The Interdisciplinary Annotated Psychedelic Research Bibliography of 2023

Produced by Michael Haichin, PharmD

Part of our Year in Review series

Every year, our Medical Advisor, Michael Haichin, PharmD (LinkedIn, Twitter), chalks up a list of the psychedelics articles he deems most important or intriguing. As his annual list exceeded five hundred publications in 2023, he came up with an idea that would a) have the list see the light of day; and, b) collate the opinions of other psychedelics researchers on last year’s papers.

As such, we are pleased to present the inaugural Interdisciplinary Annotated Psychedelic Research Bibliography. Below, Michael presents the full list of publications, along with short comments from an interdisciplinary pool of researchers.

In what follows, Michael first introduces the Bibliography along with a few comments. We then provide an indicative summary of the types of comments received from researchers, before diving into the full annotated bibliography.

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Introduction

“Before long, trying to keep up will be like trying to drink from a firehose.”

When I wrote that in my article for the 2022 Year in Review, I could not have predicted that staying up to date with psychedelic science would necessitate scuba gear.

For the past few years, with the help of the Psychedelic Alpha team, I have been tracking all the academic papers published about or related to psychedelics. Each year I would put together an internal list of what I judged to be the most important or interesting publications. In 2022, that list consisted of 183 articles. In 2023, however, that swelled to more than 500…

The size of that list is undoubtedly driven by the increasing volume of publications. However, some weight must also be attributed to my expanding interests and a deepening appreciation for disciplines I have no background in, spurred on by their intersection with the subject of psychedelics in some way.

Rather than doing another deep dive on my favourite clinical trials, or commenting on papers from fields beyond my expertise, I wondered how I might turn the list of references into something useful—with that came the idea for an interdisciplinary annotated bibliography¹.

After sharing the list with researchers across the field², I asked them to comment on any paper(s) that piqued their interest or they had particularly strong feelings about, including their own. Who better to potentially critique the flood of peer-reviewed and preprint articles and provide an overview of research from 2023?

“Here’s to hoping at least the quality of the water continues to improve.”

While that phrase was primarily pointed at clinical trials, an argument can be made for the broader psychedelic research community that last year the water was dosed with a willingness to engage with a variety of key issues³ and an increased tolerance of criticism—a sign of a maturing field. This is also reflected not only by so many researchers’ willingness to participate in this type of project⁴, but also the publications they opted to highlight and reflect on.

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

1. It is in no particular order, other than its organisation into the following categories: Reviews, Clinical Trials, Discovery & Preclinical, Editorials, Conference Abstracts & Posters, Preprints, and the broad Other.
2. Articles that were published in print in 2023 but online in 2022 were not included, except if they transitioned from preprint to peer-reviewed.
3. Not all papers were read in full (where to find the time?) and thus their inclusion is not necessarily an endorsement.
4. Amidst a continued lack of consensus about what falls under the “psychedelic” umbrella⁵, papers about MDMA, ketamine, and related entactogens and dissociatives were included.

A Brief Overview

Among those that attracted the most comments were Nardou et al.’s Nature article that suggested psychedelics “reopen the social reward learning critical period”, the product of a research project by Gül Dölen and co; Goodwin et al.’s Commentary in The American Journal of Psychiatry that pondered out loud whether psilocybin must always “assist psychotherapy” (spoiler: it’s a no from those authors); and, Moliner et al.’s article published in Nature Neuroscience which suggests psychedelics promote plasticity by “directly binding” to TrkB.

In terms of the comments we received from a decidedly interdisciplinary range of researchers, they covered the minutiae of pharmacology, mechanisms of action and technical elements of study design, right through to broad ethical and epistemological questions as well as pragmatic commercialisation-related questions like the role of group therapy, training requirements, cost-effectiveness, and so on.

Here’s a very brief, indicative look at some of the topics touched upon in this annotated bibliography…

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“The foundations of psychedelic science shook several times during 2023”, said pharmacologist Mario de la Fuente.

Indeed, as alluded to above, a number of high-profile studies complicated popular hypotheses of psychedelics’ mechanism(s) of action. Nardou et al.’s study, “breaks away from convention and represents a seminal paper for the field of psychedelic research”, according to  Joseph Benetatos, who added that the “highly intriguing hypothesis warrants further investigation!”

Psychedelic researchers interrogated the mechanism of action of antidepressants more broadly, too. Commenting on Witt et al.’s article claiming serotonin is “a common thread linking different classes of antidepressants”, Clinton Canal said that it was “thrilling to see this paper” in light of recent debate around the serotonin hypothesis of depression. “Intriguingly,” he continued, “the different antidepressants had unique effects on the kinetics of serotonin increases, unveiling a new level of analysis to study for antidepressant drug discovery.”

We are also seeing an increasing number of studies and publications looking at psychedelics’ potential utility beyond neuropsychiatric conditions.

“This has truly been an interdisciplinary approach that amazes me to this day and shows the usefulness of psychedelics beyond neuropsychiatric illnesses”, Friederike Holze said of a study by Atila et al. that suggested “clinically meaningful oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus)”. The researchers used MDMA, “a strong activator of the central oxytocinergic system”, as a provocation test to learn more about oxytocin deficiency in patients with the disease.

Last year, preclinical research continued to increase the resolution at which we understand psychedelic-induced receptor signalling.

A study by Zhu et al. sought to understand the role of Gβγ signalling in head-twitch response. “Although the head-twitch response in mice correlates with psychedelic activity in humans for most known psychedelics,” Charles Nichols commented, “the relevance of head-twitch to actual psychedelic behaviors remains unknown and it remains to be seen how relevant G-beta/gamma are to psychedelic related effects in humans.”

Commenting on Wallach et al.’s study of the 5-HT2A receptor signaling pathways associated with psychedelic potential, Alex Kwan said that, findings aside, “the study showcases the power of high-throughput screens possible in rodents, and suggests a path forward for engineering compounds with certain molecular action.”

There’s also potential for bi-directional tweaking of preclinical and in-human models and methods. Discussing Molla et al.’s study which found that low dose LSD had greater subjective effects in participants with higher baseline depression scores, Lauri Elsilä notes that this finding might warrant reverse translation to preclinical models. “I think there is something of note also for us preclinical scientists”, Elsilä noted, “questions of how we model psychiatric disorders, and the severity of the symptom-like phenotypes within these models should be under greater scrutiny if we hope for better interspecies translation.”

In terms of research methods for clinical or human studies, Tehseen Noorani commented on the “elegant” design of Molla et al.’s study that investigated both MDMA and methamphetamine’s impact on feelings of connectedness between a participant and an unfamiliar conversation partner (which could be seen as a proxy for a therapist). The study found that both substances increased feelings of connection, but that oxytocin levels were only correlated with ‘feeling closer’ to the conversation partner after MDMA ingestion. “Perhaps there is an even broader interpretation for social scientists and humanists interested in psychedelic science”, Noorani posits, “that altering our consciousness together, in ways both known and unknown, is a powerful mode of connecting.”

It would be remiss not to include Lykos Therapeutics’ (formerly MAPS PBC) second phase three study of MDMA-assisted therapy for PTSD, published in Nature Medicine last September. “[T]his study may be the last piece of evidence needed in the decades-long effort to bring MDMA to market in the US,” said  Matthew Baggott.

Psychedelic humanities gained a substantial portion of research attention last year. Commenting on Langlitz’s article, “The Making of a mushroom people”, Neşe Devenot suggests that “2023 was the year that both ‘psychedelic humanities’ and ‘critical psychedelic studies’ went primetime”, adding that Michael Pollan went “so far as to suggest that psychedelic humanities might represent the future of the field.”

Elsewhere, commenting on McNamee et al.’s Viewpoint in JAMA that calls for greater study of the harms of psychedelic-assisted therapy, Kayla Greenstien asked: “If we aren’t listening to patients, what’s the point?”

Responding to Evans et al.’s mixed methods study on extended difficulties following the use of psychedelics, Abigail Calder said that “the psychedelic field is privileged to have researchers who are both serious about understanding and preventing negative outcomes from psychedelics and wise to their potential for catalyzing growth.”

In 2023, researchers also broached topics relevant to a potential roll-out of psychedelic therapies in the medical model.

Emmerich and Humphries, for example, discussed in Cambridge Quarterly of Healthcare Ethics whether psychedelic therapists should, as part of their training, have first-person experience with psychedelics. “Perhaps I am overly risk-averse,” commented Eddie Jacobs, “but in retrofitting psychedelic therapy for a modern, mass roll-out, there is a real threat that we go about ripping up Chesterton’s fence in the absence of the right kind of evidence that speaks to whether it should stay or go.”

Max Wolff responded to Aday et al.’s preprint which asks, “Where is the psychotherapy research” when it comes to psychedelic-assisted therapy? “This paper takes on the important task of starting to overcome the historically-rooted divide that still exists between psychedelic research and psychotherapy research”, Wolff commented, characterising them as “two alienated fields that could benefit enormously from engaging more with one another.”

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Without further ado, we present the 2023 annotated psychedelic research bibliography…

Reviews

Glennon, R. A., & Dukat, M. (2023). Quipazine: Classical hallucinogen? novel psychedelic? Australian Journal of Chemistry, 76(5), 288–298. https://doi.org/10.1071/ch22256

“Glennon and Dukat also contribute to the dusting off older compounds in two reviews published last year. They review quipazine, a structurally unusual 5-HT2A agonist whose psychedelic properties in humans (or lack thereof) is guarded by an emesis medusa—its 5-HT3 action. The compound is notorious for producing gastrointestinal discomfort, nausea and vomiting, a major inconvenience to establish psychoactivity. In preclinical models, we demonstrated that quipazine checks all the boxes of a psychedelic. Despite its limitations, quipazine is nonetheless an interesting scaffold for the medicinal chemist.” – Mario de la Fuente

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Glennon, R. A., & Dukat, M. G. (2023). α-Ethyltryptamine: A Ratiocinatory Review of a Forgotten Antidepressant. ACS pharmacology & translational science, 6(12), 1780–1789. https://doi.org/10.1021/acsptsci.3c00139

“The disgraced alpha-ethyltryptamine (AET) is also covered in another review by Glennon and Dukat. The medicinal chemists explore in great detail the discriminatory stimulus of this drug once used briefly in the clinic during the 60s. Keeping up with the mythical references, AET and its enantiomers constitute the chimera. AET and isomers produce in rats a stimuli akin to various drugs. However the profile does not match exactly the profile what one would expect based on AET receptor interactions. Like the chimera, AET also meant trouble. Severe cases of agranulocytosis resulting in the death of patients lead to AET’s demise.” – Mario de la Fuente

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Linguiti, S., Vogel, J. W., Sydnor, V. J., Pines, A., Wellman, N., Basbaum, A., Eickhoff, C. R., Eickhoff, S. B., Edwards, R. R., Larsen, B., McKinstry-Wu, A., Scott, J. C., Roalf, D. R., Sharma, V., Strain, E. C., Corder, G., Dworkin, R. H., & Satterthwaite, T. D. (2023). Functional imaging studies of acute administration of classic psychedelics, ketamine, and MDMA: Methodological limitations and convergent results. Neuroscience and biobehavioral reviews, 154, 105421. https://doi.org/10.1016/j.neubiorev.2023.105421

“This well-written systematic review by Linguiti and colleagues comprehensively discusses and critiques the current state of psychedelic neuroimaging research. They highlight the methodological and analytical variability across studies which make cross-study comparisons difficult, and also flag how most studies have very small samples sizes – which limit the generalized conclusions that can be made. They also point out that there is an abundance of “data recycling”, wherein certain studies have been re-analyzed and published multiple times – thereby giving the illusion of more independent studies than there are. In addition, they flag inconsistent Type I (false positive) error control and motion artefact removal as important factors to rectify moving forward. They conclude by suggesting that future studies (1) pre-register hypotheses and analysis plans, to minimize researcher degrees of freedom and the potential for p-hacking, and (2) to use and openly share reproducible analytical protocols so that findings have potential to be independently verified and confirmed.” – Manesh Girn

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Noorani, T., Bedi, G., & Muthukumaraswamy, S. (2023). Dark loops: contagion effects, consistency and chemosocial matrices in psychedelic-assisted therapy trials. Psychological medicine, 53(13), 5892–5901. https://doi.org/10.1017/S0033291723001289 

“This paper by Noorani et al. presents a pioneering model for the manner in which psychedelic media reporting and hype spills over into psychedelic trials, changing expectancy and intervening in trial results. This confounding ‘chemo-social’ effect is said to be particularly potent in the case of psychedelics due to their context dependency, as well as other unique characteristics of the psychedelic experience, and community. The authors adumbrate three distinct ways of handling the challenge: by either chemosocial minimization (attempting to minimize chemosocial effects), chemosocial description (providing detailed accounts of trial context) or chemosocial valorization (leveraging chemosocial effects to optimize trial results). A useful paper that finally formalizes some of the distinct and crucial dynamics of the psychedelic renaissance.” – Ido Hartogsohn

 

“A key idea articulated through the article is that the impact of unblinding is not only on psychological measures of ‘expectation’, but on the connections, networks, and durative forms of care – in short, the “matrix” (Eisner, 1997) – that carry participants through to trial endpoints.” – Tehseen Noorani

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Cameron, L. P., Benetatos, J., Lewis, V., Bonniwell, E. M., Jaster, A. M., Moliner, R., Castrén, E., McCorvy, J. D., Palner, M., & Aguilar-Valles, A. (2023). Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action. The Journal of neuroscience, 43(45), 7472–7482. https://doi.org/10.1523/JNEUROSCI.1384-23.2023

“Three papers perfectly represent the divergence in psychedelics at the moment. Cameron convincingly shows that the 5-HT2A receptor are the mediator of the therapeutic effects while Moliner convincingly shows that especially psilocin binds to and promotes plasticity through the TrkB receptor, and Lewis shows that the non-psychedelic 2-Bromo-LSD has therapeutic potential. Together they tell a story about the complexity of these drugs and how much we still need to discover about their pharmacology. We ended the year coming together in a session at the Society of Neuroscience Meeting in November and wrote a review for the journal of neuroscience elucidating some of the possible other targets.” – Mikael Palner

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Holka-Pokorska J. (2023). Can research on entactogens contribute to a deeper understanding of human sexuality? Pharmacological reports: PR, 75(6), 1381–1397. https://doi.org/10.1007/s43440-023-00552-7

“This article reviews all the studies on sexual aspects of MDMA use and highlights the surprising absence of clinical studies designed to analyze the action of entactogens on human sexual function. However, studies of naturalistic users show varied and powerful socio-emotional, sensual and sexual effects, which can vary greatly according to gender. The author stresses the risks of the lack of studies on these subjects in entactogen-assisted therapy, proposing the concept of ‘pharmacotransference’.” – Zoë Dubus

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Kangaslampi, S., & Zijlmans, J. (2023). MDMA-assisted psychotherapy for PTSD in adolescents: rationale, potential, risks, and considerations. European child & adolescent psychiatry, 10.1007/s00787-023-02310-9. Advance online publication. https://doi.org/10.1007/s00787-023-02310-9

“It requires a delicate balance of courage and caution to suggest treating an extremely vulnerable group of patients, adolescents suffering from PTSD, with MDMA – a substance that is still widely regarded as a danger to young people’s mental health. In this psychologically well-informed paper, Kangaslampi and Zijlmans strike this balance with success.” – Max Wolff

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Pronovost-Morgan, C., Hartogsohn, I., & Ramaekers, J. G. (2023). Harnessing placebo: Lessons from psychedelic science. Journal of psychopharmacology (Oxford, England), 37(9), 866–875. https://doi.org/10.1177/02698811231182602

“This paper has beautifully discussed the importance of set and setting – arguing that the interactive effect between drugs and context is the main paradigmatic tension between psychedelics and the biomedical model. The randomised controlled trial (RCT) which dominates knowledge production in psychiatry, simply doesn’t fit an interactive paradigm. There is something wrong with the apparatus.” – Leor Roseman

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Pouyan, N., Younesi Sisi, F., Kargar, A., Scheidegger, M., McIntyre, R. S., & Morrow, J. D. (2023). The effects of Lysergic Acid Diethylamide (LSD) on the Positive Valence Systems: A Research Domain Criteria (RDoC)-Informed Systematic Review. CNS drugs, 37(12), 1027–1063. https://doi.org/10.1007/s40263-023-01044-1

“This article was interesting to me due to the NIH push to qualitatively categorize animal behavior using the RDoC framework. This is done to standardize behavioral testing and so we see this in psychedelics research now. They found that LSD resulted in increased reward responsiveness in humans and in the animal literature there seems to be some evidence for reinforcement of place preference without aversion and decreased responsiveness. They also point out that being limited to the RDOC framework can result in potential bias and it will be difficult to compare to the studies now that were not formed with the framework in mind.” – Zarmeen Zahid

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Thornton, N. L. R., Kawalsky, J., Milton, A., Klinner, C., Schokman, A., Stratton, E., Loo, C. K., & Glozier, N. (2023). A systematic review of the print media representation of ketamine treatments for psychiatric disorders. BJPsych open, 9(4), e104. https://doi.org/10.1192/bjo.2023.75

“Thornton et al.’s review is a meticulous assessment of reporting on ketamine therapy with lots of interesting tidbits sprinkled throughout. I was surprised to see only 26.9% of articles on ketamine included patient testimony, all of it positive or neutral. While expert testimony was more common than patient reports, experts still made exaggerations or factual errors and 37% of the articles contained at least one piece of inaccurate information about ketamine therapy. As we start to see patients with longer term experiences and broader access, it will be interesting to see whether these media narratives shift and whose expertise is reported.” – Kalya Greenstien

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Luppi, A. I., Girn, M., Rosas, F. E., Timmermann, C., Roseman, L., Erritzoe, D., Nutt, D. J., Stamatakis, E. A., Spreng, R. N., Xing, L., Huttner, W. B., & Carhart-Harris, R. L. (2024). A role for the serotonin 2A receptor in the expansion and functioning of human transmodal cortex. Brain : a journal of neurology, 147(1), 56–80. Epub 2023 Sept 13. https://doi.org/10.1093/brain/awad311

“This comprehensive paper led by Dr. Andrea Luppi and I bridges a wide-range of research, spanning human brain development, transmodal cortex structure and function, psychedelic cellular and neuroplastic effects, psychedelic neuroimaging, psychedelic therapeutic effects and more. We highlight the potentially interrelated role of the serotonin 2A receptor in both facilitating the expansion of advanced regions of the brain (i.e., transmodal cortex) in humans during development, and in modulating it with significant therapeutic potential in adulthood (i.e., via psychedelics). We use this integrative conception of the serotonin 2A receptor to provide a broader, more comprehensive context for understanding psychedelic effects and therapeutic mechanisms.” – Manesh Girn

Clinical Trials

Reif, A., Bitter, I., Buyze, J., Cebulla, K., Frey, R., Fu, D. J., Ito, T., Kambarov, Y., Llorca, P. M., Oliveira-Maia, A. J., Messer, T., Mulhern-Haughey, S., Rive, B., von Holt, C., Young, A. H., Godinov, Y., & ESCAPE-TRD Investigators (2023). Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression. The New England Journal of Medicine, 389(14), 1298–1309. https://doi.org/10.1056/NEJMoa2304145

“The Good: This large, multicentre, single-blind study comparing Quetiapine XR to intranasal esketamine achieved a rare feat in psychiatry – demonstrating superiority of one treatment over another in depression. Not only was esketamine superior to this commonly used antipsychotic at week 8, the results held over an impressive 32 weeks of follow-up.

The Bad: The major flaw in this study is that patients in the esketamine group received significantly more face-time with supportive healthcare providers because esketamine administration requires in-person administration sessions of at least two hours in duration. As a result, it’s unclear if the superiority really owe to esketamine’s unique pharmacology versus the added level of psychosocial support.

Next Steps: A similar double-blind trial that matches for hours of contact – even if blinding is difficult with esketamine – would greatly help to untangle the reasons for esketamine’s superiority over quetiapine.”

– Kyle Greenway

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Leal, G. C., Souza-Marques, B., Mello, R. P., Bandeira, I. D., Caliman-Fontes, A. T., Carneiro, B. A., Faria-Guimarães, D., Guerreiro-Costa, L. N. F., Jesus-Nunes, A. P., Silva, S. S., Lins-Silva, D. H., Fontes, M. A., Alves-Pereira, R., Cordeiro, V., Rugieri-Pacheco, S., Santos-Lima, C., Correia-Melo, F. S., Vieira, F., Sanacora, G., Lacerda, A. L. T., … Quarantini, L. C. (2023). Arketamine as adjunctive therapy for treatment-resistant depression: A placebo-controlled pilot study. Journal of Affective Disorders, 330, 7–15. https://doi.org/10.1016/j.jad.2023.02.151

“The Good: Arketamine has received a great deal of interest as the latest candidate in the search for a ketamine-like drug that is free of significant psychoactive effects. This investigator-initiated trial demonstrated that while a single dose of arketamine lacked significant “dissociative” effects, as expected, there was not much of a signal for antidepressant effects.

The Bad: The sample size of 10 patients is very small, meaning that only a very large antidepressant effect would be detectable.

Next Steps: A larger trial is necessary to better characterize arketamine’s antidepressant potential and help to answer the question: are ketamine’s psychoactive effects really independent of its psychiatric benefits?”

– Kyle Greenway

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Murphy, R. J., Sumner, R., Evans, W., Ponton, R., Ram, S., Godfrey, K., Forsyth, A., Cavadino, A., Krishnamurthy Naga, V., Smith, T., Hoeh, N. R., Menkes, D. B., & Muthukumaraswamy, S. (2023). Acute Mood-Elevating Properties of Microdosed Lysergic Acid Diethylamide in Healthy Volunteers: A Home-Administered Randomized Controlled Trial. Biological psychiatry, 94(6), 511–521. https://doi.org/10.1016/j.biopsych.2023.03.013

“As a self-identified microdosing skeptic who had strong opinions about the white papers associated with this study, this paper was something I was very much looking forward to reading. While this body of work adds an important contribution to the microdosing literature, it also had several limitations. A major one being that even though sex differences were found in previous studies, they only wanted to study males to simplify their analysis. This should have prompted for inclusion of women in the study to further elucidate potential differences in response to psychedelics, not the other way around. They also report a large blinding and expectancy effect, in which expectancy was found to play a significant role in the measures of: energy, happy, and connected. The positive of this paper is that LSD microdosing in a home-monitored paradigm is evidenced to be relatively safe both physiologically and psychologically, and the authors report potential adverse reactions like some increased risk of anxiety and overstimulation associated with LSD-microdosing. I appreciated the transparency of their analyses and reporting.” – Alaina Jaster

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Molla, H., Lee, R., Lyubomirsky, S., & de Wit, H. (2023). Drug-induced social connection: both MDMA and methamphetamine increase feelings of connectedness during controlled dyadic conversations. Scientific reports, 13(1), 15846. https://doi.org/10.1038/s41598-023-43156-0

“This experimental study reports that both MDMA and methamphetamine increase feelings of connectedness in conversation with strangers. While feelings of connectedness remain central to common understanding of the therapeutic value of empathogens like MDMA, this study supports the claim that MDMA-assisted therapy works at least in part through enhancing the therapeutic alliance. Showcasing a robust methodology, there was a careful management of expectations around what drugs participants receive, and the exclusion of one participant after discovering that he socialized with his study partner following the intervention and prior to follow-up.

A small sample size notwithstanding, this elegant study has several interesting implications. It offers a method for measuring the connectedness between patients and therapists. It suggests that changes in connectedness resulting from MDMA are mediated by oxytocin, but this is not the case for methamphetamine. Most tantalising of all, it queries whether MDMA is quite so unique in its therapeutic benefits – could similar results to those found with MDMA-assisted therapy have been achieved through methamphetamine-assisted therapy? Perhaps there is an even broader interpretation for social scientists and humanists interested in psychedelic science: that altering our consciousness together, in ways both known and unknown, is a powerful mode of connecting. Here there is the faint trace of considering participants as aware of the conceit of the trial, as a kind of ‘double bookkeeping’.”

– Tehseen Noorani

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Molla, H., Lee, R., Tare, I., & de Wit, H. (2023). Greater subjective effects of a low dose of LSD in participants with depressed mood. Neuropsychopharmacology, 10.1038/s41386-023-01772-4. Advance online publication. https://doi.org/10.1038/s41386-023-01772-4

“What’s New? The study by Molla et al. (2023) investigated the acute and sub-acute effects of a low dose of LSD (26 µg) on mood and subjective experience in healthy individuals with depressed mood compared to non-depressed individuals. So far, low doses of a psychedelic compound have only been investigated in healthy individuals (in an RCT).

What Did We Expect to See? The paper addresses a long-standing question: Are we not seeing mood improvement in all previous microdosing studies in healthy individuals because we are simply hitting a ceiling or floor effect (i.e., there is nothing to improve because people are already feeling fine)? This was somewhat confirmed by the present study, which shows that the use of small doses (as here, a dose of 26 µg LSD was used) could be worth investigating further in clinical populations.

What’s Surprising? Surprisingly, participants with higher depression scores showed a higher acute response compared to non-depressed individuals, based on ratings of the 5D-ASC, while experiencing the same drug intensity over time. This is a new finding, and the reason for this is somewhat unclear, as previous studies with high doses (i.e., Schmid et al., 2021) have shown similar responses.”

– Friederike Holze

Molla et al. reported an intriguing finding where higher baseline depression scores correlated with larger mood-elevating and subjective effects caused by a low dose of LSD. Due to the fairly modest size and the uniformity of the test population, the finding will need to be replicated to really understand its generalisability and true meaning in the clinical setting, but I think there is something of note also for us preclinical scientists: questions of how we model psychiatric disorders, and the severity of the symptom-like phenotypes within these models should be under greater scrutiny if we hope for better interspecies translation.” – Lauri Elsilä

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Aaronson, S. T., van der Vaart, A., Miller, T., LaPratt, J., Swartz, K., Shoultz, A., Lauterbach, M., Sackeim, H. A., & Suppes, T. (2023). Single-Dose Synthetic Psilocybin With Psychotherapy for Treatment-Resistant Bipolar Type II Major Depressive Episodes: A Nonrandomized Controlled Trial. JAMA Psychiatry, e234685. Advance online publication. https://doi.org/10.1001/jamapsychiatry.2023.4685

“What’s New? This was a 12-week, open-label nonrandomized controlled trial that explored the effects of psilocybin with psychotherapy in treatment-resistant patients with bipolar II disorder (BDII) during a current depressive episode. Historically, patients with BDII have been excluded from clinical trials involving psychedelic substances.

What are the main results? Depression severity exhibited a significant decrease starting one week after a single 25-mg psilocybin dose, as measured by the Montgomery-Åsberg Depression Rating Scale. This improvement was sustained until the study endpoint, 12 weeks after the dosing session, with 12 out of 15 patients meeting both response and remission criteria. Self-assessed depression symptoms yielded similar positive results. Furthermore, the overall intensity of the psychedelic experience showed a significant correlation with MADRS scores at week 12, suggesting that the intensity of the psychedelic experience can predict longer-term antidepressant effects.

What’s important to note? The observed improvement did not coincide with increases in mania/hypomania symptoms or suicidality. This research paves the way for the potential use of psychedelics in BDII patients experiencing a depressive episode.”

– Fernanda Palhano

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Straumann, I., Ley, L., Holze, F., Becker, A. M., Klaiber, A., Wey, K., Duthaler, U., Varghese, N., Eckert, A., & Liechti, M. E. (2023). Acute effects of MDMA and LSD co-administration in a double-blind placebo-controlled study in healthy participants. Neuropsychopharmacology, 48(13), 1840–1848. https://doi.org/10.1038/s41386-023-01609-0

I was quite excited about this study because I love when research actually tries to understand things happening in the real world. Candyflipping aka LSD and MDMA co-administration is something that has been happening in the rave scene for years, so this was a really cool paper to read. The large takeaway from this study was that the combination (100 mg MDMA/100 ug LSD) had subjective and drug effects that were more similar to LSD alone than to MDMA alone, and changes in physiological response and oxytocin levels were more similar to MDMA alone. This study, while having a very small sample size, does provide insight into MDMA and LSD co-administration and suggests it is relatively safe. It would be interesting to see this kind of work with other compounds commonly co-administered with psychedelics, such as THC. – Alaina Jaster

 

“This paper addresses the phenomenon of individuals using MDMA and LSD together in recreational settings to enhance subjective effects, a practice that has not been tested before under controlled conditions. Contrary to what was expected, they did not find synergistic effects, but rather a prolonged duration of acute effects. The findings provide valuable information regarding whether this practice would be beneficial for enhancing MDMA- or LSD-assisted therapy.” – Hanna Molla

***

Mitchell, J. M., Ot’alora G, M., van der Kolk, B., Shannon, S., Bogenschutz, M., Gelfand, Y., Paleos, C., Nicholas, C. R., Quevedo, S., Balliett, B., Hamilton, S., Mithoefer, M., Kleiman, S., Parker-Guilbert, K., Tzarfaty, K., Harrison, C., de Boer, A., Doblin, R., Yazar-Klosinski, B., & MAPP2 Study Collaborator Group (2023). MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nature Medicine, 29(10), 2473–2480. https://doi.org/10.1038/s41591-023-02565-4

“The second, confirmatory Phase 3 trial of MDMA-assisted therapy as a treatment for PTSD yields results that are reassuringly similar to the first Phase 3 trial. This second trial included patients with a broader range of disease severity, providing evidence the treatment also works in less severe cases of PTSD. Because the sponsor had negotiated in advance with the FDA, we know that this study will be considered acceptable evidence in support of the currently under-review application to market MDMA as a prescription medicine. Thus, this study may be the last piece of evidence needed in the decades-long effort to bring MDMA to market in the US.” – Matthew Baggott

***

Ley, L., Holze, F., Arikci, D., Becker, A. M., Straumann, I., Klaiber, A., Coviello, F., Dierbach, S., Thomann, J., Duthaler, U., Luethi, D., Varghese, N., Eckert, A., & Liechti, M. E. (2023). Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants. Neuropsychopharmacology, 48(11), 1659–1667. https://doi.org/10.1038/s41386-023-01607-2

“Very important cross-over study comparing the pharmacodynamics and pharmacokinetics of 3 classic psychedelics: mescaline, LSD and psilocybin. This study provides the most comprehensive estimates of psychedelic pharmacokinetic parameters, along with evidence from physiological and psychological outcomes suggesting equivalent psychedelic effects for 500 mg mescaline, 100 µg LSD, and 20 mg psilocybin.” – Kelan Thomas

***

Ley, L., Holze, F., Arikci, D., Becker, A. M., Straumann, I., Klaiber, A., Coviello, F., Dierbach, S., Thomann, J., Duthaler, U., Luethi, D., Varghese, N., Eckert, A., & Liechti, M. E. (2023). Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants. Neuropsychopharmacology, 48(11), 1659–1667. https://doi.org/10.1038/s41386-023-01607-2

“Very important cross-over study comparing the pharmacodynamics and pharmacokinetics of 3 classic psychedelics: mescaline, LSD and psilocybin. This study provides the most comprehensive estimates of psychedelic pharmacokinetic parameters, along with evidence from physiological and psychological outcomes suggesting equivalent psychedelic effects for 500 mg mescaline, 100 µg LSD, and 20 mg psilocybin.” – Kelan Thomas

***

Anand, A., Mathew, S. J., Sanacora, G., Murrough, J. W., Goes, F. S., Altinay, M., Aloysi, A. S., Asghar-Ali, A. A., Barnett, B. S., Chang, L. C., Collins, K. A., Costi, S., Iqbal, S., Jha, M. K., Krishnan, K., Malone, D. A., Nikayin, S., Nissen, S. E., Ostroff, R. B., Reti, I. M., … Hu, B. (2023). Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. The New England Journal of Medicine, 388(25), 2315–2325. https://doi.org/10.1056/NEJMoa2302399

“Head-to-head trials may be the most useful approach to help determine the sequence of treatment choices in a given patient population. This trial in more than 400 patients with treatment-resistant depression in an outpatient setting aimed to determine whether ketamine was no worse than (also known as a non-inferiority trial) electroconvulsive therapy (ECT) by a predetermined margin.

The trial concluded ketamine was not inferior to ECT ⁶. However, many argued the trial was effectively enriched towards showing greater benefit with ketamine based on a number of factors including a suboptimal ECT regimen and the exclusion of older patients as well as those with psychotic symptoms, both known to respond better to ECT. This trial may nonetheless meaningfully influence the treatment of treatment-resistant depression without psychosis, given the pragmatic nature of its design.”

– Michael Haichin

***

Atila, C., Holze, F., Murugesu, R., Rommers, N., Hutter, N., Varghese, N., Sailer, C. O., Eckert, A., Heinrichs, M., Liechti, M. E., & Christ-Crain, M. (2023). Oxytocin in response to MDMA provocation test in patients with arginine vasopressin deficiency (central diabetes insipidus): a single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial. The Lancet. Diabetes & endocrinology, 11(7), 454–464. https://doi.org/10.1016/S2213-8587(23)00120-1

“What’s New? The study by Atila et al. (2023) used MDMA as an innovative tool to provoke oxytocin release in patients suffering from arginine vasopressin deficiency (or central diabetes insipidus) and compared that with healthy individuals. So far, no oxytocin “provocation test” had been established, even though much effort had been put into this.

What Did We Expect to See? As hypothesized, patients with arginine vasopressin deficiency showed a reduced oxytocin release due to the anatomical proximity (both are released in the pituitary gland) compared with healthy controls. This lays the groundwork for a novel pituitary entity that has never been described before.

What’s Surprising? The patients with vasopressin deficiency not only showed a reduced oxytocin release but also had a reduced overall response to MDMA, eventually showing that oxytocin release is a crucial part of MDMA’s mechanism of action. This is indeed surprising, as several preclinical studies (e.g., by Boris Heifets and team) have shown that oxytocin might not play a significant role in MDMA’s mechanism of action. This has truly been an interdisciplinary approach that amazes me to this day and shows the usefulness of psychedelics beyond neuropsychiatric illnesses.”

– Friederike Holze

***

Timmermann, C., Roseman, L., Haridas, S., Rosas, F. E., Luan, L., Kettner, H., Martell, J., Erritzoe, D., Tagliazucchi, E., Pallavicini, C., Girn, M., Alamia, A., Leech, R., Nutt, D. J., & Carhart-Harris, R. L. (2023). Human brain effects of DMT assessed via EEG-fMRI. Proceedings of the National Academy of Sciences of the United States of America, 120(13), e2218949120. https://doi.org/10.1073/pnas.2218949120

“Timmerman et al. were pioneers in exploring large-scale dynamics following N,N-DMT administration, marking their paper as a significant contribution to the field. Their approach, integrating EEG and BOLD-fMRI, promised to enhance the interpretative power of BOLD-fMRI in better understanding underlying neuronal activity, and not relying on the assumption that BOLD-fMRI accurately indexes neuronal activity (as their group often claims). However, the study’s reliance on dynamic resting-state functional connectivity raises concerns, as it depends on instantaneous cross-regional coherence that has been criticized for being more artifactual than biologically significant. An overlooked opportunity in this research was the investigation of neurovascular coupling, especially relevant since 5-HT2A receptor activity is known to influence this process. While the study demonstrated ‘parallel’ alterations in large-scale dynamics induced by DMT through simple correlations between modalities, it did not explore the well-documented phenomenon of phase-amplitude/cross-frequency coupling between gamma band power and infraslow power, as measured by BOLD. Incorporating this aspect could have greatly enhanced the study’s significance and findings.” – Anonymous

***

Singleton, S. P., Wang, J. B., Mithoefer, M., Hanlon, C., George, M. S., Mithoefer, A., Mithoefer, O., Coker, A. R., Yazar-Klosinski, B., Emerson, A., Doblin, R., & Kuceyeski, A. (2023). Altered brain activity and functional connectivity after MDMA-assisted therapy for post-traumatic stress disorder. Frontiers in psychiatry, 13, 947622. https://doi.org/10.3389/fpsyt.2022.947622

“The first neuroimaging study performed in a cohort of MDMA-assisted therapy participants uses fMRI to measure patients’ brain response to traumatic events before and two months after a full course of MDMA-assisted therapy for PTSD. Audio recordings of each participant recounting their index trauma were played back to them while in the scanner. The researchers found that patient brain response to these recordings was lower at the two-month followup compared to baseline, particularly in the cuneus, which may suggest a decreased intensity of the relived experience. This study included 9 subjects from a MAPS phase II dose-response trial.” – Parker Singleton

 

Discovery & Preclinical

Layzell, M., Rands, P., Good, M., Joel, Z., Cousins, R., Benway, T., James, E., & Routledge, C. (2023). Discovery and In Vitro Characterization of SPL028: Deuterated N,N-Dimethyltryptamine. ACS Medicinal Chemistry Letters, 14(9), 1216–1223. https://doi.org/10.1021/acsmedchemlett.3c00143

“DMT shows therapeutic promise for psychiatric disorders, notably major depressive disorder. However, its potential is hindered by a brief half-life and swift clearance through metabolism by monoamine oxidase enzymes. Enhancing DMT’s in vivo stability and duration without relying on monoamine oxidase inhibitors, which pose safety concerns, could improve clinical outcomes. Small Pharma, now part of Cybin, took an innovative approach to modifying DMT’s structure by replacing hydrogen atoms with deuterium atoms—which form shorter and stronger bonds with carbon that are more resistant to chemical reactions—to render the structure more resistant to enzymatic degradation. In their paper, the team reveals that deuteration of the alpha carbon (αα-d2) of DMT increases its half-life and decreases its clearance by ~8-fold in liver mitochondrial fractions (attributed to inhibited oxidative deamination) while the primary serotonergic receptor pharmacodynamic properties remain intact. This discovery exemplifies an exciting optimization of a classic psychedelic by altering its pharmacokinetic properties.” – Clinton Canal

***

Zhu, H., Liu, X., Wang, X., Li, Y., Ma, F., Tan, B., Zhou, P., Fu, F., & Su, R. (2023). Gβγ subunit inhibitor decreases DOM-induced head twitch response via the PLCβ/IP3/Ca2+/ERK and cAMP signaling pathways. European Journal of Pharmacology, 957, 176038. https://doi.org/10.1016/j.ejphar.2023.176038

“This is a very interesting study. The focus on signaling pathways underlying behaviors has been on either Galpha-q or Beta-Arrestin signaling. Drug discovery efforts have focused on finding agonists at 5-HT2A receptors that only activate one or the other pathway. There have been conflicting published reports where some data suggest one pathway and other reports the other pathway, underlie the head twitch response in mice. The data in this paper suggest involvement of G-beta/gamma signaling in the head twitch response through adenylate cyclase. Although the head twitch response in mice correlates with psychedelic activity in humans for most known psychedelics, the relevance of head twitch to actual psychedelic behaviors remains unknown and it remains to be seen how relevant G-beta/gamma are to psychedelic related effects in humans.” – Charles Nichols

***

Kiilerich, K. F., Lorenz, J., Scharff, M. B., Speth, N., Brandt, T. G., Czurylo, J., Xiong, M., Jessen, N. S., Casado-Sainz, A., Shalgunov, V., Kjaerby, C., Satała, G., Bojarski, A. J., Jensen, A. A., Herth, M. M., Cumming, P., Overgaard, A., & Palner, M. (2023). Repeated low doses of psilocybin increase resilience to stress, lower compulsive actions, and strengthen cortical connections to the paraventricular thalamic nucleus in rats. Molecular Psychiatry, 28(9), 3829–3841. https://doi.org/10.1038/s41380-023-02280-z

“As far as I know, this is the first non-anecdotal evidence that microdosing may offer cognitive benefits. My favorite part of the experimental design is that they considered regular injections a stressor (which of course it is), and used the sucrose preference test properly – which is to say as a measure of reactivity to chronic stress, rather than a “depression-like” behavior. Determining recurring low-dose psilocybin’s effect on 5-HT2A receptor distribution and occupancy greatly contributes to the integrity of their findings. My only quibble is that they excluded females without justification.” – Meghan Hibicke

“Kiilerich et al. reported a sophisticated study of microdosing of psilocybin in rats with correlates of 5-HT2a receptor binding. They define a micro-dose as one in which there is less than 20% occupancy of the 5-HT2a receptor and that does not induce behavior associated with higher doses of psilocybin such as the wet back shake. Despite the lack of overt behaviors at this low, every other day dosing regimen, the rats treated in this manner demonstrated less frequent grooming episodes (suggesting less distractibility) and less anhedonia with stress (suggesting resilience to depression). The dose of psilocybin chosen as a microdose was 0.05 mg/kg. Using FDA Guidance on allometric interspecies dose conversions, this would be approximately equivalent to a dose of 0.008 mg/kg (0.05 mg/kg x 0.16), or 0.56 mg in a 70 kg human.  The rat doses were administered subcutaneously, and with reported oral bioavailability of 50%, this suggests a human microdose of approximately 1 mg. This and other studies of subperceptable doses of psychedelics are important, and support well-designed controlled clinical trials. One identifiable hurdle is to obtain regulatory acceptance for either short clinic dosing visits or even at-home dosing, and testing the effect of any therapist intervention over the course of repeated dosing.” – Paul Hutson

***

Lewis, V., Bonniwell, E. M., Lanham, J. K., Ghaffari, A., Sheshbaradaran, H., Cao, A. B., Calkins, M. M., Bautista-Carro, M. A., Arsenault, E., Telfer, A., Taghavi-Abkuh, F. F., Malcolm, N. J., El Sayegh, F., Abizaid, A., Schmid, Y., Morton, K., Halberstadt, A. L., Aguilar-Valles, A., & McCorvy, J. D. (2023). A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Cell Reports, 42(3), 112203. https://doi.org/10.1016/j.celrep.2023.112203

The publication about bromo-LSD as potential treatment for mood disorders by Vern Lewis and colleagues was one of my favourite articles in 2023. Despite various promising reports about its efficiency against cluster headache, surprisingly little was so far known about the pharmacological properties of bromo-LSD. I particularly enjoyed the detailed examination of the molecular mechanisms of bromo-LSD in comparison to its non-halogenated psychedelic analogue. I hope we will see more research on bromo-LSD as treatment for cluster headache and other indications in the near future. – Dino Luethi

“BOL is a relatively old drug. Traditionally it has been thought of as an antagonist of 5-HT2A receptors. This work shows that it has complex receptor pharmacology and acts as an agonist at several receptors, including 5-HT2A receptors. BOL has not elicited psychedelic effects in humans, therefore this work suggests that bromination of the 2’ position of lysergamides may be a mechanism to maintain agonist activity but eliminate behavioral effects. In the search to develop new ‘non psychedelic psychedelics’ 2’ bromination of lysergamides could be a productive strategy.” – Charles Nichols

See also Mikael Palner’s comment on Cameron et al., which mentions this study.

***

Malikowska-Racia, N., Koniewski, M., Golebiowska, J., & Popik, P. (2023). Acute but not long-lasting antidepressant-like effect of psilocybin in differential reinforcement of low-rate 72 schedule in rats. Journal of Psychopharmacology (Oxford, England), 37(11), 1149–1156. https://doi.org/10.1177/02698811231205692

“The authors used an alternative behavioral assay for measuring depressive-like behaviors (DRL 72), and one that has been shown to be highly predictive for the efficacy of currently marketed antidepressants, such as SSRIs and SNRIs. Using the DRL 72, they found psilocybin to have acute, but not persistent antidepressant-like effects, which is inconsistent with previously published literature in which the forced swim test was used. Likely, this is because the DRL 72 relies on acute increases in serotonergic and noradrenergic signaling, such as is seen in SSRI and SNRI antidepressants, but is not understood to be the mechanism for psilocybin’s persistent antidepressant effect. It’s reasonable that psilocybin (and potentially other psychedelics with demonstrated antidepressant effects) do not rely on the same mechanism(s) as SSRI/SNRI antidepressants, but to the best of my knowledge, the validity of the DRL 72 has not been established in chronic dosing studies with currently marketed antidepressants.” – Meghan Hibicke

***

Dwiel, L., Henricks, A., Bragg, E., Nicol, J., Gui, J., & Doucette, W. (2023). Lysergic acid diethylamide alters the effects of brain stimulation in rodents. Psychedelic Medicine, 1(1), 43–53. https://doi.org/10.1089/psymed.2022.0014

“This is an interesting take on the use of LSD to treat psychiatric and potentially other disorders. Brain stimulation is already an approved therapy for the treatment of some forms of severe depression. LSD has shown antidepressant effects in human clinical trials and animal studies alike. The promise of this research is that perhaps the effects of psychedelics like LSD on synaptic plasticity could be combined with direct brain stimulation to produce a net synergy of effects in the treatment of neurological disorders.” – Charles Nichols

***

Vargas, M. V., Dunlap, L. E., Dong, C., Carter, S. J., Tombari, R. J., Jami, S. A., Cameron, L. P., Patel, S. D., Hennessey, J. J., Saeger, H. N., McCorvy, J. D., Gray, J. A., Tian, L., & Olson, D. E. (2023). Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science (New York, N.Y.), 379(6633), 700–706. https://doi.org/10.1126/science.adf0435

“Upon observing a pool of intracellular 5HT2A receptors in cultured neurons, Vargas et al. conducted an extensive work to characterize their involvement in mediating the neurotrophic effects of psychedelics. A heavy focus on in vitro techniques, raises questions on the implications of the findings at higher biological levels. The paper is nonetheless an exquisite study of the importance of physicochemical properties in the ability of compounds to cross membranes.” – Mario de la Fuente

***

Witt, C. E., Mena, S., Holmes, J., Hersey, M., Buchanan, A. M., Parke, B., Saylor, R., Honan, L. E., Berger, S. N., Lumbreras, S., Nijhout, F. H., Reed, M. C., Best, J., Fadel, J., Schloss, P., Lau, T., & Hashemi, P. (2023). Serotonin is a common thread linking different classes of antidepressants. Cell Chemical Biology, 30(12), 1557–1570.e6. https://doi.org/10.1016/j.chembiol.2023.10.009

“There’s been a lot of debate recently about the serotonin hypothesis of depression, so it was thrilling to see this paper by Witt et al. that took on the issue. Utilizing ultrasensitive in vivo voltammetry to dynamically measure serotonin levels in the mouse hippocampus, a neural system involved in the pathology of depression, the authors found that despite having different pharmacodynamic properties, the antidepressants fluoxetine and escitalopram (SSRIs), reboxetine (NRI), and ketamine (NMDA antagonist) increased serotonin levels. These data suggest that different antidepressants converge on the same neurochemical, serotonin, keeping it in the limelight. Intriguingly, the different antidepressants had unique effects on the kinetics of serotonin increases, unveiling a new level of analysis to study for antidepressant drug discovery.” – Clinton Canal

***

Rijsketic, D. R., Casey, A. B., Barbosa, D. A. N., Zhang, X., Hietamies, T. M., Ramirez-Ovalle, G., Pomrenze, M. B., Halpern, C. H., Williams, L. M., Malenka, R. C., & Heifets, B. D. (2023). UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice. Neuropsychopharmacology, 48(12), 1798–1807. https://doi.org/10.1038/s41386-023-01613-4

“Most preclinical psychedelic neuroscience research focuses on cortical modulation and plasticity, where 5-HT2A receptors are most abundant. Using whole mouse brain neural activity mapping, Rijsketic, Casey, et al. showed that psilocybin activates not only cortical neurons but also distinct neural ensembles in the central amygdala, striatum, and parasubthalamic nucleus of the hypothalamus. Network activity in these regions became less modular, and correlative activity between modules was strongly disrupted. Moreover, by quantifying psilocybin-elicited neural activity across different environmental contexts, this work assessed whether environmental “setting” influences psychedelic-mediated neural activity, which is presumed to be relevant for therapeutic outcomes. I was struck by their observations that the effects of psilocybin were largely setting-independent.” – Clinton Canal

 

“This is a very neat study that uses state of the art genetic and imaging methodologies to highlight regions of the brain that become activated in response to psychedelics. Studies examining brain regions for the effects of psychedelics have been performed before, but they have relied on brain slices. This study takes into account the entire brain, and recreates 3D spatial representations of activated regions, and how activity between these regions is related. These data further inform on global effects of psychedelics on brain function and the data generated are useful for many follow-up studies, and may suggest additional therapeutic indications for psychedelics.” – Charles Nichols

***

Wallach, J., Cao, A. B., Calkins, M. M., Heim, A. J., Lanham, J. K., Bonniwell, E. M., Hennessey, J. J., Bock, H. A., Anderson, E. I., Sherwood, A. M., Morris, H., de Klein, R., Klein, A. K., Cuccurazzu, B., Gamrat, J., Fannana, T., Zauhar, R., Halberstadt, A. L., & McCorvy, J. D. (2023). Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential. Nature Communications, 14(1), 8221. https://doi.org/10.1038/s41467-023-44016-1

“This is my favorite study this year. They showed very convincingly that to get a head-twitch response in mice, one needs a drug that activates a threshold level of Gq pathway. Of course it remains to be seen how head-twitch response may or may not be relevant for predicting drug action in humans. Nonetheless, the study showcases the power of high-throughput screens possible in rodents, and suggests a path forward for engineering compounds with certain molecular action.” – Alex Kwan

“This work is a major structure/activity relationship study that has allowed for better understanding of how certain psychedelics interact with the orthosteric binding pocket to activate 5-HT2A receptors. Key structural insights for selectivity for 5-HT2A, as well as effector pathway biased agonism were determined that will help to guide future drug development. Significantly, their data indicate that the behavioral effects of head twitch require a threshold activation of 70% compared to serotonin for Gq signaling. Therefore, the level of agonism at 5-HT2A receptors may be a significant driver of whether or not a particular ligand is ‘psychedelic’ or not.” – Charles Nichols

Wallach et al. published an extense and elegant paper investigating the drivers behind the signaling events that unfold following 5-HT2A stimulation. Like Vargas et al. the manuscript did not skimp on a thorough blending of chemistry and pharmacology. The paper features numerous examples of compounds displaying varying levels of 5-HT2A downstream pathway engagement to devise a mechanistic explanation behind the manifestation of head-twitch responses in mice; and possibly responsible for the human psychedelic experience? Part of the beauty of this paper lies in its attempt to escape from far reaching and often exotic explanations to center the effort in providing good depth to revisit the fundamental mechanisms tied to 5-HT2A stimulation.The part that I fail to grasp is the interest of targeting the beta-arrestin pathway in drug discovery.” – Mario de la Fuente

***

Moliner, R., Girych, M., Brunello, C. A., Kovaleva, V., Biojone, C., Enkavi, G., Antenucci, L., Kot, E. F., Goncharuk, S. A., Kaurinkoski, K., Kuutti, M., Fred, S. M., Elsilä, L. V., Sakson, S., Cannarozzo, C., Diniz, C. R. A. F., Seiffert, N., Rubiolo, A., Haapaniemi, H., Meshi, E., … Castrén, E. (2023). Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nature Neuroscience, 26(6), 1032–1041. https://doi.org/10.1038/s41593-023-01316-5

“Psychedelics like lysergic acid diethylamide (LSD) and psilocybin are known for their rapid and enduring antidepressant effects, yet the specific molecular targets responsible remain unclear. Moliner et al. sheds light on this mystery, revealing that LSD and psilocin (the active metabolite of psilocybin) directly bind to TrkB, the receptor for the neurotrophin BDNF.

Using computational and experimental methods, the researchers pinpointed the binding site for LSD and psilocin on the TrkB receptor. This binding stabilized TrkB into a structural form more conducive to activation by BDNF, indicating that these compounds act as modulators enhancing the effects of BDNF, rather than activating the receptor independently.

Notably, LSD treatment led to dendritic plasticity in cultured neurons and elicited antidepressant-like effects in wild-type mice, but not in mice genetically lacking a key TrkB docking site for binding psychedelics.

Despite the established hallucinogenic effects of psychedelics by activation of the serotonin 2A receptor (5-HT2AR), the neuroplastic and antidepressant-like effects of LSD do not necessitate 5-HT2AR activation. Furthermore, the head-twitch response, indicative of hallucinogenic effects, did not involve TrkB binding, suggesting distinct mechanisms of action for these effects.

This study introduces a novel approach to unlocking the therapeutic potential of TrkB ligands that mimic the antidepressant properties of psychedelics without the accompanying hallucinogenic side effects.”

– Amy Reichelt

“The 5th of June of 2023 will be a date to remember in psychedelic science. On this day, Moliner et al. published their manuscript proposing a direct interaction between psychedelics and the BDNF receptor. This interaction was posited as necessary and sufficient to explain the neurotrophic effects of psychedelics—or at least LSD and psilocin. I was among those that dragged their jaws in awe for a while. The beauty in the simplicity of the proposition by Moliner et al. found an outstanding reception in a crowd yearning for accessible explanations. Allthewhile, some old dogs have pointed out technical complexities and potential deficiencies inherent to the study of interactions with the BDNF receptor. Calls for caution were made in the interpretation of the work of Moliner et al. as a “theory of everything” around psychedelics potential therapeutic effects.” – Mario de la Fuente

See also Mikael Palner’s comment on Cameron et al., which mentions this study.

***

Davoudian, P. A., Shao, L. X., & Kwan, A. C. (2023). Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin. ACS Chemical Neuroscience, 14(3), 468–480. https://doi.org/10.1021/acschemneuro.2c00637

“Given the argument about psychedelic nomenclature and what is considered a psychedelic, papers like these add significant evidence to challenge both sides and provides further insight into how these compounds can be developed therapeutically. I found this study quite interesting because while the findings support both compounds causing changes in cortex and visual systems, they also show that ketamine altered regions involved in memory, withdrawal and arousal states whereas psilocybin altered key regions involved in adaptations of behavior, processing and integration of information. The combination of cFOS and in situ was a great way to further understand potential correlations between region specificity and receptor selectivity.” – Alaina Jaster

***

Nardou, R., Sawyer, E., Song, Y. J., Wilkinson, M., Padovan-Hernandez, Y., de Deus, J. L., Wright, N., Lama, C., Faltin, S., Goff, L. A., Stein-O’Brien, G. L., & Dölen, G. (2023). Psychedelics reopen the social reward learning critical period. Nature, 618(7966), 790–798. https://doi.org/10.1038/s41586-023-06204-3

“I found this paper to be quite fascinating in the way that it characterized a critical learning period for social reward learning conditioned place preference (CPP). In their paradigm PSI, LSD, ketamine and ibogaine all cause a significant shift in preference score to be similar to the open state (critical period) whereas saline is no different from the closed state. While I thought the study design for CPP was great, I was left wondering: how much of the effect of psychedelics has to do with strengthening the conditioning and reinforcing effects of social reward or restoring preference through mechanisms associated with memory recall? While they attempted to get at this question, more refined methods such as recording psychedelic-induced bidirectional modulation of long-term depression (LTD) and long-term potentiation (LTP) in living animals and exploring the accumbal-hippocampal circuit may provide more insight.” – Alaina Jaster

“While the immediate effects of psychedelic drugs on consciousness fade within minutes to hours, their therapeutic benefits are thought to extend over a broader timeframe. This period of heightened neural plasticity, post-psychedelic experience, is considered pivotal for therapeutic integration and lasting shifts in mindset.

Researchers at Johns Hopkins University in Prof Gul Dolen’s laboratory, investigated the applicability of this mechanism to various psychedelics. They focused on social behaviors in mice, particularly the positive associations formed during adolescence, a critical period that diminishes in adulthood. Adult mice treated with LSD, psilocybin, ibogaine, or ketamine exhibited a greater reward response to social experiences compared to those treated with saline or the non-psychedelic drug, cocaine.

Each psychedelic reinstated the youthful critical period for social reward, revealing a unified functional mechanism. However, the duration of this reopening varied across compounds, correlating with each drug’s acute effects duration in humans rather than dose increases. Additionally, neurons in the nucleus accumbens, crucial for reward processing, exhibited heightened sensitivity to oxytocin—a hormone linked to social bonding. This increased sensitivity suggests that psychedelics may induce ‘metaplasticity,’ dynamic changes to neuroplasticity, potentially underpinning therapeutic critical period reopening.

It’s crucial to note that this study focused specifically on social reward learning, leaving room for future experiments to explore other behavioral and physiological changes induced by psychedelics.”

– Amy Reichelt

 

“This study breaks away from convention and represents a seminal paper for the field of psychedelic research. The authors demonstrate that the period for learning social reward, a process which is normally developmentally regulated, can be reopened for varying lengths of time by different psychedelics. This discovery provides the field with a more translatable preclinical behavioral readout than the commonly used head twitch response. They further demonstrate that the mechanism is not fully dependent on canonical signaling through the Serotonin 2A receptor and its downstream effector β-arrestin 2. Using gene expression data the authors provide an alternative mechanism, proposing that psychedelics remodel the extracellular matrix. This highly intriguing hypothesis warrants further investigation!” – Joseph Benetatos

 

“The paper that caused me the most mixed feelings. The social reward learning model Nardou and colleagues used here is in and of itself interesting, and the idea that such a varied group of so-called hallucinogenic compounds could modify the learning in a similar way is fascinating and certainly worth following up. However, the article also has, in my mind, several logical failings in its proposals, as well as some very bold claims not properly backed up by the presented data, especially regarding the molecular mechanisms of the effect, and yet still, we are reading it on the pages of one of the most revered science journals. This all left me with an ambiguous feeling, and rekindled animosity towards the current scientific publication landscape.” – Lauri Elsilä

***

Cameron, L. P., Patel, S. D., Vargas, M. V., Barragan, E. V., Saeger, H. N., Warren, H. T., Chow, W. L., Gray, J. A., & Olson, D. E. (2023). 5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines. ACS Chemical Neuroscience, 14(3), 351–358. https://doi.org/10.1021/acschemneuro.2c00718

“This study piqued my interest because it adds to the debate of whether the serotonin 2A receptors are needed for therapeutic actions. On one side, there is this study plus other work from Olson and Gonzalez-Maeso suggesting 2A is essential, and on the other side, there are works from Thompson and more recently Becamel that say 2A is not the key ingredient. People are finding opposing results, perhaps because there are drug-specific differences or more likely the current genetic and pharmacological tools are not perfect and have confounds.” – Alex Kwan

***

Warner-Schmidt, J., Pittenger, C., Stogniew, M., Mandell, B., Olmstead, S. J., & Kelmendi, B. (2023). Methylone, a rapid acting entactogen with robust anxiolytic and antidepressant-like activity. Frontiers in Psychiatry, 13, 1041277. https://doi.org/10.3389/fpsyt.2022.1041277

“Warner-Schmidt and colleagues present evidence that methylone, the beta-keto analogue of MDMA, has fast acting antidepressant-like effects that persist at least 72 hours after drug administration in rats. This paper is significant because it provides a clearer sense of entactogens as a class, specifically adding weight to overlooked evidence that entactogens may have fast-acting antidepressant-like effects. Although not presented as such, the current paper can be seen as a back translation of user reports and clinical observations of improved mood after MDMA.

The scientific literature on illicit ecstasy users has focused on lowered mood reportedly occurring days after some ecstasy use. Reports of subacute positive elevations in mood, sometimes called afterglows, have received less attention. However, in retrospect, the MDMA afterglow phenomenon resembles the effects of fast acting antidepressants such as ketamine. Indeed, Calvin Ly and colleagues (2018), in their supplemental materials, found MDMA had dramatic neuroplasticity-enhancing effects in rodent primary cortical cultures, analogous to those seen after ketamine. Yet, to this author’s knowledge, no previous studies had detected antidepressant-like effects from MDMA or other entactogens in vivo with any standard behavioral assay. This paper therefore provides the first evidence that an entactogen afterglow can be replicated and studied in nonhuman animals. And it further points to the forced swim test, a standard assay for screening for potential antidepressants, as a fruitful paradigm for further research.”

– Matthew Baggott

***

Alper, K., Cange, J., Sah, R., Schreiber-Gregory, D., Sershen, H., & Vinod, K. Y. (2023). Psilocybin sex-dependently reduces alcohol consumption in C57BL/6J mice. Frontiers in Pharmacology, 13, 1074633. https://doi.org/10.3389/fphar.2022.1074633

“This might be one of my favorite papers from 2023 for two reasons: they assessed differences across sexes in response to psychedelics and they are assessing psilocybin’s effects on reward. This was also a great (and long awaited) follow up to their paper with LSD and alcohol consumption. Psilocybin is able to produce a dose-dependent decrease in ethanol consumption and preference in only male mice. This effect lasted up to three days with doses greater than 0.1 mg/kg. These findings not only highlight a difference across sexes in potential therapeutic effects of psilocybin in ethanol behavior, but also highlights that ethanol consumption may be higher or more variable in female mice. This kind of work provides insights into potential differences in behavior across sexes that may be relevant to treating substance use disorders with psychedelics in humans.” – Alaina Jaster

“Touching greatly on my own research, in this article Kenneth Alper’s group replicated their own finding where a single dose of psychedelic can reduce alcohol consumption in mice for a prolonged time. Their work remains one of the only ones where these consumption-lowering effects persist beyond the acute dosing session, and I personally am very curious to know what causes these differences in findings. The sex differences they present here warrant a more rigorous replication, but certainly hint towards something potentially interesting and reminds us preclinical scientists why sex as a biological variable is so important.” – Lauri Elsilä

***

Effinger, D. P., Quadir, S. G., Ramage, M. C., Cone, M. G., & Herman, M. A. (2023). Sex-specific effects of psychedelic drug exposure on central amygdala reactivity and behavioral responding. Translational Psychiatry, 13(1), 119. https://doi.org/10.1038/s41398-023-02414-5

“This was another great paper for differences across sexes in psychedelics. It’s been reported in human studies that men and women react and process aversive experiences differently and I think this paper replicates those findings in a rodent model. They found psilocin acutely increased central amygdala activity in both sexes but produced time-dependent decreases in reactivity in male mice, but increased reactivity in females. I enjoyed this paper because it combined fiber photometry methods with behavioral methods, including the investigation of how psilocin alters reactivity to different stimuli. Overall, this paper was a great jumping off point for a lot of future studies.” – Alaina Jaster

Editorials

Dworkin, R. H., McDermott, M. P., Nayak, S. M., & Strain, E. C. (2023). Psychedelics and Psychotherapy: Is the Whole Greater than the Sum of its Parts? Clinical Pharmacology and Therapeutics, 114(6), 1166–1169. https://doi.org/10.1002/cpt.3050

“This short and sweet perspective paper was my favourite read of last year. The combined intervention of psychedelic administration and psychotherapy has long warranted the use of 2 x 2 factorial clinical trials⁷ to determine their individual effects, and whether the suggestion that their pharmacology enhances the psychotherapeutic effect (or vice versa) is accurate.

Dworkin and colleagues review the concepts of synergy (i.e. psychedelic-assisted therapy is greater than the sum of its parts) and additivity, as well as the lesser known favourable and adverse sub-additivity, neatly displayed in a figure worth reviewing.

The main question raised from Goodwin et al. about whether psilocybin must always assist psychotherapy is ultimately an empirical one, and perhaps one of the most pressing research questions in the field, best summed up by Dworkin and colleagues: “The combination of a psychedelic and time-limited psychotherapy to maximize treatment benefits must be distinguished from the combination of a psychedelic and the support required to reduce the risk of adverse events.”

– Michael Haichin

***

Goodwin, G. M., Malievskaia, E., Fonzo, G. A., & Nemeroff, C. B. (2024). Must Psilocybin Always “Assist Psychotherapy”? The American Journal of Psychiatry, 181(1), 20–25. Epub 2023 Jul 12. https://doi.org/10.1176/appi.ajp.20221043

“Psilocybin vs psychotherapy? In a flurry of 2023 papers authored by Guy Goodwin (Chief Medical Officer at Compass Pathways), the one that probably drew the most heat was “Must psilocybin always ‘assist psychotherapy’”?. In it, Goodwin and colleagues present a number of arguments – some more convincing than others – why psychedelic treatment should not be conflated with ‘psychedelic-assisted psychotherapy’, arguing that the therapeutic effects of psilocybin can be attributed to the pharmacological drug effects. As expected, this controversial position generated a heated debate, and was quickly followed by six published letters to the editor of the American Journal of Psychiatry, and several more commentaries elsewhere.

Why should we care? It is useful to challenge conventional wisdom and commonly accepted, often used concepts like ‘psychedelic-assisted psychotherapy’ (PAP). It is important to be accurate about what this means exactly; to make explicit how a psychedelic drug ‘assists’ psychotherapy, if at all; what kinds of psychotherapy they refer to (see e.g. Crowe et al.); and how we can evaluate the synergy between psychedelic drug effects and psychotherapy (Dworkin et al. provide concrete suggestions). For example, as Brennan et al. address, what this psychotherapy consists of mostly goes unreported in scientific publications. Besides, many studies (as in the Compass phase 2b trial) do merely provide psychological support pre and post psilocybin, and do not provide psychotherapy. Which is subject to additional criticism – lobbed at Goodwin by Gründer et al. – who state that reducing psychological support merely to its function as a safeguard for risk mitigation fundamentally misunderstands the psychotherapeutic nature of the psychedelic experience.

What’s next? An important question for the whole field in the coming years will be to find the right balance between cost-effectiveness and optimal treatment conditions. Extensive psychotherapy is expensive, and one way to reduce costs (in the hope of increasing the likelihood of treatments becoming reimbursed) is minimizing the amount of billable hours by costly mental health specialists. This may come at the cost of lowering efficacy and safety, may even be considered unethical (as per Deckel et al.), and, as highlighted by O’Donnell et al., could actually increase the incidence of (serious) psychiatric adverse reactions, pointing to 3 cases of suicidality in the high dose group in Compass’ psilocybin for depression trial (Goodwin et al., 2022). Extending this line of thought (cf Jacobs et al.), this ethical obligation may even extend to the period after the end of the clinical trial. What’s clear is that the final word is far from out on the combination of psychological and psychedelic therapies.”

– Joost Breeksema

 

“The question that Guy Goodwin and others address in this perspective piece is an important one, and one that none of us can answer for certain, not at least based on published, modern clinical data: what truly is the role of psychotherapy in psychedelic therapies remains one of the interesting research questions to tackle in the future. At same time, it should be of general interest to note that a group of people who are executives and major stakeholders in pharmaceutical companies developing psychedelic therapeutics can write a rather one-sided piece like this in a prestigious psychiatric journal without the need to more openly declare the vested interest in removing the psychotherapy part from the equations that the pharmaceutical companies naturally would have.” – Lauri Elsilä

***

Thomas, K. (2023). Pharmacists and psychedelic medicine. JACCP JOURNAL OF THE AMERICAN COLLEGE OF CLINICAL PHARMACY, 6(10), 1082-1083. https://doi.org/10.1002/jac5.1876

“This editorial explains the potential roles for pharmacists in psychedelic medicine, emphasizing how pharmacists are uniquely positioned to educate the public about psychedelic adverse effects and drug-drug interactions. It also highlights 2023 FDA guidance on psychedelic research and APPA professional practice guidelines, along with recognizing the myriad of ways that patients may be accessing psychedelics, from controlled clinical trials to religious settings.” – Kelan Thomas

***

Zeifman, R. J., & Maia, L. O. (2023). Methodological concerns in psychedelic research: The issues of nonequivalent psychological support and generalizability. European Neuropsychopharmacology, 78, 13–15. Advance online publication. https://doi.org/10.1016/j.euroneuro.2023.09.007

“The obvious challenges of rigorous trial design in psychedelic research have been debated ad nauseam in recent years, but Zeifman and Maia (2023) highlighted two additional issues that have been under discussed. Namely, 1) participants in psychedelic studies are given the option for additional psychotherapy sessions if wanted, which may contribute to study outcomes, but the quality and quantity of these sessions is typically not reported. 2) The context of psychotherapy sessions may shift if participants and/or therapists become unblinded to the participant’s study condition, meaning that the effects of the independent variable under study may no longer be isolated as the content of the therapy is not equivalent between conditions.” – Jacob Aday

***

Langlitz, N. (2023). The making of a mushroom people: Toward a moral anthropology of psychedelics beyond hype and anti‐hype. Anthropology Today, 39(3), 10-12. https://doi.org/10.1111/1467-8322.12813

“2023 was the year that both “psychedelic humanities” and “critical psychedelic studies” went primetime, with Michael Pollan (in a new preface to Brian Muraresku’s Immortality Key) going so far as to suggest that psychedelic humanities might represent the future of the field. This short paper is pivotal in this context, since it calls for the methodologies of the humanities and social sciences to ‘turn backwards’ on the field itself in order to analyze the social dynamics that are structuring it. In particular, Langlitz calls for anthropologists to turn an ethnographic lens on the field’s landscape of diverse discourses and actors, at a time when conflicting visions of “psychedelic hype” and “anti-hype” are advancing incompatible moral priorities and knowledge claims. For Langlitz, such an anthropological project would not ‘enter the fray’ by taking sides and making moral judgments; instead, it would study how the discourses of hype and anti-hype are “produc[ing] effects” on the field, which are—in turn—influencing the development of frameworks for psychedelic use across the world. Since the possible uses of psychedelics (which include social, political, spiritual, therapeutic, and cognitive effects) can be influenced by their contexts of use, such an ethnography of the field could explore how psychedelic applications (both actual and envisioned) might differ according to the affordances created by “distinct ethical projects.” By correlating uses with contexts, anthropologists could help to correct reductive assumptions about psychedelics and their outcomes (e.g., “psychedelics are X and do Y”), which opens a door for cross-disciplinary research on psychedelics’ evolving range of’ “moral and political effects.” – Neşe Devenot

***

McNamee, S., Devenot, N., & Buisson, M. (2023). Studying Harms Is Key to Improving Psychedelic-Assisted Therapy-Participants Call for Changes to Research Landscape. JAMA Psychiatry, 80(5), 411–412. https://doi.org/10.1001/jamapsychiatry.2023.0099

“This viewpoint article is concise and powerful. Its importance can’t be overstated. The depth of expertise and unique epistemological perspectives of the three authors, two of whom were MDMA trial participants, make it essential reading. The authors’ proposed paths forward require serious consideration from researchers and policymakers dedicated to safer psychedelics. I’m curious to see how these suggestions will be addressed in future research and policy. The article also raises the question of why participants don’t already have a more significant role in research and trial design. If we aren’t listening to patients, what’s the point?” – Kayla Greenstien

***

Cheung, K., Patch, K., Earp, B. D., & Yaden, D. B. (2023). Psychedelics, Meaningfulness, and the “Proper Scope” of Medicine: Continuing the Conversation. Cambridge quarterly of healthcare ethics, 1–7. Advance online publication. https://doi.org/10.1017/S0963180123000270

“I really enjoyed these papers [this one, as well as another from Cheung, Earp and Yaden (2023)], which, as the authors say, continue the conversation about the place of the subjective psychedelic experience. A common conclusion reached by participants in the ongoing debate is that this is an empirical matter: cleverly-designed and rigorously-executed clinical trials will determine whether subjective effects are necessary for desired patient outcomes. Cheung and colleagues invite us to take a broader view, exploring what might be valuable about the psychedelic experience beyond therapeutic outcomes. They offer a compelling response to critiques about whether the meaningfulness of the psychedelic experience is relevant to the debate (and indeed whether meaningfulness should be considered “within the scope of medicine” at all). And they explore numerous ways in which the psychedelic experience might be considered valuable – again, aside from any potential enduring therapeutic benefits – including in terms of aesthetic value, the psychological richness psychedelic experience can bring to our lives, and by considering the notion of “process goods” (those that are attained via the climbing of the mountain, as opposed to being dropped off at the top). Two very rich, worthwhile papers.” – Daniel Rosenbaum

***

Lepow, L., Kronman, H., & Yehuda, R. (2023). A Heuristic Approach: Against Consensus Definitions of Psychedelics. Psychedelic Medicine, 1(4), 190-194. https://doi.org/10.1089/psymed.2023.0031

“This is one of multiple responses to a call for a consensus definition of ‘psychedelic’. The authors question whether, at this time, the benefits of a consensus definition outweigh various outlined risks. In order to remain open to novel insights that may come from psychedelic research, the authors suggest an alternative framework in which definitions are understood as heuristic tools rather than rules for inclusion or exclusion.” – Lauren Lepow

***

McIntyre R. S. (2023). Serotonin 5-HT2B receptor agonism and valvular heart disease: implications for the development of psilocybin and related agents. Expert Opinion on Drug Safety, 22(10), 881–883. https://doi.org/10.1080/14740338.2023.2248883

“This editorial explains the potential risk of psychedelics with 5-HT2B affinity, particularly in the setting of repeated long-term dosing, which may lead to valvular heart disease (VHD). The editorial explains that entactogens such as MDMA have already been associated with VHD and draws attention to the recent FDA Guidance on Clinical Trials with Psychedelic Drugs that specifically mentions the need for evaluation of VHD risk.” – Kelan Thomas

***

Thomas, K. L., Jesse, R., Mehtani, N. J., Mitchell, J. M., & Anderson, B. T. (2023). Commentary: Evidence-Informed Recommendation to Achieve Approximate Parity in the Allowed Number of Doses for Common Psychedelics. Journal of Psychoactive Drugs, 1–5. Advance online publication. https://doi.org/10.1080/02791072.2023.2201244

“This commentary is a response to policymakers proposing personal psychedelic possession limits for decriminalization. The authors suggested if such limits are proposed in legislation, then there should be relative parity regarding how many doses of each psychedelic are allowed. This evidence-informed recommendation for the total number of typical moderate-high doses allowed for each psychedelic is an attempt to provide a rough equivalence informed by dose-dependent psychedelic subjective effects.” – Kelan Thomas

***

Ponomarenko, P., Seragnoli, F., Calder, A., Oehen, P., & Hasler, G. (2023). Can psychedelics enhance group psychotherapy? A discussion on the therapeutic factors. Journal of Psychopharmacology (Oxford, England), 37(7), 660–678. https://doi.org/10.1177/02698811231155117

“An excellent review of the psychedelic-assisted group psychotherapy (PAGP) literature, organized according to Irvin Yalom’s 11 therapeutic factors of group therapy. The article paints a rich and coherent picture of PAGP, including outlining different PAGP models, and challenges that emerge in group modalities of therapy. One theme that arises is the importance of carefully setting up the container for PAGP in order to offset the complex transference and group catalytic processes that spring from iterated group sessions.

Ponomarenko et. al’s article is the latest to showcase practices developed in Switzerland, where the Swiss Medical Society for Psycholytic Therapy (SAePT) has been conducting PAGP since 1988. As an organization comprised mostly of clinicians rather than researchers, relatively little has been written about SAePT’s knowledge base to date. By helping to fill this gap, the article will be a resource for those wanting to move beyond the usual individualized modes of administration of psychedelic therapy.”

– Tehseen Noorani

***

Girn, M., Rosas, F. E., Daws, R. E., Gallen, C. L., Gazzaley, A., & Carhart-Harris, R. L. (2023). A complex systems perspective on psychedelic brain action. Trends in Cognitive Sciences, 27(5), 433–445. https://doi.org/10.1016/j.tics.2023.01.003

“This paper, led by me in collaboration with Dr. Fernando Rosas, Dr. Robin Carhart-Harris, and others introduces a new theoretical model for how psychedelics affect the brain, drawing on the latest neuroimaging findings and emerging perspectives from complexity science. Complexity science highlights the brain’s nature as a dynamic system of integrated parts, and characterizes it in terms of the dynamic states it moves through over time. This paper argues that, rather than looking for specific brain networks or regions to understand psychedelic brain affects, we should look at the way in which the brain as a whole dynamically varies over time and reacts to stimuli. More specifically, we posit that psychedelics induce a mode of brain function that is more dynamically flexible, diverse, globally integrated, and tuned for information sharing. We use this conception to describe inter-individual variability in psychedelic effects, the influence of set and setting, and to help reconcile discrepancies in the psychedelic neuroimaging literature.” – Manesh Girn

***

Emmerich, N., & Humphries, B. (2023). Is the Requirement for First-Person Experience of Psychedelic Drugs a Justified Component of a Psychedelic Therapist’s Training? Cambridge Quarterly of Healthcare Ethics, 1–10. Advance online publication. https://doi.org/10.1017/S0963180123000099

“With psilocybin entering the last stages of safety and efficacy testing that will lead to its licensing, attention is now turning to the nuts and bolts of how psychedelic therapies will be rolled out at a large scale. In that context, this paper asks an important and timely question about how tomorrow’s psychedelic therapists will be best prepared for delivering a new modality of treatment.

Emmerich and Humphries’ answer to the question they pose is ‘no’, arguing that whatever epistemic benefits a therapist may derive from their own psychedelic experience (i) might otherwise be garnered to a sufficient degree by other means holotropic breathwork or ‘the Dreamachine’, and, besides, (ii) there is as yet no strong evidence that personal psychedelic experience would improve their competence as a psychedelic therapist. Against this background, the authors suggest that the principle of autonomy – the trainee therapist’s autonomy – should win out, and that personal psychedelic experience should be optional.

Like many aspects of clinical practice in psychedelic therapies, the norm of personal experience for therapists is an inheritance of the first wave of research in the ‘50s and ‘60s. In the absence of RCTs to determine the impact of therapists’ psychedelic experience on patient outcomes (two attempts last century were unfortunately thwarted before analysis could be completed), it is hard to determine which measures are historically contingent traditions, and which are borne of accumulated, if non-systematic, clinical judgement.  Perhaps I am overly risk-averse, but in retrofitting psychedelic therapy for a modern, mass roll-out, there is a real threat that we go about ripping up Chesterton’s fence in the absence of the right kind of evidence that speaks to whether it should stay or go.

The authors note (and seem to endorse) the requirement that, outside psychedelic contexts, therapists must undergo their own therapy. But there’s more to be said here: it is not all modalities that require personal experience of therapists. A significant range of three-letter, behavioural therapies (CBT, CFT, SFT, DBT, etc) do not require personal experience; whereas all psychodynamic and psychoanalytic practices do. In those domains, personal experience of therapy is needed to internalise the theoretical framework of the practice, understand what it feels like to be in the patient’s position, and to better understand the subtle and complex features of the psyche, including the manifestations of transference and countertransference in the therapy room. Indeed, the more personal psychotherapy a practitioner has had, the better able they are to identify potential countertransference issues. In sum, there is lots of psychic terrain you must learn to navigate to practise such a modality, and personal experience of therapy is the only way to map it.

As such, the question of whether psychedelic therapists must have their own psychedelic experience, might really be a question of whether psychedelic therapy is more akin to CBT or psychodynamic therapy in this regard. My own sense is that navigating the subtle and complex terrain of the psychedelic experience towards healing will be best done by those who have done more than read the travel blogs or travelled to broadly similar climes, but I fear these questions may be swept away by the larger battle set up by the year’s most controversial paper, “Must psilocybin always assist psychotherapy?” One answer to that question minimises the importance of practitioners’ personal experience.

Of Emmerich and Humphries’ arguments against demanding personal experience for practitioners, I find most compelling the example of otherwise competent therapists who, due to some contraindication or another, cannot undertake a psychedelic experience themselves, and I struggle to find an answer that I am satisfied with. I think that, until better evidence comes in, psychedelic therapists should have their own experience, and that demand must fall on those who cannot have a psychedelic experience as those who will not. Nonetheless, the progress of psychedelic science and practice needs psychedelic naive people: psychedelic experiences can be, as we know, one of the most meaningful experiences in many people’s lives. And I can’t help but think that a group of people – even scientists – who all share a high-saliency, positive attitude for some experience, are going to come to the most accurate conclusions about it, in the absence of others to serve as a reality check.”

– Eddie Jacobs

***

Langlitz N. (2023). What good are psychedelic humanities? Frontiers in Psychology, 14, 1082933. https://doi.org/10.3389/fpsyg.2023.1082933

“This beautifully written perspective article from a Frontiers in psychology special issue about the psychedelic humanities makes the convincing case for psychedelic humanities and why we need them. The domain of psychedelic humanities comprises social-science and humanities-oriented attempts to go beyond the conventional framework for medical and scientific psychedelic research, and allow broader sociocultural, ethical and philosophical considerations to enter the picture: Who and how should use psychedelics? Does the psychedelic experience promote specific values? Which ones? And how are value-laden psychochemical medications to be treated? How should we conceptualize, and understand the meaning of psychedelic conversions and experiences? Psychedelic humanities offer new ways of broadening the imaginative horizons of the psychedelic renaissance, of complexifying issues and developing alternative perspectives. Going forward it paves the way for valuable insights that emerge in the fertile convergence point between humanities scholars, neuroscientists, and psychologists.” – Ido Hartogsohn

Other

Simonsson, O., Hendricks, P. S., Stenfors, C. U., Goldberg, S. B., Honk, L., & Osika, W. (2023). Longitudinal associations between psychedelic use and unusual visual experiences in the United States and the United Kingdom. Journal of Psychopharmacology. Advance online publication. https://doi.org/10.1177/02698811231218931

“Although there have been case reports of hallucinogen persisting perception disorder (HPPD) and unusual visual experiences in psychedelic users previously published, that research has been largely limited by cross-sectional survey designs that are subject to recall bias and non-representative samples. Simonsson et al. (2023) addressed this using a longitudinal observational research design with samples representative of the US and UK adult populations, finding that those who had used psychedelics during the 2-month study period were more likely to report past-week unusual visual experiences.” – Jacob Aday

***

Jacobs, E., Murphy-Beiner, A., Rouiller, I., Nutt, D., & Spriggs, M. J. (2023). When the Trial Ends: The Case for Post-Trial Provisions in Clinical Psychedelic Research. Neuroethics, 17(1), 3. https://doi.org/10.1007/s12152-023-09536-z

“This paper, which I co-authored with a group of researchers from Imperial’s Centre for Psychedelic Research and a former participant in one of their trials, was borne out of findings that have repeatedly been mentioned in passing in the literature, but not paid any sustained attention. A number of participants, following a psychedelic trial, will either seek out further psychedelic experiences, or begin further psychotherapy as individuals.

These choices are worth taking seriously: in many cases they reflect otherwise treatment-resistant patients “desperately grasping to retain the benefits from psychedelic therapy,” as our patient co-author put it, or participants finding that the trial initiated, but did not complete, a process of psychological work that they could not opt out of, but had to find external help in concluding. In my own research interviews with former trial participants, one described her experience as being “ripped open, left with all the mess and having to deal with it on my own.” Cases of both kinds indicate an unmet need that has been awoken by the trial: a need that should, we argue, be fulfilled by those responsible for running trials.

In making this argument, we effectively question whether the traditional norms of clinical research ethics are appropriate for psychedelic trials. Several features of psychedelic treatments – including the illicit availability of the experimental drugs, the risk of trial endpoints coming too soon to end therapy safely, and the lack of psychedelic integration expertise in the mainstream healthcare system – suggest that simply referring trial participants back to existing support is not sufficient.

Our recommendations are, we acknowledge, expensive ones, especially in the context of already resource-intensive trials. But a participant’s journey doesn’t end with the conclusion of the trial, and our responsibility to them extends beyond it. By providing post-trial access and care where clinically indicated, we could also gain valuable insights about long-term support that will help build the well-functioning psychedelic ecosystem of tomorrow. Research trial norms can take time to change, but we hope this paper invites reflection on how the practice of future clinical trials might improve participant experiences. They are, after all, the very people who make progress in psychedelic science possible.”

– Eddie Jacobs

***

Evans, J., Robinson, O. C., Argyri, E. K., Suseelan, S., Murphy-Beiner, A., McAlpine, R., Luke, D., Michelle, K., & Prideaux, E. (2023). Extended difficulties following the use of psychedelic drugs: A mixed methods study. PLOS One, 18(10), e0293349. https://doi.org/10.1371/journal.pone.0293349

“As the field of psychedelic research matures, I think people are realizing something: despite years of overly negative information about psychedelics, we actually have very little real data about their risks. I’ve been happy to see many scientists starting to fill in this gap, but one paper that stands out is last year’s Extended difficulties following the use of psychedelic drugs: A mixed methods study by Jules Evans and colleagues. They surveyed and interviewed hundreds of people who reported struggling with the aftermath of a psychedelic experience, including everything from mild but persistent symptoms to feelings of being profoundly destabilized. The result is a comprehensive catalogue of post-trip difficulties that every expert in the field should be familiar with. It includes rather unsurprising symptoms like visual disturbances and anxiety, but also some unexpectedly common symptoms such as derealization & depersonalization (15-16% of the sample), social difficulties (52%), and persistent sleep disturbances (9%). The authors are also not shy about including descriptions of ontological and spiritual difficulties, which may elude clinical definitions but are clearly relevant to peoples’ experiences with psychedelics.

The paper is accessible, concise, and dense with information. At the same time, it is clearly opening a nascent scientific conversation that must continue until we have a better understanding of how to prevent and minimize negative outcomes from psychedelics. The paper also treats the topic of post-psychedelic difficulties with the nuance it deserves. In their data, you will find people who felt that even severe challenges led to growth in the long run, and who wholeheartedly endorse the benefits of psychedelics. You will also find people who regret taking psychedelics and still suffer from debilitating symptoms years after a bad trip, with little hope for recovery. Both of these potential outcomes, and everything in between, will accompany the psychedelic field for its entire lifespan, and it is in everyone’s best interest to learn to contend with them. The psychedelic field is privileged to have researchers who are both serious about understanding and preventing negative outcomes from psychedelics and wise to their potential for catalyzing growth.”

– Abigail Calder

***

Lebedev, A. V., Acar, K., Horntvedt, O., Cabrera, A. E., Simonsson, O., Osika, W., Ingvar, M., & Petrovic, P. (2023). Alternative beliefs in psychedelic drug users. Scientific Reports, 13(1), 16432. https://doi.org/10.1038/s41598-023-42444-z

“When exploring the potential clinical utility of any new drug, it is always paramount to carefully note and characterize any adverse effects that may have been attributable to the intervention. In psychiatry, it is common to monitor for somatic symptoms or declines in mood or cognition, but changes in beliefs are often not considered. Lebedev et al. (2023) make a valuable contribution to our characterization of potential adverse effects of psychedelics by demonstrating a moderate positive association between psychedelic use and beliefs in alternative facts, as well as the specific belief that facts are politically influenced.” – Jacob Aday

***

Nayak, S. M., Jackson, H., Sepeda, N. D., Mathai, D. S., So, S., Yaffe, A., Zaki, H., Brasher, T. J., Lowe, M. X., Jolly, D. R. P., Barrett, F. S., Griffiths, R. R., Strickland, J. C., Johnson, M. W., Jackson, H., Garcia-Romeu, A. (2023). Naturalistic psilocybin use is associated with persisting improvements in mental health and wellbeing: results from a prospective, longitudinal survey. Frontiers in Psychiatry, 14, 1199642. https://doi.org/10.3389/fpsyt.2023.1199642

“It’s common to hear that psychedelics are only effective when used under the supervision of a trained clinician, yet many people anecdotally know this is simply not true. Although there are some methodological limitations as a self-reported online survey of mostly white men, I appreciated the insights into “naturalistic” use across multiple time points. While most reports were positive, 7-11% of people experience negative long-term effects like mood fluctuations and depressive symptoms. It seems like a rich data set so hopefully we’ll see more papers coming out that delve into more of the findings.” – Kayla Greenstien

***

Williams, M. T., Cabral, V., & Faber, S. (2023). Psychedelics and Racial Justice. International Journal of Mental Health and Addiction. Advance online publication. https://doi.org/10.1007/s11469-023-01160-5

“The article by Williams, Cabral and Faber (2023) provides an important exploration of the intersection between psychedelics and racial justice. Three of my favourite quotes:

“While the psychedelic community may aspire to unity, it is important to recognise that we continue to live in largely segregated societies, with segregated neighbourhoods and friendship groups. In order to use psychedelics as a tool for promoting connection and understanding between different groups, we must be intentional in our efforts and actively work to bridge these divides.”

“Specialised training should be provided for clinicians working with psychedelics so they can better understand how racism impacts mental health outcomes in their patients and provide culturally competent care. Furthermore, clinicians must have a deep understanding of the historical context surrounding psychedelics so they can appropriately address cultural material and issues related to colonialism or cultural appropriation.”

“Many people are asking how diverse voices can better be integrated into research. When homogenous research groups are doing the work, it is impossible to understand different ethnic communities if there are no people from those communities as part of the team. To ensure that psychedelic research is conducted with equitable representation, community-based participatory research is recommended.”

– Lisa Luan

***

Graziosi, M., Singh, M., Nayak, S. M., & Yaden, D. B. (2023). Acute Subjective Effects of Psychedelics within and Beyond WEIRD Contexts. Journal of Psychoactive Drugs, 55(5), 558-569. https://doi.org/10.1080/02791072.2023.2255274

“Graziosi and colleagues’ article on acute subjective effects beyond WEIRD contexts is timely, and encourages the field to consider what cultural variations may exist in psychedelic experiences. It additionally highlights the importance of anthropologists’ work in this field (for example, Alex Gearin’s work on ayahuasca use in China) in examining the various uses and experiences with psychedelics.” – Katherine Cheung

***

Garel, N., Greenway, K. T., Dinh-Williams, L. L. L., Thibault-Levesque, J., Jutras-Aswad, D., Turecki, G., Rej, S., & Richard-Devantoy, S. (2023). Intravenous ketamine for benzodiazepine deprescription and withdrawal management in treatment-resistant depression: a preliminary report. Neuropsychopharmacology, 48(12), 1769-1777. https://doi.org/10.1038/s41386-023-01689-y

“The Good: This article demonstrated that initiating ketamine treatments for refractory depression can be a powerful moment to revisit patients’ conventional treatments and potentially stop benzodiazepines. The preliminary findings challenge a longstanding clinical notion that, because benzodiazepines are challenging to discontinue, one should wait until patients have recovered from depression before addressing them.

The Bad: The small sample size of 22 patients and the lack of randomization make it challenging to generalize the results and disentangle the potential underlying mechanisms. I.e., were the high rates of successful abstinence from benzodiazepines due to pharmacological effects of ketamine, to patients being particularly motivated to stop benzodiazepines when starting this very hyped treatment, and/or due to more psychedelic mechanisms about learning to better tolerate distress?

Next Steps: A larger, randomized trial where only some patients discontinue benzodiazepines would help to better explore the mechanisms at play and to potentially answer an important open question in the ketamine literature: do benzodiazepines really blunt its benefits?”

– Kyle Greenway

***

Garel, N., Lévesque, J. T., Sandra, D. A., Lessard-Wajcer, J., Solomonova, E., Lifshitz, M., … & Greenway, K. T. (2023). Imprinting: expanding the extra-pharmacological model of psychedelic drug action to incorporate delayed influences of sets and settings. Frontiers in Human Neuroscience, 17, 1200393. https://doi.org/10.3389/fnhum.2023.1200393

“The Good: While current-moment “Sets and Settings” are well-known determinants of psychedelic experiences, this is the first paper to clearly raise the possibility that past environments can powerfully influence psychedelic experiences as well. If the results hold, there are many important implications for how patients are prepared for psychedelic treatments and how their experiences can be understood.

The Bad: Although the literature review of the article covered many psychoactive drugs, all of the original data came from a few dozen patients receiving one fairly unique drug: ketamine. It’s therefore unclear how strong “imprinting” effects are in other populations and especially with other substances.

Next Steps: Replication of these results in other clinical contexts, with other drugs, and especially with prospective and/or designs that involve experimental manipulation of environmental exposures would be essential for better characterizing Imprinting and its potential utility.”

– Kyle Greenway

***

Zare, M., & Williams, M. T. (2023). Muslim Women and Psychedelics: a Look at the Past, Present, and Future. International Journal of Mental Health and Addiction, 1-16. https://doi.org/10.1007/s11469-023-01108-9

“As an overview of a huge and under researched area, I feel like I could spend days going down various rabbit holes in the wealth of research cited. In terms of religious prohibition and stigma, this paper brings up interesting considerations around the assessment of what medicinal and “necessary” really mean and how this will be interpreted in Islam (to my surprise, guided psychedelic therapy was declared permissible (halal) by Iran’s Grand Ayatollah in 2014). I hope we’ll see more nuanced research and perspectives emerging on medicalised/wellness uses of psychedelics in various cultural/religious communities coming out in the coming years.” – Kayla Greenstien

***

McCrone, P., Fisher, H., Knight, C., Harding, R., Schlag, A. K., Nutt, D. J., & Neill, J. C. (2023). Cost-effectiveness of psilocybin-assisted therapy for severe depression: exploratory findings from a decision analytic model. Psychological Medicine, 53(16), 7619-7626. https://doi.org/10.1017/s0033291723001411

“The pharmacoeconomic analysis by McCrone, et al. adds significantly to the literature that seeks to interpret the value of adding psilocybin to psychotherapy for the treatment of depression, relative to existing care. Their sensitivity analysis is illuminating in its inclusion of potential effects of differences in the cost of the drug and in the number of therapists and the number and duration of their interactions with patients. Multiple assumptions are made of necessity in this analysis, yet this work is valuable in pointing to variables that may lend themselves to testing in future clinical trials in an attempt to make such treatment both more practical and accessible.” – Paul Hutson

***

Mosurinjohn, S., Roseman, L., & Girn, M. (2023). Psychedelic-induced mystical experiences: An interdisciplinary discussion and critique. Frontiers in Psychiatry, 14, 1077311. https://doi.org/10.3389/fpsyt.2023.1077311

“This paper led by Sharday Mosurinjohn and I, with contributions from Leor Roseman, offers an interdisciplinary critique of the concept of “mystical experiences” as defined in psychedelic research. We highlight how the study of psychedelic mystical experiences has only minimally intersected with relevant scholarship in the humanities regarding the nature of “mysticism” and “the mystical”, and has not yet been properly historically situated. The paper traces the history of assessments and conceptions of mystical experiences in psychedelic research and outlines several of its biases and limitations. These include, for example, its inherent positive and Christian-Protestant biases, and the cultural-specificity/ambiguity of items on the Mystical Experience Questionnaire. We end by offering suggestions on how to move toward stronger theoretical and empirical approaches in the study of psychedelic-induced mystical experiences.” – Manesh Girn

***

Aday, J. S., Skiles, Z., Eaton, N., Fredenburg, L., Pleet, M., Mantia, J., … Woolley, J. D. (2023). Personal Psychedelic Use Is Common Among a Sample of Psychedelic Therapists: Implications for Research and Practice. Psychedelic Medicine, 1(1), 27-37. https://doi.org/10.1089/psymed.2022.0004

“Aday and colleagues’ research raises interesting questions as to whether personal experience with psychedelics contributes to their competency. It may be fruitful here to apply a competency-based approach, e.g. Janice Phelp’s framework of competencies for psychedelic therapists, to see if competencies exist that can only be fulfilled with personal experience. Other interesting continuations of Aday and colleagues’ research may be to examine whether patients have preferences for therapists with personal experience.” – Katherine Cheung

***

Barnett, B. S., Sweat, N. W., & Hendricks, P. S. (2023). Case report: Prolonged amelioration of mild red-green color vision deficiency following psilocybin mushroom use. Drug Science Policy and Law, 9, 205032452311725. https://doi.org/10.1177/20503245231172536

“How cool is this case report! This was one of those accounts that stuck with me because in this we find that after consuming 5 g of psilocybin mushrooms, an individual had significant improvements in their red-green color blindness that lasted up to 16 days. This begs the questions, how is the visual system being so profoundly impacted by psychedelics? And how are these changes so robust and long lasting?” – Zarmeen Zahid

***

Edelsohn, G. A., & Sisti, D. (2023). Past Is Prologue: Ethical Issues in Pediatric Psychedelics Research and Treatment. Perspectives in Biology and Medicine, 66(1), 129-144. https://doi.org/10.1353/pbm.2023.0007

“This paper was one that I read very closely this year. The idea of extending psychedelic therapy to adolescents is one we should absolutely consider and parse through. The authors point out older literature that was rife with ethical violations and urges researchers today to consider ethically sound practices and strict adherence to extensive criterion if and when engaging in such research.” – Zarmeen Zahid

***

Carhart-Harris, R. L., Chandaria, S., Erritzoe, D. E., Gazzaley, A., Girn, M., Kettner, H., … Friston, K. J. (2022). Canalization and plasticity in psychopathology. Neuropharmacology, 226, 109398. https://doi.org/10.1016/j.neuropharm.2022.109398

“This paper by Dr. Robin Cahart-Harris and colleagues, on which I’m also a co-author, introduces a novel theoretical model of mental health conditions that highlights the concept of “canalization” and its relationship to the brain’s plasticity mechanisms. In essence, it proposes that mental health conditions such as depression and addiction develop as a result of plasticity mechanisms that progressively make certain behaviours difficult to escape from. In other words, whereas we might adaptively choose to engage in a behaviour initially, a given behaviour can become deeply ingrained as the “go-to” to the extent that it becomes maladaptive and pathological. The paper highlights how the pro-plasticity mechanisms of psychedelics – at both the neural and psychological level – can help counteract this canalization and facilitate a recovery of adaptive behavioural flexibility.” – Manesh Girn

***

Devenot, N., Seale-Feldman, A., Smith, E., Noorani, T., Garcia-Romeu, A., & Johnson, M. W. (2022). Psychedelic Identity Shift: A Critical Approach to Set And Setting. Kennedy Institute of Ethics Journal, 32(4), 359-399. https://doi.org/10.1353/ken.2022.0022szig

“Based on 43 anonymized “experience reports” from 15 participants in the Johns Hopkins psilocybin-assisted smoking cessation trial, this paper by Devenot et al. performs a long-due examination of the role of therapeutic modalities in shaping the outcomes of psychedelic assisted therapy. Devenot et al. point to the manner in which conceptualizations and techniques originating in treatment frameworks and manuals end up shaping the insights and realizations of trial participants, focusing on the case of identity shift and its role in psychedelically assisted smoking cessation. The enhanced perception of the central role of identity shift in psychedelic therapy raises ethical questions unique to the case of psychedelic therapy.” – Ido Hartogsohn

***

Maggio, C., Fischer, F.M., Modlin, N.L., Rucker, J. (2023). Psychoanalytic Formulations in Psychedelic Assisted Psychotherapy for Treatment Resistant Depression (TRD). Journal of Psychology & Psychotherapy, 13:451. DOI: 35248/2161-0487.23.13.456

“In explaining the state of knowledge in psychedelic-assisted therapies to people I often invoke the image of a console with dozens and dozens of switches and dials, the setting of each of which might have some impact on the acute and downstream effects of the treatments. The cumulative research of the mid-20th Century and the last two decades has managed to nail down, with some confidence, the role of a good number of these settings. There remain many more dials that we don’t yet know the best settings for – a natural situation for any nascent field, not least one that revolves around a controlled, as-yet-unlicensed, drug. We will get to adjusting some of the bigger, shinier dials once psychedelics are more widely available clinically: how many drug sessions is best, and at what interval? How much integration is needed, and what level of clinical training should be required for those supporting this process?

Among those big questions that we’re still not sure about – which therapeutic modalities should contain and support clinical psychedelic administration? – is to me one of the most salient. With some researchers last year already proposing that we should consider third-wave behavioural therapies as default, this paper is important for reopening space for the inclusion of psychoanalytic frameworks for understanding psychedelic therapies. The authors point out that at least some of these frameworks, which prioritise the workings of the unconscious, receive a ‘silent agreement’ in much psychedelic therapy anyway, given that the drugs are widely conceived as ‘mind-manifesting,’ tending to make visible otherwise unconscious material.

Explaining how the treatment of two individuals in a trial of psilocybin for treatment-resistant depression can be understood in psychoanalytic terms, the authors seek to ‘[challenge] a paradigm that may compartmentalise patients’ experience by breaking it down into its component parts to fit a familiar and finite scientific model’. When psychedelic treatments are licensed, it may be that insurers will only pay for interventions involving the so-called ‘evidence-based’ models of therapy. Even so, the article demonstrates how psychoanalytic thinking can still be valuably deployed to better manage intake, preparation, and patient care during psychedelic treatments.

Firm sceptics of psychoanalytic approaches are not going to be converted by this article, but I nonetheless recommend its addition to your ‘to-read’ list. More than any other paper this year, this article clearly communicates a curiosity and human respect for the profundity of the psychedelic experience, both of which can regrettably come out in the wash when preparing a scientific article according to contemporary publishing norms.”

– Eddie Jacobs

***

Mallaroni, P., Mason, N. L., Kloft, L., Reckweg, J. T., van Oorsouw, K., Toennes, S. W., Tolle, H. M., Amico, E., & Ramaekers, J. G. (2023). Shared functional connectome fingerprints following ritualistic ayahuasca intake. NeuroImage, 285, 120480. Advance online publication. https://doi.org/10.1016/j.neuroimage.2023.120480

“Mallaroni and colleagues have conducted a timely assessment of system-level organization following ayahuasca consumption. Notably, they delve into the nuances of individual differences using functional metrics, a critical aspect often overlooked in psychedelic research. This approach could potentially explain the significant variability observed in many psychedelic human neuroimaging studies. However, the study’s reliance on dynamic functional connectivity (FC) (and ‘cofluctuation’-like metrics) is problematic, as highlighted by existing literature. The influence of head-motion, a frequent issue in psychedelic neuroimaging, further complicates the interpretation of dynamic FC since movement artifacts are not entirely removable from BOLD signals owing to spin history effects. To that end, the study lacks a null model to examine whether ‘subjective effects’ correlate with the degree of head-motion, such as whether more intense psychedelic experiences result in increased head movement. Furthermore, it would be valuable to investigate how the spectral content or related measures (like spectral densities, entropy, or fragmentation) of FC matrices contribute to these findings. A fascinating aspect of the study is the observation that individuals under the influence of ayahuasca lose their distinct FC matrix patterns, yet there remains a high degree of similarity between their baseline and ayahuasca states. This aspect could be investigated more, particularly in the context of spectral content of FC. In conclusion, while this study addresses important questions, it falls short in rigorously determining the drivers behind the observed changes in functional connectivity and relies on calculations of FC (e.g., dynamic FC) which are misleading.” – Anonymous

***

Eckernäs, E., Timmermann, C., Carhart-Harris, R., Röshammar, D., & Ashton, M. (2023). N,N-dimethyltryptamine affects electroencephalography response in a concentration-dependent manner-A pharmacokinetic/pharmacodynamic analysis. CPT: pharmacometrics & systems pharmacology, 12(4), 474–486. https://doi.org/10.1002/psp4.12933

“The 2023 paper by Eckernäs and colleagues evaluated the relationship between measured plasma concentrations of DMT in subjects receiving an intravenous dose of the drug and the change in brain activity measured by EEG. The report uses pharmacometric methods commonly applied to the assessment of drug effects to address the question of the extent to which there is an objective effect of increasing dose as opposed to qualitative perceptions of greater effect.  Although the number of subjects is limited, a significant effect of DMT concentration upon alpha and beta wave power and Lempel-Ziv complexity was noted.  The extent to which these EEG changes and related drug concentrations correlate with therapeutic outcome is not known. The same approach would appear to lend itself to pharmacodynamic evaluation of the effects of LSD, psilocybin, and similar compounds.” – Paul Hutson

***

Dai, R., Larkin, T. E., Huang, Z., Tarnal, V., Picton, P., Vlisides, P. E., Janke, E., McKinney, A., Hudetz, A. G., Harris, R. E., & Mashour, G. A. (2023). Classical and non-classical psychedelic drugs induce common network changes in human cortex. NeuroImage, 273, 120097. https://doi.org/10.1016/j.neuroimage.2023.120097

“Dai et al. put together a multi-drug (nitrous oxide, ketamine, and LSD) comparative functional connectivity (FC) study that assessed alterations in inter- and intra-network connectivity. Modularity (which, in essence, assesses the ratio between inter- and intra-network connectivity) is a powerful method to assess the hierarchical structure functional organization, which has been implicated in psychedelics. Although they never use this metric (or even refer to literature on it), the concept is the same. The study found a consistent decrease in intra-network FC and an increase in inter-network FC across all three substances. Notably, four common FC pairs were altered consistently, all involving the default mode network. To discern whether these effects were merely due to an altered state of consciousness, they included a comparison with the anesthetic propofol, which did not replicate the psychedelic results. Despite its insights into common FC patterns across different psychedelics, the study does not delve into the receptor affinity of each drug or the underlying mechanisms potentially driving these observations. Nonetheless, this research marks a significant initial step in identifying common biomarkers for rapid-acting antidepressant drugs.” – Jonah Padawer-Curry

Conference Abstracts & Posters

Preprints

Aday, J., Horton, D., Fernandes-Osterhold, G., O’Donovan, A., Bradley, E., Rosen, R., & Woolley, J. (2023). Psychedelic-assisted psychotherapy: Where is the psychotherapy research? PsyArXiv. https://doi.org/10.31234/osf.io/s3yjd

“This paper takes on the important task of starting to overcome the historically-rooted divide that still exists between psychedelic research and psychotherapy research – two alienated fields that could benefit enormously from engaging more with one another.” – Max Wolff

***

Ekins, T. G., Brooks, I., Kailasa, S., Rybicki-Kler, C., Jedrasiak-Cape, I., Donoho, E., Mashour, G. A., Rech, J., & Ahmed, O. J. (2023). Cellular rules underlying psychedelic control of prefrontal pyramidal neurons. bioRxiv, 4(11-09), 2023.10.20.563334. https://doi.org/10.1101/2023.10.20.563334

“Classical psychedelics are thought to increase excitability of prefrontal cortex pyramidal neurons through activating serotonin 2A (5-HT2A) receptors. We instead found that although serotonergic psychedelics do acutely enhance some forms of neuronal excitability (i.e., membrane depolarization and enhanced excitatory synaptic drive), the dominant effect is dose-dependent suppression of intrinsic excitability. This occurs via both 5-HT2R-independent activation of ubiquitous potassium channels (Kv7 or “M-current”) and 5-HT2R-dependent sodium channel inactivation. The resulting dynamics may contribute to both the acute subjective and lasting therapeutic effects of classical psychedelics; a single psychedelic dose produces a lasting enhancement of excitatory synaptic drive without causing long-term changes to intrinsic excitability.” – Tyler Ekins

***

Mathai, D. S., Roberts, D. E., Nayak, S. M., Sepeda, N. D., Lehrner, A., Johnson, M., Lowe, M. X., Jackson, H., & Garcia-Romeu, A. (2023). Shame, guilt and psychedelic experience: Results from a prospective, longitudinal survey of real-world psilocybin use. https://doi.org/10.31234/osf.io/hm6jn

“In a prospective longitudinal survey of n=679 psilocybin users, acute experiences of shame or guilt during psilocybin use were found to occur in two-thirds of the sample and were generally mild. Notably, the extent to which participants worked through these acute experiences predicted wellbeing weeks later. Along the same lines, mystical experience ratings were higher in the group that worked through guilt and shame as compared to participants who did not experience these emotions. Psychotherapeutic implications are discussed.” – Lauren Lepow

***

Chiu, Y-T., Deutch, A. Y., Wang, W., Schmitz, G. P., Huang, K. L., Kocak, D. D., Llorach, P., Bowyer, K., Liu, B., Sciaky, N., Hua, K., Chen, C., Mott, S. E., Niehaus, J., DiBerto, J. F., English, J., Walsh, J. J., Scherrer, G., Herman, M. A., Wu, Z., Wetsel, W. C., & Roth, B. L. (2023). A suite of engineered mice for interrogating psychedelic drug actions. bioRxiv, 4(10-06), 2023.09.25.559347. https://doi.org/10.1101/2023.09.25.559347

“If mice make bad human models, then let’s humanize them. Bryan L Roth leads this Frankeistenian effort to generate not one, but two, genetically engineered mice. The newly created mice lines reported by Chiu et al. bear a humanized version of 5-HT2A receptor, as well as a reporter gene system to map its expression. While lacking in breakthrough findings, the paper presents tools that can make a big difference facilitating ongoing efforts to better understand the relationship between 5-HT2A pharmacology and psychedelics actions. The microscopy images are stunning.” – Mario de la Fuente

***

Padawer-Curry, J. A., Snyder, A. Z., Bice, A. R., Wang, X., Nicol, G. E., McCall, J. G., Siegel, J. S., & Bauer, A. Q. (2023). Psychedelic 5-HT2A receptor agonism: neuronal signatures and altered neurovascular coupling. bioRxiv, 2023.09.23.559145. https://doi.org/10.1101/2023.09.23.559145

“This study reveals that classic hallucinogenic 5-HT2A receptor agonists alter neurovascular coupling (NVC) in mice. Consequently, both task-based and resting-state analysis (e.g., power and functional connectivity) showed notable differences when assessed with calcium (neuronal) and hemodynamic measures. These findings prompt caution in the interpretive power of functional assessments conducted using blood-based functional neuroimaging techniques, such as BOLD-fMRI.” – Jonah Padawer-Curry

***

McCulloch, D. E-Wen, Olsen, A. S., Ozenne, B., Stenbæk, D. S., Armand, S., Madsen, M. K., Knudsen, G. M., & Fisher, P. M. (2023). Navigating the chaos of psychedelic neuroimaging: A multi-metric evaluation of acute psilocybin effects on brain entropy. https://doi.org/10.1101/2023.07.03.23292164

“A much needed and overdue contribution to the field. Last year, several of the same authors famously showed that the amount of fMRI papers using a couple datasets actually outnumbered the number of subjects in those datasets! Here, they show that the psychedelic fMRI field has been guilty of a similar offense: labeling innumerable metrics as “entropy” in service of arguing for or against the “entropic brain hypothesis”. The authors test 12 of these entropy metrics on a novel, independent dataset. Despite these metrics seemingly all measuring entropy, the authors report that many are un- or anti-correlated with one another. They find changes in entropy on ~3 of these metrics, and the largest effect they report (DCC entropy) suggests that psilocybin is associated with greater entropy of dynamic functional connectivity values between most within- and between-network edges. The authors have made their mostly user-friendly MATLAB code available for anyone interested in calculating the entropy metrics on their own data. While the study does not bring any new analyses to the table, perhaps that’s just what the field needed.” – Brian Winston

***

Cheung, K., Earp, B. D., Yaden, D. B. (2023). Valuing the acute subjective experience. Perspectives in Biology and Medicine, in press.

“I really enjoyed these papers [this one, as well as another from Cheung, Patch, Earp and Yaden (2023)], which, as the authors say, continue the conversation about the place of the subjective psychedelic experience. A common conclusion reached by participants in the ongoing debate is that this is an empirical matter: cleverly-designed and rigorously-executed clinical trials will determine whether subjective effects are necessary for desired patient outcomes. Cheung and colleagues invite us to take a broader view, exploring what might be valuable about the psychedelic experience beyond therapeutic outcomes. They offer a compelling response to critiques about whether the meaningfulness of the psychedelic experience is relevant to the debate (and indeed whether meaningfulness should be considered “within the scope of medicine” at all). And they explore numerous ways in which the psychedelic experience might be considered valuable – again, aside from any potential enduring therapeutic benefits – including in terms of aesthetic value, the psychological richness psychedelic experience can bring to our lives, and by considering the notion of “process goods” (those that are attained via the climbing of the mountain, as opposed to being dropped off at the top). Two very rich, worthwhile papers.” – Daniel Rosenbaum

***

Polito, V., & Liknaitzky, P. (2023). Is Microdosing a Placebo? PsyArXiv. https://doi.org/10.31234/osf.io/3ykst

“This article immediately stuck out to me as one of the good conversation starters of this year. Microdosing is in and of itself an area in which we seem to have differing human accounts and preclinical data. The issue of an appropriate placebo is also at the forefront in the field and the authors, contrary to a lot of opinions currently, argue against the use of microdoses as placebo. This paper really forces people to contend with the weakness of the disparate literature on microdosing currently.” – Zarmeen Zahid

***

Wall, M. B., Demetriou, L., Giribaldi, B., Roseman, L., Ertl, N., Erritzoe, D., Nutt, D. J., & Carhart-Harris, R. L. (2023). Reduced brain responsiveness to emotional stimuli with escitalopram but not psilocybin therapy for depression. https://doi.org/10.1101/2023.05.29.23290667

“This paper was very exciting for me because we see a direct comparison between an SSRI, escitalopram, and a psychedelic, psilocybin. They find that there is reduced emotional responsiveness, specifically fear, in the SSRI group that we don’t see with the psychedelic group, suggesting another point of divergence for traditional antidepressant therapy and psychedelic therapy. Really interesting to see data on emotional responsiveness being directly compared because one common side effect of antidepressants is blunted affect, not necessarily a desirable outcome.” – Zarmeen Zahid

Pα: Thanks for reading The Interdisciplinary Annotated Psychedelic Research Bibliography of 2023, produced by Psychedelic Alpha Medical Advisor, Michael Haichin, PharmD (LinkedIn, Twitter). We hope you enjoyed it! ∎

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