? Journal of Neurochemistry, 168(9), 2022–2042. https://doi.org/10.1111/jnc.16149

“MDMA’s oxygen-containing side ring is readily metabolized in the body into two hydroxyl groups, creating a reactive metabolite that resembles dopamine. A large and somewhat contradictory literature has investigated whether this and downstream metabolites might contribute to the toxicity of MDMA. If these metabolites really are toxicologically important, there could be great value in finding new chemical structures that resist metabolism but are otherwise pharmacologically similar to MDMA. The current paper describes three novel replacements for MDMA’s side ring and shows they successfully resist metabolism while still causing the monoamine release that is predictive of acute MDMA-like emotional effects. However, without animal assays, we cannot yet tell whether these promising analogues are truly entactogens. The authors also report reduced activity at 5-HT2A/2B/2C receptors, although MDMA’s effects at these receptors are weak enough that it remains unclear how much direct agonist effects at 5-HT2Rs contribute to its pharmacology at therapeutic exposures. There is certainly evidence that valvular heart disease can occur with extensive MDMA use, but this may be caused indirectly, by released 5-HT stimulating 5-HT2BRs. An interesting question would be whether the corresponding MDA analogues of this paper’s compounds, which would be expected to be better 5-HT2R agonists, also show reduced 5-HT2R activity.” – Matthew Baggott

Alitalo, O., Kohtala, S., Rosenholm, M., Saarreharju, R., González-Hernández, G., Sarparanta, M., Rozov, S., & Rantamäki, T. (2024). Nitrous oxide induces hypothermia and TrkB activation: Maintenance of body temperature abolishes antidepressant-like effects in mice. Neuropharmacology, 261, 110172. https://doi.org/10.1016/j.neuropharm.2024.110172

“The paper by Alitalo et al. extends their previous findings linking body temperature and TrkB signalling, this time also adding some antidepressant–relevant behavioural outcomes. Their finding where the modification of body temperature of an animal changes both the neurotrophic signalling and behavioural effects of a drug is highly intriguing. Even though their drug of choice, nitrous oxide, is often not considered a psychedelic, the relevance to classical serotonergic psychedelics and ketamine is obvious, as TrkB signalling pathway has been implicated in their actions in many ways, directly and indirectly. As with any neurotrophin– and plasticity–related findings, the translation to humans and clinical relevance remain to be demonstrated, but I am interested and happy in seeing this kind of physiology-as-a-whole approach in psychopharmacology.” – Lauri Elsilä

Anderson, T. L., Keady, J. V., Songrady, J., Tavakoli, N. S., Asadipooya, A., Neeley, R. E., Turner, J. R., & Ortinski, P. I. (2024). Distinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI. Progress in Neurobiology, 240, 102660. https://doi.org/10.1016/j.pneurobio.2024.102660

“I had to give this paper a shout out because it had been a long time coming. I remember seeing a presentation at Society for Neuroscience on some of this work in 2023 and then was so excited to see the complete work published this past year. My favorite thing about this study is that it looks at projections from the claustrum to the cortex instead of projections from the cortex to other brain regions, which is what we typically see in preclinical circuitry studies. They find that the claustrum is enriched primarily with serotonin 2C receptors on excitatory neurons and that there are differential effects of serotonin and DOI on the signaling in this region. These findings break the mold of the canonical serotonin 2A receptor pathway as a mechanism of action for psychedelics and open the door to an entirely new line of research in the field.” – Alaina Jaster

Braun, D., Rosenberg, A. M., Rabaniam, E., Haruvi, R., Malamud, D., Barbara, R., Aiznkot, T., Levavi-Sivan, B., & Kawashima, T. (2024). High-resolution tracking of unconfined zebrafish behavior reveals stimulatory and anxiolytic effects of psilocybin. Molecular Psychiatry, 29(4), 1046–1062. https://doi.org/10.1038/s41380-023-02391-7

“I find myself thinking more about how to make our research useful for drug discovery. Cell lines are sometimes too simplistic, but mouse experiments take a long time. Here, this study shows that zebrafish behavioral assay may be a promising approach for high throughput screens with live animals. The authors did a very thorough job in quantifying how psilocybin affects the fishes’ movements, which was distinct from those changes elicited by ketamine and fluoxetine.” – Alex Kwan

Hinchcliffe, J. K., Stuart, S. A., Wood, C. M., Bartlett, J., Kamenish, K., Arban, R., Thomas, C. W., Selimbeyoglu, A., Hurley, S., Hengerer, B., Gilmour, G., & Robinson, E. S. J. (2024). Rapid-acting antidepressant drugs modulate affective bias in rats. Science Translational Medicine, 16(729), eadi2403. https://doi.org/10.1126/scitranslmed.adi2403

“The paper led by Justyna Hinchcliffe and Emma Robinson is one of my favourites from the previous year. The findings themselves are interesting, but I greatly appreciate their efforts in developing rodent models that have better translational validity: as far as I know, the effects of psychedelics and ketamine are and have already been studied in a human version of affective bias test with similar results. (I personally also love to see a paper with only behavioural results published in such a high impact journal, it gives me hope).” – Lauri Elsilä

Jeanblanc, J., Bordy, R., Fouquet, G., Jeanblanc, V., & Naassila, M. (2024). Psilocybin reduces alcohol self-administration via selective left nucleus accumbens activation in rats. Brain, 147(11), 3780–3788. https://doi.org/10.1093/brain/awae136

“The findings by Jerome Jeanblanc and others are highly interesting to me as a preclinical addiction researcher: it is an addition to the literature where a single dose of psychedelic reduces alcohol consumption in rodents, this time in rats, but it further emphasises the interesting question – where do the differences in effects and their lengths in the rodent models of alcohol use stem from? Why do some only see acute effects, some prolonged, and some no effects at all? Is it about the drinking levels and styles (operant vs. home cage, binge vs. continuous?) or about the treatment schedule? Their findings also raise interesting questions about the lateralisation of the rat brain and its reward system worth further enquiry.” – Lauri Elsilä

Pohořalá, V., Kuchař, M., Spanagel, R., & Bernardi, R. E. (2024). Psilocybin administered following extinction sessions does not affect subsequent cocaine cue reinstatement in male and female rats and mice. Neuroscience, 559, 156–165. https://doi.org/10.1016/j.neuroscience.2024.09.006

“As someone who spent several years researching psychedelics in preclinical models related to addiction, I can appreciate this study. They aimed to understand how psilocybin can alter cocaine-seeking behaviors in models of self-administration. Not only did this study use male and female mice to understand differences across sexes, but they also tested extinction of drug-seeking and cue-induced reinstatement of drug-seeking. While the authors found no effects of psilocybin on cocaine cue reinstatement, this could be due to when the psilocybin was administered. This study provides a great start to understanding the addiction-related processes and how psychedelics can reduce drug-seeking. More studies assessing different time points of administration of psilocybin and the extinction process will be an exciting addition to the field.” – Alaina Jaster

Tiwari, P., Davoudian, P. A., Kapri, D., Vuruputuri, R. M., Karaba, L. A., Sharma, M., Zanni, G., Balakrishnan, A., Chaudhari, P. R., Pradhan, A., Suryavanshi, S., Bath, K. G., Ansorge, M. S., Fernandez-Ruiz, A., Kwan, A. C., & Vaidya, V. A. (2024). Ventral hippocampal parvalbumin interneurons gate the acute anxiolytic action of the serotonergic psychedelic DOI. Neuron, 112(22), 3697-3714.e6. https://doi.org/10.1016/j.neuron.2024.08.016

“This was another long-awaited publication in the preclinical sciences. I’m such a sucker for a paper with a circuit component and this paper delivers. The authors were interested in determining how psychedelics produce their anxiolytic effects in rodent models. They combined multiple sophisticated techniques in both rats and mice, to produce a large body of work showing that the acute anxiolytic effects of psychedelic DOI and the cell-types involved are preserved across rodent species. While the work focused primarily on the acute effects of DOI, I would be very interested to see if this anxiolysis is observed post-acutely and whether the same cell types are responsible for those potential post-acute effects.” – Alaina Jaster

Warren, A. L., Lankri, D., Cunningham, M. J., Serrano, I. C., Parise, L. F., Kruegel, A. C., Duggan, P., Zilberg, G., Capper, M. J., Havel, V., Russo, S. J., Sames, D., & Wacker, D. (2024). Structural pharmacology and therapeutic potential of 5-methoxytryptamines. Nature, 630(8015), 237–246. https://doi.org/10.1038/s41586-024-07403-2

“Despite a long history of ritual, traditional, and more-recent clinical therapeutic use, 5-MeO-DMT is an understudied tryptamine – few explorations of the drug’s molecular underpinnings and mechanism of action exist. Warren et al. provide pharmacological profiles of 5-MeO-DMT and associated analogues, structural and morphological profiles of 5-MeO-DMT and highlight the 5-HT1A receptor as a locus of therapeutic activity. This work seems to align with an outstanding question in the field – are hallucinogenic effects necessary for therapeutic benefits? What I am left thinking about is how we continually see derivatives and analogues of naturally-occurring compounds synthesized and monopolized, without considering or appreciating historical and cultural practices and knowledge.” – Juliet Meccia

Alpert, M. D., O’Donnell, K. C., Paleos, C. A., Sola, E., Stauffer, C. S., Wagner, A. C., Nicholas, C. R., & Mithoefer, M. C. (2024). Psychotherapy in Psychedelic Treatment: Safe, Evidence-Based, and Necessary. American Journal of Psychiatry, 181(1), 76–77. https://doi.org/10.1176/appi.ajp.20230665

“A diverse series of thoughtful and often impassioned arguments against active efforts to minimize or excise entirely — both theoretically and practically — the psychosocial component (or so-called “psychotherapy component”) of psychedelic therapy.” – CJ Healy (also responding to other Goodwin et al. replies)

“PAT, PAP, PT…there is yet to be consensus on language for psychedelic treatments in development. This lack of alignment has resulted in the role of psychotherapy being an increasingly contentious issue for many stakeholders. Valid arguments have been made regarding the role of psychotherapy in potentially FDA-approved psychedelic treatments. No one company, organization, or stakeholder group should be responsible for establishing best practices – a coordinated approach is required to support the entire industry. The opportunity is ripe for psychology to enter the chat. As experts continue to make valid and at times conflicting arguments, perhaps the conversation should evolve to identify who might “own” the psychotherapy of it all. There are highly qualified therapists with hundreds and thousands of hours of experience in psychedelic clinical trials confused about what their roles in real-world settings will be should products come to market. Isn’t everyone in this space confused about what their roles will be in the future? After all, this has never been done at commercial scale in the U.S. medical system. In an incipient and diverse industry might the current debate be missing the forest for the trees?

In December 2024 The American Psychiatric Association (APA) published updated practice guidelines on the treatment of Borderline Personality Disorder (BPD). The APA recommendation is tiered to include both psychosocial interventions and pharmacotherapy treatments. Importantly, they suggest that patients with BPD treated with “any psychotropic medication be time-limited, aimed at addressing a specific measurable target symptom, and adjunctive to psychotherapy.”  Of note for emerging psychedelic treatments the APA does not distinguish between the numerous types of psychosocial interventions available; rather, the APA calls for a structured approach to psychotherapy, recognizing that many effective evidence-based options exist. Other examples of treatment models involving psychosocial interventions provide additional food for thought e.g. – SUD, HIV, bariatric surgery, dialysis, etc.

If the ultimate goal for those pursuing FDA approval is to provide treatment options that are safe and more effective than those presently available, shouldn’t the through line be meeting patients’ needs? Are we asking what patients want and incorporating that into decision-making or are we leaning into biased assumptions? All of the papers focused on this topic have provided space for healthy and much needed reflection and research.” – Gretchen Shaub (also responding to Weintraub et al. and Aday et al.)

Andrews, C. M., Hall, W., Humphreys, K., & Marsden, J. (2024). Crafting effective regulatory policies for psychedelics: What can be learned from the case of cannabis? Addiction, 120(2), 201–206. https://doi.org/10.1111/add.16575

“Andrews et al. note that early efforts with cannabis involved misrepresentation of medical use through “poorly-evidenced therapeutic claims”.  A lack of movement at the federal level resulted in a disjointed regulatory policy landscape at the state and local levels – history is repeating itself in the psychedelic space. States lack the rigorous safety and efficacy data needed to develop appropriate regulatory policies for access to psychedelics. The cannabis access playbook seems to be copied and pasted with little regard for potential long-term impacts. The authors outline five pivotal considerations including challenges setting limits on potency and dosing with little safety data available, setting limits on advertising, packaging, warning labels, and how to handle false claims, the need for investment in public education, coordinated federal and state policies, and tax implications. For those pursuing FDA approval, many of these issues are solved for within the existing highly regulated medical model. Non-medical access pathways at the state and local levels may suffer from replicating piecemeal strategies – a concerted effort to separate access pathways is needed for all to succeed.” – Gretchen Shaub

Bogenschutz M. P. (2024). Pharmacological and Nonpharmacological Components of Psychedelic Treatments: The Whole is Not the Sum of the Parts. The American journal of psychiatry, 181(1), 75. https://doi.org/10.1176/appi.ajp.20230643

“A diverse series of thoughtful and often impassioned arguments against active efforts to minimize or excise entirely — both theoretically and practically — the psychosocial component (or so-called “psychotherapy component”) of psychedelic therapy.” – CJ Healy (also responding to other Goodwin et al. replies)

Colloca, L., & Fava, M. (2024). What should constitute a control condition in psychedelic drug trials? Nature Mental Health, 2(10), 1152–1160. https://doi.org/10.1038/s44220-024-00321-2

“Colloca and Fava explore the neurobiology of placebo and expectation effects, highlighting the longstanding methodological challenge of blinding in psychedelic trials. A key strength of the article is its structured presentation of trial designs aimed at managing expectancy effects and minimizing bias, including the balanced placebo, sequential parallel comparison, and overt–covert administration designs; each with their strengths and limitations. Epistemologically, the authors appear to operate within an additive model rooted in isolating drug effects from contextual influences. This is particularly evident in their proposal to use virtual reality to disentangle the “phenomenology of psychedelics” from their “pharmacological effects” – an idea that risks reinforcing an outdated mind–brain dualism. For the field to move forward, we may need to acknowledge the complex and interactive nature of psychedelic therapy. The challenge, of course, is to design trials that reflect this complexity; but a preprint by Muthukumaraswamy et al. (2025) suggests there might be a way.” – Chloé Pronovost-Morgan

Deckel, G. M., Lepow, L. A., & Guss, J. (2024). “Psychedelic Assisted Therapy” Must Not Be Retired. American Journal of Psychiatry, 181(1), 77–78. https://doi.org/10.1176/appi.ajp.20230667

“The late Dr. Garret Deckel was an outstanding clinician and thinker, and she is surely missed by all of us who knew her. She and co-authors Dr. Lauren Lepow and Dr. Jeffrey Guss have made a critical point in this letter that is too easily forgotten: not all patients receiving psychedelic therapy are the same. While efforts to strip psychedelic-assisted therapy of its therapy in clinical settings could work for some people, it may be unethical and even dangerous to do so for those who are most vulnerable and at increased risk for adverse psychological outcomes.” – David Mathai

“A diverse series of thoughtful and often impassioned arguments against active efforts to minimize or excise entirely — both theoretically and practically — the psychosocial component (or so-called “psychotherapy component”) of psychedelic therapy.” – CJ Healy (also responding to other Goodwin et al. replies)

Earleywine, M., De Leo, J., Bhayana, D., Rajanna, B., & Scott, K. (2024). Psilocybin Without Psychotherapy: A Cart Without a Horse? The American journal of psychiatry, 181(1), 78–79. https://doi.org/10.1176/appi.ajp.20230572

“A diverse series of thoughtful and often impassioned arguments against active efforts to minimize or excise entirely — both theoretically and practically — the psychosocial component (or so-called “psychotherapy component”) of psychedelic therapy.” – CJ Healy (also responding to other Goodwin et al. replies)

Hanshaw, B. D., Fusunyan, M., Anderson, C. T. M., & Turban, J. L. (2024). Psychedelic-assisted therapy among sexual and gender minority communities. Nature Mental Health, 2(6), 636–644. https://doi.org/10.1038/s44220-024-00252-y

“Non-white, non-Western individuals with low incomes and educational levels from Global South countries are virtually absent from psychedelic research, resulting in significant biases. In this important article, the authors emphasize that this lack of diversity also affects sexual and gender minorities. These groups are particularly exposed to mental health issues caused by contemporary society’s oppressive and stigmatizing practices. The “minority stress theory” is a concept derived from this observation, referring to the specific experiences of these populations. To date, however, no clinical study has attempted to investigate the impact of psychedelic use on alleviating this particular stress. The authors express surprise that, “With nearly 21% of Generation Z identifying within the sexual and gender minority community, this is a notable gap in the psychedelic research landscape”. They note that two explanatory models for the action of psychedelics—the REBUS model and the CANAL model—can readily incorporate an analysis of the “minority stress” experience, which would allow for a better understanding of the therapeutic effects in this specific indication.” – Zoë Dubus

Jacobs, E., Earp, B. D., Appelbaum, P. S., Bruce, L., Cassidy, K., Celidwen, Y., Cheung, K., Clancy, S. K., Devenot, N., Evans, J., Lynch, H. F., Friesen, P., Romeu, A. G., Gehani, N., Maloof, M., Marcus, O., Martin Moen, O., Mertens, M., Nayak, S. M., … Yaden, D. B. (2024). The Hopkins-Oxford Psychedelics Ethics (HOPE) Working Group Consensus Statement. The American Journal of Bioethics, 24(7), 6–12. https://doi.org/10.1080/15265161.2024.2342764

“The HOPE Consensus Statement is an offering from a group of 32 stakeholders— Indigenous scholars, psychiatrists, ethicists, psychedelic scientists, anthropologists, philosophers, and harm reduction specialists—convened to develop a shared understanding of ethical practice with psychedelics. The need for developing an ethics of psychedelics is crucial given the field’s history of serious transgressions—including MK Ultra experiments, abuses of patients and prisoners, sexual boundary violations by guides, and appropriative practices toward Indigenous communities—transgressions that regrettably are not confined to the distant past.

At four pages, the statement is deliberately minimal, offering a common orientation rather than exhaustive guidance. Many complex issues, such as the ethics of therapeutic touch during psychedelic experiences, will require considerable collaborative work among patients, practitioners, and ethicists.

For me, it was particularly important that the statement recognise that psychedelic ethics extends beyond medical contexts. Though clinical applications dominate headlines, the majority of psychedelic use always has, and always will, occur outside medical settings, including for spiritual, self-development, and recreational purposes. Such use is just as worthy of care and thoughtful attention, and we need ethical frameworks that look beyond the clinical, acknowledging the broader societal currents that psychedelic use is situated in.

The HOPE statement represents only a beginning in the conveners’ intention to better establish psychedelic ethics as a field of inquiry. Ethics is a conversation everyone has a stake in, not something to be agreed by 32 people. That’s why we were pleased to host an August summit for 200 people in Washington, D.C., expanding the conversation to include more diverse voices. But neither is ethics the preserve of academic and clinical circles, which is why we’ve made efforts to make the statement accessible—translating it into six languages to reach beyond traditional spheres of influence.” – Eddie Jacobs

Lemarchand, C., Chopin, R., Paul, M., Braillon, A., Cosgrove, L., Cristea, I., Fried, E. I., Turner, E. H., & Naudet, F. (2024). Fragile promise of psychedelics in psychiatry. BMJ (Clinical research ed.), 387, e080391. https://doi.org/10.1136/bmj-2024-080391

“Alongside the overly positive, and in many places highly repetitive, reviews on psychedelic medicine, there has been an emergence of more critical points of view, of which the analysis/opinion by Cédric Lemarchand and others is a great example. I, for one, welcome the more sceptical and wary approaches to the field where e.g. the poor experimental designs and small numbers of participants are properly acknowledged. Studies with psychedelics also pose problems to the tradition of clinical investigation, especially in controlling blinding and expectations, and I think addressing these will be of utmost importance, but also something that should then be applied to clinical (psycho)pharmacological studies in large.” – Lauri Elsilä

McInnes, L. A., Marton, T. F., & Qian, J. J. (2024). Embracing pragmatism for ketamine insurance coverage: Leveraging real-world evidence. Journal of Affective Disorders, 352, 199–200. https://doi.org/10.1016/j.jad.2024.02.033

“In recent years, regulatory bodies like the FDA have been increasingly open to using real world evidence (RWE) to support new indications for approved drugs. RCTs remain a gold standard for establishing efficacy, but results may not be generalizable to more complex patients in community care settings, as opposed to controlled research populations and environments. A shift in the medical community towards embracing RWE could help move the needle on coverage of novel treatments with payors. Our current complex healthcare delivery environment necessitates innovative tactics.

The authors cite a recent review of evidence for ketamine infusion therapy (KIT), suggesting RWE could be leveraged for KIT insurance coverage. As a strength, they note the data on KIT effect size are quite consistent. But, significant amounts of missing data, which could lead to inflated effect size estimates, is a limitation, as are lack of demographic information and placebo control. There is also likely to be bias toward higher patient socioeconomic status given the out-of-pocket cost of KIT, and less diversity than a clinical trial which might seek to address inclusivity as an aim.

Since ketamine is off-patent, there is little financial incentive for any company to pursue FDA-registered trials to support a label for depression, making RWE even more relevant. RWE can increase access to KIT if it is packaged in such a way as to increase willingness towards reimbursement by payers. Efforts have been made to synthesize health records and claims data for presentation to CMS, and with a few recent local Medicaid wins, there is a clear opportunity to continue this trend, perhaps even bringing private payors along in the near future. This is a faster and less expensive pathway than interventional studies, and payors can feel confident in this approach, given FDA’s publication of a Framework, as well as prior approvals of label expansions in other therapeutic areas using RWE.

The pragmatic call to action here is: ketamine attributes present a unique opportunity to capitalize on existing safety, effectiveness, and cost-effectiveness data. A public benefit approach when pharma profit isn’t possible presents ripe conditions for transforming innovative treatment option access for the world’s 3rd leading cause of disability.” – Hailey Gilmore

Mian, M. N., Dinh, M. T., Coker, A. R., Mitchell, J. M., & Anderson, B. T. (2024). Psychedelic Regulation Beyond the Controlled Substances Act: A Three-Dimensional Framework for Characterizing Policy Options. The American journal of psychiatry, 182(1), 6–9. https://doi.org/10.1176/appi.ajp.20230787

“Mian et al.’s 3D framework is a refreshing and much-needed addition to the U.S. psychedelic policy dialogue. By defining the legality, therapeutic intent, and structure of psychedelics, the authors articulate the context for psychedelics across critical domains and subdimensions that often get lost in translation within and among various stakeholder groups. This 3D framework is timely, especially with an increased need to define various efforts for legal access. FDA-regulated medical use is wholly different from state-level use and there are valid arguments for defining, separating, and protecting individual efforts. Ultimately, policymakers need support as they are tasked with ensuring access to medical use and creating regulations for safe non-medical use. The goal of these multidimensional frameworks is to develop sound, evidence-based public health campaigns that drive risk mitigation and improve public safety regardless of access pathway. The Controlled Substances Act indeed impacts all efforts, some more acutely than others – hopefully, this work helps decision makers understand this critical access lever. This work creates a path forward for productive policy development in a nebulous space.” – Gretchen Shaub

Newson, M., Haslam, S. A., Haslam, C., Cruwys, T., & Roseman, L. (2024). Social identity processes as a vehicle for therapeutic success in psychedelic treatment. Nature Mental Health, 2(9), 1010–1017. https://doi.org/10.1038/s44220-024-00302-5

“The authors highlight not just the general influence of the immediate social environment on a psychedelic experience but also the specific influence of having a psychedelic experience as part of a group and the potential unique therapeutic benefits that might be gained from using psychedelics in group settings.” – CJ Healy

O’Donnell, K. C., Anderson, B. T., Barrett, F. S., Bogenschutz, M. P., Grob, C. S., Hendricks, P. S., Kelmendi, B., Nayak, S. M., Nicholas, C. R., Paleos, C. A., Stauffer, C. S., & Gukasyan, N. (2024). Misinterpretations and Omissions: A Critical Response to Goodwin and Colleagues’ Commentary on Psilocybin-Assisted Therapy. American Journal of Psychiatry, 181(1), 74–75. https://doi.org/10.1176/appi.ajp.20230661

“A diverse series of thoughtful and often impassioned arguments against active efforts to minimize or excise entirely — both theoretically and practically — the psychosocial component (or so-called “psychotherapy component”) of psychedelic therapy.” – CJ Healy (also responding to other Goodwin et al. replies)

Ostrovsky, A., & Barnett, B. S. (2024). New Billing Codes Offer Opportunity to Investigate Psychedelic Treatment. Psychedelic Medicine, 2(3), 184–186. https://doi.org/10.1089/psymed.2023.0071

“This piece is a call to action for medical model stakeholders – systems change is arduous, slow, and necessitates informed coalition development. Despite enormous efforts by drug development companies seeking FDA approval for psychedelic treatments, uptake has been sluggish. In June 2024 the American Medical Association (AMA) approved the Category III CPT codes for ‘‘Continuous In-Person Monitoring and Intervention During Psychedelic Medication Therapy’’ (0820T, 0821T, and 0822T); these codes were created to capture the work of qualified healthcare professionals responsible for psychosocial interventions during the drug administration of novel psychedelic treatments. Adequate CPT I codes exist for the psychosocial interventions that occur during preparation and integration sessions.

CPT III codes are temporary research tools that expire after five years if not used or deliberately extended; these codes (0820T, 0821T, and 0822T) are due to sunset in 2028. Albeit an exceptional and historic effort, the ultimate success of these codes is in their adoption and evaluation to inform the conversion to permanent CPT I codes. There is much work to be done in coordination with manufacturers, health systems, coding professionals, professional societies, and agencies of jurisdiction to ensure effective implementation and adoption of these codes. The full extent of the workforce needed for the implementation of psychedelic treatments in the U.S. healthcare system is unknown – these data are a vital piece of the puzzle we are attempting to solve. These codes must be used so that we can start to answer product and indication agnostic questions like, who is doing what work, at what degree of input, what should the pay scale be for emerging qualified HCPs during administration, etc.? There are helpful examples across the practice of medicine to help inform sustainable policy solutions that ensure professionals doing the work are appropriately compensated. As Ostrovsky and Barnett layout in this paper – adopt these codes to support critical implementation research.” – Gretchen Shaub

Schenberg, E. E., King, F., 4th, da Fonseca, J. E., & Roseman, L. (2024). Is Poorly Assisted Psilocybin Treatment an Increasing Risk? The American journal of psychiatry, 181(1), 75–76. https://doi.org/10.1176/appi.ajp.20230664

“A diverse series of thoughtful and often impassioned arguments against active efforts to minimize or excise entirely — both theoretically and practically — the psychosocial component (or so-called “psychotherapy component”) of psychedelic therapy.” – CJ Healy (also responding to other Goodwin et al. replies)

Weintraub, M. J., & Miklowitz, D. J. (2024). How should psychotherapy proceed when adjoined with psychedelics? World Psychiatry, 23(1), 157–158. https://doi.org/10.1002/wps.21170

“PAT, PAP, PT…there is yet to be consensus on language for psychedelic treatments in development. This lack of alignment has resulted in the role of psychotherapy being an increasingly contentious issue for many stakeholders. Valid arguments have been made regarding the role of psychotherapy in potentially FDA-approved psychedelic treatments. No one company, organization, or stakeholder group should be responsible for establishing best practices – a coordinated approach is required to support the entire industry. The opportunity is ripe for psychology to enter the chat. As experts continue to make valid and at times conflicting arguments, perhaps the conversation should evolve to identify who might “own” the psychotherapy of it all. There are highly qualified therapists with hundreds and thousands of hours of experience in psychedelic clinical trials confused about what their roles in real-world settings will be should products come to market. Isn’t everyone in this space confused about what their roles will be in the future? After all, this has never been done at commercial scale in the U.S. medical system. In an incipient and diverse industry might the current debate be missing the forest for the trees?

In December 2024 The American Psychiatric Association (APA) published updated practice guidelines on the treatment of Borderline Personality Disorder (BPD). The APA recommendation is tiered to include both psychosocial interventions and pharmacotherapy treatments. Importantly, they suggest that patients with BPD treated with “any psychotropic medication be time-limited, aimed at addressing a specific measurable target symptom, and adjunctive to psychotherapy.”  Of note for emerging psychedelic treatments the APA does not distinguish between the numerous types of psychosocial interventions available; rather, the APA calls for a structured approach to psychotherapy, recognizing that many effective evidence-based options exist. Other examples of treatment models involving psychosocial interventions provide additional food for thought e.g. – SUD, HIV, bariatric surgery, dialysis, etc.

If the ultimate goal for those pursuing FDA approval is to provide treatment options that are safe and more effective than those presently available, shouldn’t the through line be meeting patients’ needs? Are we asking what patients want and incorporating that into decision-making or are we leaning into biased assumptions? All of the papers focused on this topic have provided space for healthy and much needed reflection and research.” – Gretchen Shaub  (also responding to Aday et al. and Alpert et al.)

Wolfgang, A. S., McClair, V. L., Schnurr, P. P., Holtzheimer, P. E., Woolley, J. D., Stauffer, C. S., Wolf, R. C., States, L. J., Benedek, D. M., Capaldi, V. F., Bradley, J., Fuller, M. A., Smyth, M. J., Hermes, E. D. A., Tenhula, W., & Wiechers, I. R. (2024). Research and Implementation of Psychedelic-Assisted Therapy in the Veterans Health Administration. The American journal of psychiatry, 182(1), 17–20. https://doi.org/10.1176/appi.ajp.20240751

“Wolfgang et al.’s report outlines important details behind essential work within the Department of Veterans Affairs to move potentially FDA-approved psychedelic treatments forward. The convening of the “State of the Art (SOTA) Conference: Psychedelic Treatments for Mental Health Conditions” in 2023 successfully created four workgroups to tackle complex issue areas. This tactical approach resulted in successful dedicated funding for continued research as well as the inception of an Integrated Project Team (IPT) consisting of diverse experts to focus on forward-looking planning for future research and implementation. There is an enormous need for collaboration across industry and agencies to adapt clinical development to infrastructure and implementation development. In a nascent area it is often a challenge to create space for future planning – there is always pressure to focus on immediate, short-term work. The establishment of SOTA and resulting efforts are an important step forward. This report adeptly shares the learnings and the need to educate on the multi-layered approaches necessary across diverse stakeholders in order to develop a sustainable and dynamic industry that keeps patients as the focal point.” – Gretchen Shaub

Breeksema, J. J., Niemeijer, A., Krediet, E., Karsten, T., Kamphuis, J., Vermetten, E., Van Den Brink, W., & Schoevers, R. (2024). Patient perspectives and experiences with psilocybin treatment for treatment-resistant depression: A qualitative study. Scientific Reports, 14(1), 2929. https://doi.org/10.1038/s41598-024-53188-9

“This paper explores patient experiences with psilocybin treatment through qualitative interviews, providing important insights into subjective experiences informing outcomes. This qualitative study is a valuable contribution to the psychedelic literature as it centers on patient narratives, offering a rich understanding of subjective experiences with psilocybin for treatment-resistant depression. Its strength lies in its focus on patient voices, which complements the growing body of quantitative research on psilocybin’s efficacy. This paper highlights individual variability in therapeutic outcomes and underscores the importance of integrating qualitative insights into clinical trial design and post-treatment integration practices. Given the small sample sizes of current clinical trials, I look forward to seeing more papers such as this one, with well-designed and intentional qualitative and mixed methods to bolster the evidence with more nuanced approaches to data collection, analysis, and application of findings.” – Meghan DellaCrosse

Calder, A. E., & Hasler, G. (2024). Validation of the Swiss Psychedelic Side Effects Inventory: Standardized assessment of adverse effects in studies of psychedelics and MDMA. Journal of Affective Disorders, 365, 258–264. https://doi.org/10.1016/j.jad.2024.08.091

“The lack of standardized measures to capture adverse side effects in psychedelic clinical trials is surprising. Publication of the Swiss Psychedelic Side Effects Inventory is an important development for the field, and should help better characterize the full spectrum of potential side effects with psychedelics as well improve comparability between studies.” – Jacob Aday

R., Rej, S., Gloeckler, S., Erritzoe, D., Carhart-Harris, R., & Greenway, K. T. (2024). Longitudinal experiences of Canadians receiving compassionate access to psilocybin-assisted psychotherapy. Scientific Reports, 14(1), 16524. https://doi.org/10.1038/s41598-024-66817-0

“It’s exciting to see a publication following patient health outcomes after Health Canada’s decisions to provide access to psilocybin via two pathways: first, through individual-specific “Section 56” exemptions, and second, through the federal Special Access Program (“SAP”), allowing licensed physicians and NPs to prescribe the drug. We are seeing regulatory shifts and changes to legislature regarding access to psilocybin in many countries – this self-report, observational study by de la Salle et al. provides data (though limited in scope and with a very small number of participants) highlighting how individuals have been impacted by such changes in Canada. Adding to the body of real-world evidence, participants variously reported their psilocybin experience (accessed through SAP) as meaningful and insightful yet difficult – the authors conclude that such results align with results from clinical trials. Importantly, the authors note, “Use of the compassionate access pathways for PAP would greatly benefit from adopting the same high standards of psychological support and risk assessments currently employed in clinical trials, given adequate training and resources”. As the public shows increasing interest in removing barriers to accessing psilocybin therapy, studies such as this emphasize the need to simultaneously create frameworks for education and support that ensures safety standards and promotes harm-reduction.” – Juliet Meccia

Doss, M. K., Kloft, L., Mason, N. L., Mallaroni, P., Reckweg, J. T., Van Oorsouw, K., Tupper, N., Otgaar, H., & Ramaekers, J. G. (2024). Ayahuasca enhances the formation of hippocampal-dependent episodic memory without impacting false memory susceptibility in experienced ayahuasca users: An observational study. Journal of Psychopharmacology, 02698811241301216. https://doi.org/10.1177/02698811241301216

“Reading anecdotes from places like the r/ayahuasca subreddit, one cannot avoid noticing how often people report uncovering seemingly lost or never remembered memories of trauma or abuse. Some recent clinical research, too, has described clients worrying about the veracity of events they feel they have recalled under psychedelics for the first time. As a researcher in trauma and autobiographical memory, it’s difficult not to see the potential dangers here, keeping in mind the unethical recovered-memory therapies and Satanic ritual abuse panics of decades past. So, given that psychedelics appear to increase suggestibility and perceptions of salience and certainty, could they promote the formation of false memories? In this fascinating study by Manoj Doss and colleagues at least, pre-encoding administration of ayahuasca in fact appeared to enhance aspects of memory accuracy and did not increase susceptibility to false memories. Notably, the participants were Santo Daime members, very experienced ayahuasca users. Replication and extension of this research with more diverse samples is sorely needed. It will also be crucial to separate effects on the different memory phases, as here both encoding and retrieval took place under ayahuasca, and to test whether there is something specific about the effects of ayahuasca (e.g., due to the beta-carbolines present, as the authors suggest), as compared with other psychedelics.” – Samuli Kangaslampi

Eaton, E., Capone, C., Gully, B. J., Brown, Z. E., Monnig, M., Worden, M. S., Swift, R. M., & Haass-Koffler, C. L. (2024). Design and methodology of the first open-label trial of MDMA-assisted therapy for veterans with post-traumatic stress disorder and alcohol use disorder: Considerations for a randomized controlled trial. Contemporary Clinical Trials Communications, 41, 101333. https://doi.org/10.1016/j.conctc.2024.101333

“This protocol is notable for being the first VA-funded trial (in addition to NIAAA funds) of MDMA-AT, building on evidence from the BIMA study. Substance use disorder is highly co-occurring with PTSD in veterans – the rule not the exception at 63% – and treating each individually has limitations; therefore, interventions to address both are urgently needed for this comorbid population which experiences more severe symptomatology. A significant contribution of this study design will be the neuroimaging and biomarker data, which are included to evaluate connectivity changes and neuroinflammation, pre- and -post treatment. The therapeutic component, meanwhile, aims to disrupt patterns of alcohol use that are associated with self-medication in PTSD.

The authors review their study start-up activities to date as well as study structure (only 2 medication sessions + prep/integration), hypotheses, analysis plan, and outcomes, i.e. the FDA-approved clinical outcome assessments (COAs) for alcohol reduction (TLFB) as primary, and PTSD symptom reduction (CAPS-5) as secondary. Interestingly, they discuss the challenges they grappled with in this study design, particularly around the health monitoring needs in this potentially higher cardiac-risk population, and measures to mitigate and assess for tolerability.” – Hailey Gilmore

Izmi, N., Carhart-Harris, R. L., & Kettner, H. (2024). Psychological effects of psychedelics in adolescents. Frontiers in Child and Adolescent Psychiatry, 3, 1364617. https://doi.org/10.3389/frcha.2024.1364617

“Similarly to the other adolescent psychedelic study (Simonsson et al., 2024), I was thrilled to see more work being done in this area. I think that both the adolescent papers that came out in 2024 had their strengths and weaknesses. The strength of this paper was the direct comparison of adolescents and young adults (ages 16-24) to adults (over age 25). While the study was an observational self-report, the direct comparison of these two groups yields important information about psychiatric symptoms and psychedelic use. The findings are intriguing as well because they find improvements in well-being and mental health, but at the same time acute subjective effects are conveyed as more negative in adolescents. Further, higher prevalence of hallucinogen persisting perceptual disorder (HPPD)-related symptoms was found in adolescent populations. This begs the question…is earlier use of psychedelics a potential risk factor for developing HPPD? I can’t wait to see more research to that end.” – Alaina Jaster

Kuiper, H., Alley, C., Harris, Z., Kuiper Rauch, C., Robbins, M., Rodriguez, P., Tomczak, P., Urrutia, J., & Magar, V. (2024). Psychedelic public health: State of the field and implications for equity. Social Science & Medicine, 357, 117134. https://doi.org/10.1016/j.socscimed.2024.117134

“Founders of the Center for Psychedelic Public Health, cover one of the most exciting potentialities in the psychedelic space, elevating the power of inter-field knowledge-sharing. This review characterizes current Schools and Programs of Public Health (SPPH) involvement in Psychedelic Research Centers (PRC). Given the nascent stage, it was unsurprising they found that the involvement of SPPH in PRC was limited, and faculty of PRC were not often from PH backgrounds. What’s more, while reciprocity and equity are core public health principles, and given the predominance of Indigenous knowledge in psychedelic practice, Indigeneity was not prominently or commonly addressed, and PRCs included limited Indigenous leadership.

There is significant overlap of public health expertise with emergent needs of the psychedelic space, notably: social determinants of health; health promotion strategy; addressing mental health crises and intersecting vulnerabilities; harm reduction principles; engagement with public policy; understanding of community as a key driver and dynamic; proven methodology for implementing and scaling interventions; an embrace of holistic health and the nested ecologies of individual /community/societal health; focus on health equity; and systems mapping and impact evaluation. With this initial work, one hopes that much future research is inspired to leverage this synergy and avoid missed opportunities, thereby giving researchers, practitioners and policymakers the best shot at balancing the risk/benefit profile of psychedelics as they proliferate to the broader population.

That is, pending the future of public health – which already navigates the challenges of the Controlled Substances Act and other federal regulations, but more importantly – which largely occurs via dedicated federal funding and offices within Health & Human Services.” – Hailey Gilmore

Maples-Keller, J. L., Dunlop, B. W., & Rothbaum, B. O. (2024). The METEMP protocol: Massed exposure therapy enhanced with MDMA for PTSD. Contemporary Clinical Trials Communications, 43, 101400. https://doi.org/10.1016/j.conctc.2024.101400

“This open label pilot of 100 mg MDMA in combination with massed exposure therapy (PE) for PTSD, leverages a VA Gold standard treatment, which has both translational support and potential for dissemination. PE uses fear extinction as a mechanism, aided in this protocol by the pharmacologic action of the MDMA. The massed approach has prior evidence in the ongoing Wounded Warriors-funded project at Emory, which consists of PE daily for two weeks instead of the usual once per week for several months. This leads to comparable effect and durability of the traditional approach, and a robust 96% completion rate compared to 30-50% dropout in the regular schedule.

The study builds on the team’s prior healthy human RCT studying fear extinction learning in which the MDMA group were more likely to retain fear extinction than placebo. Additionally, prior PE trials have shown high responders demonstrated significant extinction retention learning, compared to low responders whose fear returned. Finally, the authors postulate the 2-week treatment period as being optimal for neural plasticity, citing the Nardou et al. paper indicating that the social reward learning critical period remained open in mice that long following MDMA administration.

The pilot study is considered a “treatment development” protocol since best practices for incorporating the strong subjective effects of MDMA with imaginal exposure procedures need to be studied for feasibility and potentially refined. Novel elements include a handout provided on use of touch and available options, and skin conductance electrodes track physiological response during imaginal exposure, which occurs twice – 90 minutes and 240 minutes – into the MDMA experience, between which participants are encouraged in MAPS-lingo to “go inside”.

The strong dissemination potential lies in VA centers’ mandate to provide either PE or CPT for PTSD, with large numbers of providers trained in each, and the single dose (compared to the 3 in the Lykos protocols) could easily be incorporated into many different ongoing program models. The team seeks to further streamline implementation burdens by having 2 therapists present only for the first 3 of the 10 total sessions, as opposed to 2 therapists for all.” – Hailey Gilmore

Mathai, D. S., Hull, T. D., Vando, L., & Malgaroli, M. (2024). At-home, telehealth-supported ketamine treatment for depression: Findings from longitudinal, machine learning and symptom network analysis of real-world data. Journal of Affective Disorders, 361, 198–208. https://doi.org/10.1016/j.jad.2024.05.131

“This study on telehealth-supported ketamine treatment represents a significant contribution to the field, primarily due to its unprecedented scale (n=11,441) and use of machine learning and network analysis to study treatment outcomes and predictors. The identification of depressed mood and anhedonia as symptoms that sustain depression despite ketamine treatment points to important targets for augmentation strategies. The promising findings and low adverse events of using a digital intervention address a critical access barrier in psychedelic medicine and offer a blueprint to scale ketamine-assisted treatments in a cost-effective manner.” – Matteo Malgaroli

Morland, L. A., Perivoliotis, D., Wachsman, T. R., Alam, A., Knopp, K., Khalifian, C., Ramanathan, D., Chargin, B. E., Bismark, A. W., Glynn, S., Stauffer, C., & Wagner, A. C. (2024). MDMA-assisted brief cognitive behavioral conjoint therapy for PTSD: Study protocol for a pilot study. Contemporary Clinical Trials Communications, 40, 101314. https://doi.org/10.1016/j.conctc.2024.101314

“PTSD impacts both individual and relational functioning, particularly among veteran couples who face unique challenges, and a cyclic relationship exists between PTSD symptoms, overall veteran health, and health of relationships. The VA is the largest provider of PTSD treatment in the world. This intervention acts on the unit of the dyad, using brief Cognitive Behavioral Conjoint Therapy (bCBCT) – a VA accepted couples-level PTSD intervention – as the integration model for 2 MDMA sessions. It is brief – and therefore perhaps more scalable – because it is reduced from the usual 15 sessions to 8, which are delivered in a massed approach. Integration also includes two couple-level emotion- focused sessions using a technique of “empathic joining” to support couples in developing a deeper understanding of and connection with one another following MDMA sessions.

The team is building on the work of Monson et al. who gave couples a condensed 15 session CBCT and 2 MDMA session intervention, which saw large improvements in PTSD in the PTSD+ partner and medium to large improvements in partner mental health and relationship functioning. However, due to VA regulations prohibiting MDMA administration to non-veteran partners, only the veteran receives MDMA in this study. Eight couples are participating in this single site open label study, which in addition to looking at CAPS-5 (primary) is measuring outcomes on the Couples Satisfaction Index (CSI-32, secondary). The study further pulls implementation levers by utilizing 2 therapists for dosing, but only 1 therapist to deliver the bCBCT. Dose escalation occurs as in the MAPS/Lykos studies, though at slightly lower levels due to active engagement during medicine sessions, since the partner is present for part of them. Another strength of the study is evaluating outcomes out to 6 months post-treatment.

A notable element of the analytic plan is to include a moderation analysis of LEC-5 and ACE on CAPS scores. The team plans to proceed to a larger RCT if there is a signal.” – Hailey Gilmore

Myran, D. T., Pugliese, M., Xiao, J., Kaster, T. S., Husain, M. I., Anderson, K. K., Fabiano, N., Wong, S., Fiedorowicz, J. G., Webber, C., Tanuseputro, P., & Solmi, M. (2024). Emergency Department Visits Involving Hallucinogen Use and Risk of Schizophrenia Spectrum Disorder. JAMA Psychiatry. https://doi.org/10.1001/jamapsychiatry.2024.3532

“Myran et al. (2024) analysed a dataset of over nine million visits to Canadian emergency departments (2008-2021) and picked out 5,217 cases involving hallucinogen use. They then tracked how many of these patients developed a schizophrenia spectrum disorder (SSD – a seldom-used umbrella term for schizophrenia, a psychotic disorder, and schizotypal personality disorder, which is a less severe condition characterised by unusual thinking, eccentric behaviours, and social isolation) over the next three years. The results indicated that hallucinogen users had three-to-four times greater odds of receiving this diagnosis than the general population – even after adjusting for pre-existing substance use and mental health problems.

It is important that we take these findings with a pinch of salt. The definition of ‘hallucinogens’ was very broad, with known neurotoxic substances (e.g. PCP and amphetamines) included alongside LSD, MDMA and psilocybin. It is telling that for the subgroup of patients coded as ‘LSD poisoning’ there was no significant increase in rates of SSD. It is also difficult to conclude that the patients who did receive the diagnosis were not taking adulterated or mis-labelled LSD.

It is also possible that a “third variable” might have influenced results. We wondered whether there could be causative factors that increase hallucinogen use and risk of SSD. For example, we know that adverse childhood experiences are associated with drug abuse and psychosis later in life. The authors acknowledge this in the paper and speculate that the earliest phases (“prodrome”) of psychosis may be associated with an increased interest in mind-altering substances.

We believe that this paper is helpful for our work in the emergency department. It has encouraged us to be inquisitive about patients who come in after taking hallucinogens. What is motivating them? Do they feel they are self-medicating a different problem? Are they having any unusual experiences when they are not tripping? Most users of these drugs are psychologically well, but if there is a vulnerable minority – as is suggested by this study – then it is probably good to identify them sooner rather than later. They may benefit from a supportive conversation and sign-posting to mental health services.” – Gregory Yates & Harriet Phelan

“The risk of developing psychosis is one of the most concerning side effects associated with psychedelic use. Myran et al., evaluated whether individuals who visited the emergency department for hallucinogen-related issues subsequently developed schizophrenia spectrum disorder. Their analysis revealed a 21-fold increased risk compared to the general population. This heightened vulnerability persisted even after controlling for other substance use and mental health conditions. These alarming findings underscore the need for proactive follow-up and preventive strategies for this high-risk group.” – Lucie Berkovitch

Palitsky, R., Kaplan, D. M., Perna, J., Bosshardt, Z., Maples-Keller, J. L., Levin-Aspenson, H. F., Zarrabi, A. J., Peacock, C., Mletzko, T., Rothbaum, B. O., Raison, C. L., Grant, G. H., & Dunlop, B. W. (2024). A framework for assessment of adverse events occurring in psychedelic-assisted therapies. Journal of psychopharmacology (Oxford, England), 38(8), 690–700. https://doi.org/10.1177/02698811241265756

“The systematic assessment of adverse events (AEs) in P-AT remains an important challenge for researchers and clinicians. With psychedelics not yet licensed, regulators rightly demand robust information about adverse events as well as treatment efficacy. Yet there is considerable room for improvement on AE reporting in psychedelic trials: a systematic review and meta-analysis last year found that nearly half of psychedelic trials reported no AE data whatsoever, and only 23.5% of post-2005 trials reported systematic approaches for ascertaining AEs (Hinkle et al., 2024).

The typical definition of AE deployed in standard pharmaceutical trials is “any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.” While this definition is appropriate for conventional pharmacotherapy, it may not adequately capture the full spectrum of challenging outcomes that may follow P-AT. Scholars are increasingly recognising this gap and developing specialised tools to address it, with Palitsky and colleagues’ Psychedelic Assisted Therapy Adverse Events assessment protocol (PATAE) joining the Swiss Psychedelic Side Effect Inventory (SPSI, Calder & Hasler, 2024) among last year’s important contributions to this evolving conversation.

At the heart of PATAE is the recognition that P-AT’s distinctive characteristics —combining pharmacological effects, psychotherapeutic processes, and spiritual-existential dimensions— require tailored approaches to AE detection. The framework developed by Palitsky et al. acknowledges that not all adversities arising from P-AT are best understood as “medical” in nature. They propose 54 AEs to track across seven categories specifically relevant to P-AT—sociocultural, psychospiritual, interpersonal, behavioural, psychotherapy-related, affective/cognitive/metacognitive, and perceptual—outcomes that are broadly invisible to standard AE frameworks.

The paper from Palitsky et al. implicitly raises an important issue about the entire enterprise of AE assessment: the question of what constitutes an adverse event is not merely technical but normative. Much as we may strive to be objective in scientific research, our measurement systems inevitably encode judgments about which outcomes matter and which don’t. When we privilege certain types of outcomes (like “adverse drug reactions”) over others (like shifts in worldview, difficulties in integration, or newly-challenging relationship dynamics), we risk imposing a narrow conception of what constitutes therapeutic success that may not align with patients’ own priorities and concerns. Palitsky’s framework invites us to reconsider what forms of adversity merit attention in P-AT. This is not merely a methodological choice, but a value-laden one with real implications for patients and for the development of the field itself.

The ethical implications of this measurement gap extend beyond research methodology into the realm of informed consent and patient autonomy. From an ethical perspective, what matters for informed consent is not whether an outcome meets regulatory criteria for an AE, but whether knowledge of its possibility would materially affect a prospective patient’s decision-making. By prioritising patient narratives and subjective appraisals over clinician determinations of therapeutic value, PATAE represents an important step toward fulfilling our ethical duty to properly inform patients about outcomes that may be highly salient to them, regardless of whether those outcomes fit neatly into conventional AE categories.

While offering an ambitious and much-needed expansion of what counts as “adverse,” the framework’s comprehensiveness raises important practical questions about implementation. The tension between thorough detection and feasible assessment represents one more dilemma for the field. As Cheung et al. note in their commentary on this paper, any assessment framework must balance the twin imperatives of comprehensiveness and practicality. A protocol too burdensome may lead to poor compliance and incomplete data collection; one too sparse may miss crucial outcomes.

The challenge ahead lies in operationalising these expanded AE criteria in a way that enhances both research integrity and patient care, without compromising feasibility or clinical applicability. At stake is not just regulatory compliance, but our capacity to understand the true risk:benefit profile of P-AT, and to communicate that understanding accurately to those who might wish to experience it.” – Eddie Jacobs

Simon, M. W., Olsen, H. A., Hoyte, C. O., Black, J. C., Reynolds, K. M., Dart, R. C., & Monte, A. A. (2024). Clinical Effects of Psychedelic Substances Reported to United States Poison Centers: 2012 to 2022. Annals of Emergency Medicine, 84(6), 605–618. https://doi.org/10.1016/j.annemergmed.2024.06.025

“Simon et al. (2024) reviewed 54,605 medical cases (2012-2022) in which ‘psychedelic exposures’ had required consultation with a poison centre in the US. The majority of patients in this study (87%) were taken to the emergency department and over half were reported to have ‘symptoms that required treatment, severe residual or prolonged symptoms, or death.’ From these findings the authors concluded that ‘[i]ncreases in psychedelic use may lead to increased frequency of adverse events and health care utilization.’

The trouble with this conclusion is that many of the drugs taken in this study were not what we would consider in emergency medicine to be ‘psychedelics,’ by convention or pharmacology. Ketamine (6.3%) and PCP (11%) were included, as were methamphetamine and its derivatives under the header ‘hallucinogenic amphetamines’ (40.6%). As might be expected, the worst outcomes were seen with these drugs, and not the minority of the sample using LSD (17.7%) or mushrooms (13.8%).

Fortunately, because the authors shared drug-specific data, we can make our own conclusions about the ‘adverse events’ in the study. And it seems there were indeed problems with psychedelics. Looking at LSD, for example, roughly half the sample required sedation and a concerning number (5.7%) required ‘intubation / ventilation’ — which is our shorthand for a patient who needs to be put into a “medical coma” and transferred to the intensive care unit with a breathing tube in. But this was unsurprising. The patients in this study were a sick minority. They required treatment in hospital and referral to a poison centre, which is inherently an ‘adverse event’ for psychedelic users. Individuals who were able to cope with a bad trip at home, or who were easily managed in the emergency department, would not have made it into this dataset.

Our impression overall was this: the data clearly show that psychedelics are not without risk — almost nothing is! – but it is reassuring that even in the most severe subset of patients, true emergencies are rare. We do not anticipate that increased use of psychedelics will change the situation for us in hospital. Cocaine, amphetamines, and alcohol will still be the biggest troublemakers.” – Gregory Yates & Harriet Phelan

Simonsson, O., Mosing, M. A., Osika, W., Ullén, F., Larsson, H., Lu, Y., & Wesseldijk, L. W. (2024). Adolescent Psychedelic Use and Psychotic or Manic Symptoms. JAMA Psychiatry, 81(6), 579. https://doi.org/10.1001/jamapsychiatry.2024.0047

“This was one of my favorite papers from 2024 because it’s one of the first to examine adolescent use of psychedelics. This cross-sectional study utilized a large sample of adolescent twins assessed at multiple ages over adolescence and young adulthood to determine association between past psychedelic use and psychotic or manic symptoms at age 15. The findings suggest that naturalistic use of psychedelics may be associated with lower rates of psychotic symptoms among adolescents, but the use of psychedelics and manic symptoms may have an interaction related to genetic vulnerability to disorders like schizophrenia and some types of bipolar. Given adolescence is such an important time for brain development and the development of neuropsychiatric symptoms, these studies are very necessary. I was excited to see more interest in this topic in 2024 and hope it continues this year.” – Alaina Jaster

Weiss, B., Roseman, L., Giribaldi, B., Nutt, D.J., Carhart-Harris, R.L., Erritzoe, D. (2024). Unique Psychological Mechanisms Underlying Psilocybin Therapy Versus Escitalopram Treatment in the Treatment of Major Depressive Disorder. Int J Ment Health Addiction, 22, 806–841. https://doi.org/10.1007/s11469-024-01253-9

“This article not only presents important empirical findings of differential psychological mechanisms of therapeutic action that distinguish psychedelic therapy and treatment with SSRIs but also elaborates rich and nuanced comparative theoretical models for interpreting these findings that vitally contribute to an understanding of psychedelic therapy as essentially a form of psychotherapy.” – CJ Healy

Yaden, M. E., Ching, T. H. W., Goldway, N., Roberts, D. E., Hokanson, J., Gukasyan, N., Pittenger, C., Kelmendi, B., Ross, S., Glick, G., & O’Donnell, K. C. (2024). Psychedelic medicine in psychiatry residency training: A survey of psychiatric residency program directors. International Review of Psychiatry, 1–6. https://doi.org/10.1080/09540261.2024.2397039

“It’s one thing to be excited about the potential benefits of psychedelic therapies but another thing entirely to understand the state of the research and how psychedelics might be safely used as clinical tools. This work by Dr. Mary Yaden and colleagues illuminates significant gaps in current education and training for US Psychiatry programs, which are likely to exist for other training programs also. Importantly, this group of educators is also working toward addressing this need through the development of a first-of-its-kind standardized curriculum for psychedelic education.” – David Mathai

Yoo, M., & Sakopoulos, S. (2024). The Birth of the Psychedelic Industry: Capitalising on the Psychedelic Renaissance. Future Humanities, 3(1), e70004. https://doi.org/10.1002/fhu2.70004

“An important publication that should be essential reading for everyone operating in this sector – from research to industry. As psychedelics are pushed through the R&D pipeline towards commercialization, it is critical to pause, reflect, and consider the ramifications of who will control the playing field, and who will be left on the sidelines. While the “psychedelic renaissance” is often framed as a breakthrough in mental health treatment, Yoo & Sakopoulos highlight the underlying financial and corporate interests that shape how these substances are studied, marketed, and accessed. Stepping outside our idealistic bubbles, we can ask ourselves: what are we working towards? Are we operating ethically? Who are we helping? Who are we leaving out? What interests are at play?” – Juliet Meccia

Aboharb, F., Davoudian, P. A., Shao, L.-X., Liao, C., Rzepka, G. N., Wojtasiewicz, C., Indajang, J., Dibbs, M., Rondeau, J., Sherwood, A. M., Kaye, A. P., & Kwan, A. C. (2024). Classification of psychedelics and psychoactive drugs based on brain-wide imaging of cellular c-Fos expression. https://doi.org/10.1101/2024.05.23.590306

“Going beyond the head-twitch response? In this preprint now published in Nature Communications, Aboharb et al present a pipeline for drug classification using light sheet fluorescence microscopy and machine learning. Mice were given a large panel of drugs, including psilocybin, ketamine, 5-MeO-DMT, 6-fluoro-DET, MDMA, acute fluoxetine, chronic fluoxetine, and saline. Their models were able to distinguish between these drugs and they were further able to identify which brain regions were driving the predictions.” – S. Parker Singleton

“It’s always exciting to see a significant body of work that sets new standards in molecular and behavioral psychedelic neuroscience. This preprint is just that, providing clear demonstration of how a novel psychedelic characterization pipeline can sort compounds of varying psychoactive profiles. While we typically think of receptor-binding assays and behavioral paradigms traditionally dominating drug screening, here the authors have developed a unique approach by quantifying c-Fos expression and using machine learning models to capture the functional “footprint” of each compound across the entire brain. I always look forward to new publications from the Kwan lab, who are leaders in preclinical psychedelic research.” – Juliet Meccia

Blackburne, G., McAlpine, R. G., Fabus, M., Liardi, A., Kamboj, S. K., Mediano, P. A. M., & Skipper, J. I. (2024). Complex slow waves radically reorganise human brain dynamics under 5-MeO-DMT. https://doi.org/10.1101/2024.10.04.616717

“Pertaining to the field of psychedelics, this paper by Blackburne et al. is a landmark study. It represents the first comprehensive human neuroimaging analysis of 5-MEO-DMT, driving insights into how slow-frequency brain dynamics may contribute to the deconstruction of subjective experience. However, this study also has huge implications for cognitive neuroscience more broadly, opting to move beyond univariate analyses and instead characterising spatiotemporal profiles of neural activity, thus calling into question the putative theoretical mechanisms of psychedelic brain action. A must read for anyone interested in psychedelic neuroscience.” – Evan Lewis-Healey

Gordon, A. R., Carrithers, B. M., Pagni, B. A., Kettner, H., Marrocu, A., Nayak, S., Weiss, B. J., Carhart-Harris, R. L., Roberts, D. E., & Zeifman, R. J. (2024). The Effect of Psychedelics on Individuals with a Personality Disorder: Results from two Prospective Cohort Studies. https://doi.org/10.21203/rs.3.rs-4203641/v1

“While there is now considerable literature on the effects of psychedelics on personality, there has been much less attention to whether psychedelics can be useful for the impairments seen in individuals with personality disorders, who also tend to be screened out of clinical research trials. Personality impairment is a known predictor of poor outcomes with mental health treatment and can contribute to over-medicating individuals who struggle with these disorders. However, evidence from this preprint suggests that psychedelics could provide therapeutic benefit in this difficult-to-treat population. Psychedelic therapies may be uniquely well-suited for this kind of intervention given how they target processes like cognitive flexibility and emotion regulation that are related to personality function.” – David Mathai

Healy, C. J., Frazier, A., Kirsch, S., Sanford, A., Garcia-Romeu, A., Todman, M., Varon, J., & D’Andrea, W. (2024). Acute subjective effects of psychedelics in naturalistic group settings prospectively predict longitudinal improvements in trauma symptoms, trait shame, and connectedness among adults with childhood maltreatment histories. https://doi.org/10.31234/osf.io/3rbxe

“A few words on this article: it’s a naturalistic use study but as much a mechanisms study, it’s a research article but as much a theory article, and it’s a psychology article but as much an anthropology article. And a couple specific findings to highlight that could get missed amidst the main results: equivalent longitudinal therapeutic effects were observed from facilitated group ceremonies as from raves or other electronic dance music events, and drug dose predicted the intensity of acute subjective effects but not longitudinal therapeutic effects.” – CJ Healy

Pomrenze, M. B., Vaillancourt, S., Llorach, P., Rijsketic, D. R., Casey, A. B., Gregory, N., Salgado, J. S., Malenka, R. C., & Heifets, B. D. (2024). Opioid receptor expressing neurons of the central amygdala gate behavioral effects of ketamine in mice. https://doi.org/10.1101/2024.03.03.583196

“This is a fascinating study. It would be interesting to explore whether activation of CeA PKCδ neurons interferes with other treatments, such as psychedelics, classical antidepressants, or electroconvulsive therapy, or if their permissive effect is specific to ketamine. More broadly, investigating how opioid receptors and other pharmacological targets outside NMDARs interact with ketamine’s antidepressant effects is valuable. Such insights could deepen our understanding of ketamine’s mechanism of action and its potential clinical interactions.” – Marc Duque Ramirez

Purple, R. J., Gupta, R., Thomas, C. W., Golden, C. T., Froudist-Walsh, S., & Jones, M. W. (2024). Short- and long-term reconfiguration of rat prefrontal cortical networks following single doses of psilocybin. https://doi.org/10.1101/2024.12.10.627734

“I thought this paper was brilliant. They found that psilocybin induces dose-dependent decreases in the firing rates of prefrontal pyramidal cells and interneurons, which supports some fantastic work from last year by Tyler Ekins on psychedelic-induced reductions in intrinsic excitability via potassium M-currents. They also provide evidence that psilocybin significantly reduces the entropy rate, and steepens the energy landscape of cortical dynamics, which contrasts with what a lot of people would have predicted. I think the increasingly sophisticated electrophysiology research in rodents may school us folk working on large-scale neuroimaging in humans.” – George Blackburne

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