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How AI and language can help predict psychedelic treatment outcomes

Language is increasingly being used as a diagnostic tool in biomedical research and has recently begun to be leveraged in psychedelic research. It turns out analysing language through machine learning can help increase diagnostic accuracy and predict psychedelic treatment outcomes, which will play an important role in the future of psychedelic research.


Illustration: Anna Temczuk

Language as a diagnostic tool

Sigmund Freud and Carl Jung are arguably the most influential figures of the 20th century when it comes to psychological functioning and the human mind. Although their theories about the psyche eventually differed, they both considered language as a manifestation of the unconscious. Indeed, Freudian psychoanalysis proposed free association as a way of gaining access to unconscious processes, while Jungian psychology considered every act of speech as a psychic event, with each word carrying particular archetypal energies. Fast forward 100 years, innovations in biomedical science and technology have transformed language into a diagnostic tool for both affective and degenerative neuropathology, and language is increasingly being used as such in psychedelic research. 

Natural Language Processing, also known as NLP, is a field combining linguistics, computer science, and artificial intelligence. It applies computational techniques to the analysis and synthesis of natural language. One of the problems with natural language is that it often contains ambiguities in meaning, also known as semantic ambiguities, which are easily detectable by humans but not so much by computers. Luckily, models such as distributional semantics, count vectorisation and encoder-decoder modeling help decipher semantic ambiguities. Since its development, NLP has predominantly been used as an automation tool for google searches, spam email categorisation, voice recognition, and translations, but it is increasingly being used as a diagnostic tool in medicine. 

A few years ago, a team of researchers in Canada were able to identify linguistic features within narrative speech that were specific to Alzheimer’s Disease. Semantic impairment, acoustic abnormality, and syntactic impairment were all factors enabling the accurate identification of Alzheimer’s, based on patients’ short descriptions of a picture.

This led to the realisation that beyond its unconscious, psyche-revealing properties, natural language might also possess neuropathology-revealing properties. So what if language could be used as a biomarker for psychosis or affective disorders? More importantly, what if language could be used as a predictor of treatment outcome? It turns out these tools have already begun to be leveraged in psychedelic research.

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Around four years ago, a team of researchers from Buenos Aires University’s Applied Artificial Intelligence Lab and Imperial College London’s Psychedelic Research Group decided to test a combination of NLP and machine learning. They tested this combination both as a diagnostic tool for patients suffering from treatment-resistant depression, and as a predictor of treatment outcome following a psilocybin challenge. 

Participants first underwent a psychological interview known as an Autobiographical Memory Test, an interview used to assess the degree of specificity of autobiographical memory. This interview was analysed using an NLP method known as Emotional Analysis, which quantifies the emotional content of spoken or written text. The NLP output was then fed as input into a machine learning algorithm, known as a classifier, trained at recognising depressed patients. 

On the basis of emotional analysis and specifically the use of positive words, which were less frequently used in depressed patients compared to healthy controls, the classifier was able to differentiate between depressed patients and healthy controls with a mean accuracy of 82.85%, close to 15% better than the mean accuracy of general practitioners unassisted by screening tests.  

Accurate Predictions

Perhaps more impressive than its ability to differentiate between depressed patients and healthy controls, was the classifier’s ability to differentiate between treatment responders and non-responders. Based on the same parameters it had previously used to diagnose depressed patients (NLP output and positive word frequency), the classifier was able to predict which patients would respond to a psilocybin challenge and which would not. 

Only the patients identified as “responders” were given the psilocybin challenge, whereas the “non-responders” were removed from the treatment arm. This manoeuvre had the effect of improving overall treatment response by 34% compared to the original experiment.  

Last year, a team at Johns Hopkins University used a similar approach to predict changes in substance use following a psychedelic challenge. They recruited individuals who reported quitting or reducing a number of addictive drugs following a psychedelic experience, and asked them for a verbal narrative of the experience.

They used an NLP method known as Latent Semantic Analysis, which analyses the relationship between semantic structures across different texts, to derive topic models that described the psychedelic narratives. These topic models were fed as input into three different machine learning algorithms to predict long-term drug reduction. The machine learning algorithms had an average predictive accuracy of 65%, and additional analyses revealed between-group differences in psychedelic experience narratives based on the derived topic models.

John Hopkins’ semantic analysis of psychedelic narratives and Buenos Aires University’s use of machine learning to identify patients suffering from depression, are two early but powerful examples of the ways in which language can be leveraged in psychedelic research through new technology.

The combination of NLP and machine learning as methods to analyse language have reliably shown their value as both diagnostic and predictive tools, and can be used to optimise clinical trials. They allow for a more personalised treatment, whereby non-responders are spared the emotional rollercoaster of an acute psychedelic experience. 

Freudian psychoanalysis, Jungian psychology and NLP share the conception that hidden semantic structures within language are associated with underlying processes, whether psychological, social, or physiological. A century ago, language was the glass through which Freud saw the unconscious mind. Today, language analysed by machine learning may very well be one of the prisms through which we can come to understand the psychedelic experience.

References:

1. N.B. This is different from “Neuro-linguistic programming” (NLP), which is a form of psychotherapy developed in California in the 1970s, mainly used as a method of personal development by promoting skills including communication.

2. Fraser, K. C., Meltzer, J. A., & Rudzicz, F. (2016). Linguistic Features Identify Alzheimer’s Disease in Narrative Speech. Journal of Alzheimer’s disease : JAD, 49(2), 407–422

3. Carrillo, F., Sigman, M., Fernández Slezak, D., Ashton, P., Fitzgerald, L., Stroud, J., Nutt, D. J., & Carhart-Harris, R. L. (2018). Natural speech algorithm applied to baseline interview data can predict which patients will respond to psilocybin for treatment-resistant depression. Journal of affective disorders, 230, 84–86

4. Carey, M., Jones, K., Meadows, G., Sanson-Fisher, R., D’Este, C., Inder, K., Yoong, S. L., & Russell, G. (2014). Accuracy of general practitioner unassisted detection of depression. The Australian and New Zealand journal of psychiatry, 48(6), 571–578.

5. The original experiment consisted of a combination of psychotherapy and pharmacological treatment with psilocybin that resulted in 41% treatment response. By differentiating between treatment responders and non-responders this experiment resulted in 75% treatment response

6. Cox, D. J., Garcia-Romeu, A., & Johnson, M. W. (2021). Predicting changes in substance use following psychedelic experiences: natural language processing of psychedelic session narratives. The American journal of drug and alcohol abuse, 47(4), 444–454

Farewell Letter to OPEN

After 15 years, Dorien Tatalas says goodbye

22-02-2022

After 15 years of service, I recently resigned from the board of the OPEN Foundation. In these words of goodbye, I’d like to share some personal reflections on the foundation’s (and to some extent, my own) journey into adulthood, as well as some of my hopes for the future. 

Magic Carpet Ride

In 2006 I was a psychedelically inquisitive cultural anthropology student, looking for her tribe. I longed for connection with others who were personally and academically curious about psychedelics and the states of consciousness they give us access to. The legendary LSD Symposium in Basel opened my eyes to the existence of a community of sciency psychonauts and I wanted to be part of it. Since the Netherlands lacked an organization that combined science and psychedelics, I did what young and naive idealists do: I decided to start a new organization. Little did I know that this foundation would become so intertwined with my life and identity, on so many levels. If psychedelics are the red thread in all of my adult life, OPEN is a delicately woven magic carpet – and I’m immensely grateful for the ride. It has brought me to new places, new ideas, and aspirations and it connected me with so many like-minded people, who over the years have become my colleagues, friends, and advisers. I even met my significant other – yes, OPEN has quite literally led me to my family. 

OPEN’s Journey

We started out as a local student-run organization with many dedicated and loyal volunteers. The taboo on the topic of psychedelics was still palpable, even in a country with a supposedly progressive drug policy like the Netherlands. To give an example: when OPEN wanted to become a customer at a national sustainable bank in 2007, we were denied a bank account because the topic of psychedelics was deemed too controversial – even in the context of academic research. How much has changed since those early days.

Over the past decade, OPEN has developed into a mature organization with an official tax-deductible non-profit status. If our foundation excelled in one thing, it’s in organizing conferences: the Interdisciplinary Conference on Psychedelic Research (ICPR) has become an internationally renowned event praised for its high academic quality. When we organized our first lecture in 2007 – “Ayahuasca & Anthropology” with Jeremy Narby – we could only fantasize about a psychedelic conference with accreditation for Dutch mental healthcare professionals. At ICPR 2016 this fantasy became a reality and ever since, our conference has been officially accredited by the leading professional mental healthcare organizations. 

Some of OPEN’s recent achievements that I’m proud of are the 2020 publication of the “Tijdschrift voor Psychiatrie” (the leading Dutch journal for psychiatrists) which was dedicated entirely to psychedelics; the ongoing collaboration with the KNAW (Royal Dutch Academy of Sciences) which so far has resulted in a several very interesting symposia; and the very recent manifest “Therapeutic use of Psychedelics” which has opened up a constructive dialogue with the Dutch Ministry of Public Health about the regulation of psychedelics assisted therapy. All of the above are examples of collaborative efforts and they illustrate one of OPEN’s core qualities: its ability to connect people and organizations, to build bridges between academic and professional fields. I haste to add that my felt pride in these achievements is purely from the sideline, as a board member – I haven’t been actively involved in any executive tasks for quite a long time. Full credits and gratitude for these achievements go to all of OPEN’s executive employees and the team of dedicated volunteers.

Exciting Times, New Challenges

As a network organization in the psychedelic field, OPEN is witnessing a huge change in the professional climate. Psychedelics are now being hailed as “the new promise in mental healthcare” by professionals from a multitude of backgrounds, as well as by mainstream media and multi-billion investors. The psychedelic renaissance has definitely shifted gears – and although these times are definitely exciting, they also come with challenges.

Commodification

One of the challenges that non-profit organizations like OPEN currently face, is how to relate to and navigate in an increasingly complex field, that includes stakeholders whose interests in psychedelics are mainly economical. What’s at stake in the rapidly commodifying field of psychedelics are, among others, safety and equal access. Such topics involve exploring ethical questions  – the answers to which will reverberate in the ways in which psychedelics will be integrated into our healthcare systems and societies. If you ask me, answering these far-reaching ethical questions should not be left to the market. Solving these complex issues is not the prerogative of the academic world either. The future of psychedelics now belong to a – primarily local, but increasingly global –  public debate, in which non-profit organizations in the psychedelic domain are contributing their independent, evidence-based, and objective voice.

Diversity

Another issue that I take at heart, which I hope OPEN will address within its own organization and events in the coming years, is the matter of equal representation and diversity. The psychedelic research world in 2022 is still primarily a white, middle/upper class, heterosexual, cisgender, male-dominated domain. Other ‘flavors’ of being human are painfully underrepresented or lacking entirely – not only as presenters at conferences but also as participants in psychedelic research and members of (advisory) boards. Alas, OPEN is no exception –  there is certainly room for improvement to diversify our board, advisory board as well as presenters at ICPR. Our very diverse base of volunteers does look very promising in this regard and hopefully will inspire other segments of the organization.

For a topic so rich and colorful as psychedelics, that pertains to a universal human experience, the lack of diversity is not only an embarrassing fact but such a missed opportunity. We are all biologically wired to experience psychedelic states of consciousness – but how we experience these states subjectively, how we reflect upon and interpret them, how we give meaning to them… how can this not be influenced by our subjective experience of ourselves and our relation to the world? Time and time again, it is stressed that set and setting are paramount in determining the psychedelic experience. Let’s not forget that gender, cultural background, ethnicity,  socioeconomic status (among others) are all part of that set. Diversity is a rich palette of all the different hues of human experience – if there’s one research area that can’t get away with using greyscale only, it’s psychedelic research. 

Precious Jewel

As my concluding thoughts, I want to build on a well-known metaphor of psychedelics as a multi-faceted diamond. In contemporary western societies, psychedelics have long been a diamond in the rough, valued for their potential by a relatively small group of people. They have been polishing the gemstone by using the scientific method, and by doing so, are attracting more and more people who, for various reasons, are interested in this jewel. Although psychedelics are being hailed as a promising tool in medicine, it’s important to emphasize that clinical research into these substances is just one of the diamond’s many facets. Psychedelics and the states they induce are such a rich and complex research subject – to study them from one discipline only wouldn’t do justice to it. The sociological, anthropological,  philosophical, neurobiological, and psychological perspectives – just to name a few – are all equally deserving of being studied. They are also intricately related to each other. By stimulating an interdisciplinary approach, organizations like OPEN contribute to the polishing of the entire diamond.

It’s worth noting here that many non-western cultural traditions have appreciated the richness of psychedelic consciousness for centuries and that there is a lot to be learned from such traditions – even if they take an angle that at first glance doesn’t seem compatible with our materialist scientific approach. The reverence and respect with which they treat psychedelic agents are exemplary and there is much wisdom in the ritual infrastructure in which psychedelic journeys are embedded in their societies.

As the academic world at large is becoming increasingly attracted to the precious gemstone called psychedelics, so are other domains of our society drawn to its shimmer and shine. The resulting tension raises fundamental questions, a few of which I will leave you with to consider. If all humans are biologically wired to get a glimpse of this diamond – can it ever be claimed as someone’s property? Will this diamond divide us, once again? Or does its true power lie in its ability to connect us?

Thank You & Fare Well

On this note, I would like to say goodbye. I wish OPEN all the best – may you continue to connect people, organizations, and the many different academic disciplines from which psychedelics can be studied. May you show the academic world what a fascinating diamond the psychedelic state of consciousness is while maintaining an objective and independent voice.

A huge thank you to everyone who has been involved with OPEN in the past 15 years – and a prospective word of appreciation for all of the foundation’s future supporters. 

Farewell, dear OPEN Foundation! I will happily take a seat in the audience at ICPR 2022. Or… perhaps I will apply as a volunteer!)

Yours truly,

Dorien Tatalas

Co-founder, former Chairwoman & former board member of the OPEN Foundation

With my dear friends and (former) board members of OPEN, at the first ICPR in 2012

Psychedelic Harm Reduction and Integration: A Transtheoretical Model for Clinical Practice

Abstract

Psychedelic Harm Reduction and Integration (PHRI) is a transtheoretical and transdiagnostic clinical approach to working with patients who are using or considering using psychedelics in any context. The ongoing discussion of psychedelics in academic research and mainstream media, coupled with recent law enforcement deprioritization of psychedelics and compassionate use approvals for psychedelic-assisted therapy, make this model exceedingly timely. Given the prevalence of psychedelic use, the therapeutic potential of psychedelics, and the unique cultural and historical context in which psychedelics are placed, it is important that mental health providers have an understanding of the unique motivations, experiences, and needs of people who use them. PHRI incorporates elements of harm reduction psychotherapy and psychedelic-assisted psychotherapy, and can be applied in both brief and ongoing psychotherapy interactions. PHRI represents a shift away from assessment limited to untoward outcomes of psychedelic use and abstinence-based addiction treatment paradigms and toward a stance of compassionate, destigmatizing acceptance of patients’ choices. Considerations for assessment, preparation, and working with difficult experiences are presented.

Gorman, I., Nielson, E. M., Molinar, A., Cassidy, K., & Sabbagh, J. (2021). Psychedelic Harm Reduction and Integration: A Transtheoretical Model for Clinical Practice. Frontiers in psychology, 12, 645246. https://doi.org/10.3389/fpsyg.2021.645246

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The Use of Classic Hallucinogens/Psychedelics in a Therapeutic Context: Healthcare Policy Opportunities and Challenges

Abstract

Psychedelics or serotonergic hallucinogens are a group of substances that share the agonism of serotonergic 5-HT2A receptors as their main mechanism of action. Its main effects include changes in perception, cognitive process, and mood. Despite being used for centuries by different cultures in ritual contexts, these substances have currently aroused the interest of science and industry for their promising antidepressant, anxiolytic, and anti-addictive effects. Considering this evidence, this article aims to explore some of the possible health policy challenges to integrate these therapeutic tools into broad and heterogeneous health systems. As a main benefit, these substances produce rapid and enduring effects with the administration of single or few doses, which could lead to new treatment possibilities for patients with severe mental disorders resistant to the usual medications. The main challenge is associated with the fact that these substances remain scheduled in most countries and are associated with social stigma related to their recreational use (especially LSD and psilocybin). This situation makes it exceedingly difficult to conduct clinical trials, although international conventions allow such research. Ethically, this could be interpreted as a violation of human rights since thousands of people are prevented from having access to possible benefits. Interestingly, ritual ayahuasca use is more acceptable to the public than the use of psilocybin-containing mushrooms or LSD. The controlled, clinical use of LSD and psilocybin seems to be less criticized and is being explored by the industry. Rigorous scientific evidence coupled with industrial interests (LSD and psilocybin), together with respect for traditional uses (ayahuasca) and international conventions, seems to be the best way for these drugs to be integrated into health systems in the next years. Which highlights the need for an urgent dialogue between science, health system, society, and politics.

Dos Santos, R. G., Bouso, J. C., Rocha, J. M., Rossi, G. N., & Hallak, J. E. (2021). The Use of Classic Hallucinogens/Psychedelics in a Therapeutic Context: Healthcare Policy Opportunities and Challenges. Risk management and healthcare policy, 14, 901–910. https://doi.org/10.2147/RMHP.S300656

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Trends in the Top-Cited Articles on Classic Psychedelics

Abstract

This study was designed to identify trends in the top-cited classic psychedelic publications. The top 50 publications on classic psychedelics with the greatest total of number of citations and annual citation rate were identified and pooled. Unique articles (n = 76) were dichotomized by median year of publication (2010.5); the differential distribution of study characteristics between the “Recent Cohort” (n = 38) and “Older Cohort” (n = 38) were documented. The Recent Cohort had a greater annual citation rate (median 76.0, IQR 38.5 to 101.5) compared to the Older Cohort (median10.0, IQR 5.2 to 19.3, p < .001). The Recent Cohort included a greater number of clinical studies (n = 26 [68.4%] vs. n = 9 [23.7%]) while the Older Cohort included more basic science and preclinical studies (n = 21 [55.3%] vs. n = 2 [5.3%], p < .001). Psilocybin was the predominant psychedelic studied in the Recent Cohort (n = 25 [65.8%] vs. n = 9 [23.7%]) while lysergic acid diethylamide (LSD) was predominantly studied in the Older Cohort (n = 25 [65.8%] vs. n = 18 [47.4%], p = .013). The Recent Cohort included more studies examining affective disorders (n = 15 [39.5%] vs. n = 3 [7.9%]) and substance use disorders (n = 6 [15.8%] vs. n = 0 [0.0%]), while the Older Cohort included a greater number of pharmacological outcomes (n = 29 [76.3%] vs. n = 6 [15.8%], p < .001). This study identified and documented trends in the top-cited classic psychedelic publications. The field is continuing to form a foundational understanding of the pharmacological effects of psychedelics and is now advancing with the identification of therapeutic uses within clinical populations.

Lawrence, D. W., Sharma, B., Griffiths, R. R., & Carhart-Harris, R. (2021). Trends in the Top-Cited Articles on Classic Psychedelics. Journal of psychoactive drugs, 53(4), 283–298. https://doi.org/10.1080/02791072.2021.1874573

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Harmine inhibits the proliferation and migration of glioblastoma cells via the FAK/AKT pathway

Abstract

Aims: Glioblastoma is one of the most invasive tumors of the central nervous system, and has a high degree of malignancy and poor prognosis. Harmine, an active ingredient extracted from perennial herbs, has been reported to have obvious antitumor effects on various tumors. However, the effects of harmine on glioblastoma growth remain unknown. We here explored the effects of harmine on glioblastoma and its underlying molecular mechanisms related to tumorigenesis.

Materials and methods: CCK-8 and immunofluorescent assay were performed to measure anti-proliferative effect of harmine on U251-MG and U373-MG cells. Wound healing assay was performed to measure the effects of harmine on cell migration. qRT-PCR and western blot were performed to detect the protein/gene expression. BALB/c nude mice bearing U251-MG xenografts was used to measure the effects of harmine on the growth of glioblastoma in vivo.

Key findings: Harmine treatment significantly suppressed the proliferation of U251-MG and U373-MG cells in a dose and time-dependent way. Mechanistically, harmine reduced the basal and EGF-enhanced the phosphorylation level of FAK and AKT. Moreover, harmine inhibited the cell viability of U251-MG and U373-MG cells by downregulating the phosphorylation of the FAK/AKT pathway. Besides, harmine significantly suppressed the migration of U251-MG cells by suppressing the expression of MMP2, MMP9 and VEGF. Subsequently, orthotopic xenograft models revealed that harmine treatment dramatically inhibited the growth of glioblastoma in vivo.

Significance: In conclusion, these results suggest that harmine suppresses the proliferation and migration of U251-MG and U373-MG cells by inhibiting the FAK/AKT signaling pathway. Our findings elucidate harmine could be a promising drug for glioblastoma therapy.

Zhu, Y. G., Lv, Y. X., Guo, C. Y., Xiao, Z. M., Jiang, Q. G., Kuang, H., Zhang, W. H., & Hu, P. (2021). Harmine inhibits the proliferation and migration of glioblastoma cells via the FAK/AKT pathway. Life sciences, 270, 119112. https://doi.org/10.1016/j.lfs.2021.119112

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Investigating the role of 5-HT2A and 5-HT2C receptor activation in the effects of psilocybin, DOI, and citalopram on marble burying in mice

Abstract

Psychedelic drugs acting as 5-hydroxyptryptamine 2A receptor (5-HT2AR) agonists have shown promise as viable treatments of psychiatric disorders, including obsessive-compulsive disorder. The marble burying test is a test of compulsive-like behavior in mice, and psychedelics acting as 5-HT2AR agonists can reduce digging in this test. We assessed the 5-HT2R contribution to the mechanisms of two 5-HT2A agonists on digging behavior in female NMRI mice, using citalopram as a reference compound. While the 5-HT2AR antagonist M100907 blocked the effect of DOI and the 5-HT2CR antagonist SB242084 blocked the effect of citalopram, neither antagonist blocked the effect of psilocybin. This study confirms 5-HT2AR agonism as a mechanism for reduced compulsive-like digging in the MB test and suggests that 5-HT2A and 5-HT2CRs can work in parallel on this type of behavior. Our results with psilocybin suggest that a 5-HT2R-independent mechanism also contributes to the effect of psilocybin on repetitive digging behavior.

Odland, A. U., Kristensen, J. L., & Andreasen, J. T. (2021). Investigating the role of 5-HT2A and 5-HT2C receptor activation in the effects of psilocybin, DOI, and citalopram on marble burying in mice. Behavioural brain research, 401, 113093. https://doi.org/10.1016/j.bbr.2020.113093

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How psychedelic researchers’ self-admitted substance use and their association with psychedelic culture affect people’s perceptions of their scientific integrity and the quality of their research

Abstract

Across three studies (total N = 952), we tested how self-admitted use of psychedelics and association with psychedelic culture affects the public’s evaluation of researchers’ scientific integrity and of the quality of their research. In Studies 1 and 2, we found that self-admitted substance use negatively affected people’s assessment of a fictitious researcher’s integrity (i.e. being unbiased, professional, and honest), but not of the quality of his research, or how much value and significance they ascribed to the findings. Study 3, however, found that an association with psychedelic culture (i.e. presenting work at a scientific conference that includes social activities stereotypically associated with psychedelic culture) negatively affected perceived research quality (e.g. less valid, true, unbiased). We further found that the latter effect was moderated by participants’ personal experience with psychedelic substances: only participants without such experience evaluated research quality more negatively when it was presented in a stereotyped context.

Forstmann, M., & Sagioglou, C. (2021). How psychedelic researchers’ self-admitted substance use and their association with psychedelic culture affect people’s perceptions of their scientific integrity and the quality of their research. Public understanding of science (Bristol, England), 30(3), 302–318. https://doi.org/10.1177/0963662520981728

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Consciousness, Religion, and Gurus: Pitfalls of Psychedelic Medicine

Abstract

This viewpoint identifies pitfalls in the study of psychedelic compounds, including those that pose challenges for the potential use of psychedelics as medicines. They are as follows: (1) Sloppiness regarding use of the term “consciousness”. (2) Inappropriate introduction of religious/spiritual beliefs of investigators or clinicians. (3) Clinical boundaries and other ethical challenges associated with psychedelic treatments.

Johnson M. W. (2020). Consciousness, Religion, and Gurus: Pitfalls of Psychedelic Medicine. ACS pharmacology & translational science, 4(2), 578–581. https://doi.org/10.1021/acsptsci.0c00198

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Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin

Abstract

While anecdotal evidence suggests that select 5-hydroxytryptamine 2A (5-HT2A) receptor ligands, including psilocybin, may have long-lasting therapeutic effects after limited dosing in headache disorders, controlled investigations are lacking. In an exploratory double-blind, placebo-controlled, cross-over study, adults with migraine received oral placebo and psilocybin (0.143 mg/kg) in 2 test sessions spaced 2 weeks apart. Subjects maintained headache diaries starting 2 weeks before the first session until 2 weeks after the second session. Physiological and psychological drug effects were monitored during sessions and several follow-up contacts with subjects were carried out to assure safety of study procedures. Ten subjects were included in the final analysis. Over the 2-week period measured after single administration, the reduction in weekly migraine days from baseline was significantly greater after psilocybin (mean, – 1.65 (95% CI: – 2.53 to – 0.77) days/week) than after placebo (- 0.15 (- 1.13 to 0.83) days/week; p = 0.003, t(9) = 4.11). Changes in migraine frequency in the 2 weeks after psilocybin were not correlated with the intensity of acute psychotropic effects during drug administration. Psilocybin was well-tolerated; there were no unexpected or serious adverse events or withdrawals due to adverse events. This exploratory study suggests there is an enduring therapeutic effect in migraine headache after a single administration of psilocybin. The separation of acute psychotropic effects and lasting therapeutic effects is an important finding, urging further investigation into the mechanism underlying the clinical effects of select 5-HT2A receptor compounds in migraine, as well as other neuropsychiatric conditions. Clinicaltrials.gov : NCT03341689.

Schindler, E., Sewell, R. A., Gottschalk, C. H., Luddy, C., Flynn, L. T., Lindsey, H., Pittman, B. P., Cozzi, N. V., & D’Souza, D. C. (2021). Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 18(1), 534–543. https://doi.org/10.1007/s13311-020-00962-y

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