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What are the effects of psychedelics on neuroplasticity?

Psychedelics appear to consistently produce long-lasting behavioural changes in the individuals who use them. Research focus has recently shifted to understand the accompanying changes in brain function and structure, which are hypothesised to occur through neuroplasticity. In this interview, Cato de Vos, MSc, explains what neuroplasticity is, how it can be measured in humans and animals, its importance in brain development, and the mechanisms by which psychedelic compounds and other practices can generate it.

Author: Maxim Siegel
Interviewee: Cato de Vos

Over the past couple of decades, accumulating evidence has shown that psychedelics consistently produce strong subjective effects, often leaving a perennial imprint on the individuals ingesting them. 

The subjective effects of the acute psychedelic experience are remarkable in and of themselves. At higher doses, they may occasion mystical-type experiences, considered by the individuals who have them as some of the most meaningful experiences of their lives, on par with one’s wedding day or the birth of a child. Perhaps even more remarkable are the sustained effects of these experiences on positive changes in attitudes and behaviours, lasting up to 14 months following the experience in one study.

Other studies have found similar long-lasting effects of these acute psychedelic experiences on depressive symptoms in patients with treatment-resistant depression, on smoking cessation in nicotine-dependent individuals, and on alcohol consumption in alcohol-dependent individuals. In each case, the quality of the acute psychedelic experience predicted the long-term changes from 6 to 12 months later. 

It is clear from the available scientific literature that psychedelics have an important therapeutic potential that needs to be investigated, and that therapeutic outcome may be determined by the subjective psychedelic effects. As a neuroscientist however, it is challenging to consider long-term behavioural changes without any accompanying structural or functional brain alterations. These findings pose the following question: do psychedelics affect brain structure and/or function in a way that can lead to long-term changes? And if so, by which processes?

Cato M. H. de Vos holds an MSc in neurobiology at the University of Amsterdam. She currently works as a research-assistant at the mental health organisation 1nP in the Netherlands where she assists Dr. Heval Özgen and Gerard van Kesteren (PhD cand.) in several clinical trials investigating the safety, feasibility, and efficacy of MDMA-assisted therapy. Soon, she will also start a part-time study in Psychology to become a therapist. In September 2021, she published a systematic review in Frontiers in Psychiatry, with Natasha L. Mason, PhD., and Professor Kim P. C. Kuypers, PhD., from Maastricht University. 

The aim of the paper was to review the evidence pertaining to psychedelics’ ability to induce molecular and cellular adaptations related to neuroplasticity, and to see whether they paralleled clinical effects. In total, 16 preclinical and 4 clinical studies were reviewed, revealing that a single administration of a psychedelic produced rapid, multi-level changes in plasticity-related mechanisms, including changes in the expression of BDNF, a neurotrophin involved in the growth, maturation, and maintenance of neurons.

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Q&A with Cato de Vos, MSc.

Question 1. What is neuroplasticity? What is its role in brain development?

Neuroplasticity is the brain’s ability to change throughout life. These changes may occur in cell structure, known as structural plasticity, or in the efficacy of synaptic transmission, known as functional plasticity. An example of structural plasticity is dendritogenesis, where dendrites – the receiving end of neurons – expand, and an example of functional plasticity is synaptogenesis, where new synapses – neuronal junctions – are formed, enabling better communication between neurons. 

Structural and functional plasticity are interconnected processes at a molecular and subcellular level, which eventually give rise to changes at the behavioural level. These changes allow your brain to adapt and change, promoting the ability to learn new things, enhancing your existing cognitive capabilities, supporting recovery from strokes and traumatic brain injuries, strengthening brain areas where functionality has been lost or has declined, and boosting brain fitness. However, neuroplasticity is a double-edged sword. Changes in the structure and function of the brain can confer adaptive benefits but can also lead to maladaptive disadvantages. To illustrate, misdirected activation of neuroplasticity can cause forms of severe tinnitus (‘ringing in the ears’) and neuroplasticity in the brain’s reward system induced by repeated use of certain drugs, such as cocaine, leads to more compulsive drug use. So the risk / benefit ratio also depends on the area where neuroplasticity is occurring.

For a long time researchers believed that the brain stopped developing during adolescence, and that there was a fixed number of neurons in the adult brain that could not be replaced when the cells died. In the 1960s, neurobiologist Joseph Altman discovered the creation of new neurons in the brain. His discovery was largely ignored, until the rediscovery of adult neurogenesis by Elizabeth Gould in 1999. Ensuing research on neurogenesis has since shown that the brain can change throughout life. Specifically the hippocampus, that part of the brain involved in spatial memory, learning processes and even emotion, continues to form new neurons throughout life. Thus,  neuroplasticity is the process by which the brain can modify, change and adapt structure and function in response to the environment.

Question 2. How can neuroplasticity be measured?

There are different ways to measure neuroplasticity in animals and in humans, but it really depends on the level you’re looking at. Neuroplasticity occurs at different levels in the brain (molecular and cellular), involves communication between different brain regions (structural and functional), and eventually affects behaviour, so it depends on the particular area that is being studied. When looking at the molecular level, for example, certain protein levels can be measured. If certain proteins are more expressed than others, then you can infer that they play a bigger role in the process, which can be an indication of neuroplasticity, although it’s a fairly indirect measure.

At a cellular level, a microscope can be used to examine dendrites. If you see that neurons have progressively more elaborate dendrites, that they look like a tree with more branches than before, then you can assume dendritogenesis is at work. 

This type of examination can be performed in animals, but is not as easy in humans, whose brains are not as easily available for research. An alternative is measuring the levels of certain proteins – like BDNF –  in the blood and other parts of the body. With humans, unlike with animals, biological and psychological parameters can be combined, which enables you to investigate the relation between biological and behavioural changes. That’s one of the things that is lacking in animal research: you can’t ask a mouse how it’s feeling. 

Question 3. By which mechanisms do psychedelics induce neuroplasticity?

The changes in neuroplasticity induced by psychedelics are believed to result from the neurobiological pathways they activate. Classic psychedelics act on a serotonergic receptor called “2A” (5-HT2AR). When psychedelics activate this receptor, specific pathways – cascades of different proteins communicating and transferring a signal – are activated. These cascades, or pathways, are different to non-psychedelic-induced activations of the same receptor. 

Following the activation of these cascades, two neurotransmitter systems are activated: the inhibitory serotonergic system, and the excitatory glutamatergic system. The activation of these systems leads to the release of both serotonin and glutamate and subsequently, brain-derived neurotrophic factor (BDNF), a direct indicator of neuroplasticity. Indeed, high levels of BDNF in the brain are associated with increased neuroplasticity. Psychedelics also influence neuroplasticity indirectly, by affecting the transcription of plasticity-related genes and proteins, which modulates the expression of other genes and proteins involved in neuroplasticity. 

Not every study shows that psychedelic administration necessarily stimulates neuroplasticity. It’s therefore not possible to say that it always happens, but there are some good indications that it does. There is also a lot of uncertainty when it comes to the molecular mechanisms I mentioned because measuring molecular cascades is very challenging, so more research is needed to draw definite conclusions.

Question 4. Have the clinical findings in humans mirrored the preclinical findings in animals so far ?

It’s hard to compare the two. Since different techniques are used to investigate humans and animals, making any comparison is like comparing apples and oranges. They both have their pros and cons. 

Clinical research can investigate both the biological and psychological parameters, which is good because you can then investigate correlations between the two. I believe the psychological state is important if you want to be able to observe improvements in the state of a patient, but it’s more difficult to measure direct biological parameters such as cerebrospinal fluid BDNF, like you can in animals. There are many translational issues, which is why we need to keep combining clinical and pre-clinical research, and be mindful of these limitations.

Question 5. Can neuroplasticity alone be therapeutic? What are your thoughts on psychedelic-inspired, neuroplasticity-inducing compounds like TBG, that lack the subjective effects of classic psychedelics?

Personally I am somewhat sceptical about not having the hallucinogenic effects in the context of therapy, but I think it really depends on the reason for psychedelic therapy, because there is a difference between using it for cluster headaches, or PTSD and depression. I believe you need to look at the origin and underlying layers or deep processes within yourself, within your system, that could cause these pathologies which are different in each of these cases. Cluster headaches might be solved with non-hallucinogenic neuroplasticity-inducing compounds, but for the psychiatric disorders – PTSD and depression for example – which are often accompanied by deep-rooted psychological issues, the hallucinogenic effects may be very important. In those cases the peak subjective experience might be necessary, as has already been shown in some studies: the stronger the psychedelic experience, the better the therapeutic outcome. 

That said, I believe that everything is connected – mind and body – and we’re so conditioned to be in our heads and not be aware of what’s going on in our bodies. I feel that psychedelics can restore some of this connection, on a psychological level. Perhaps the hallucinogenic effects may also have a positive impact on cluster headaches. David Olson’s work with TGB is great in that  he is making psychedelics accessible to a bigger audience. A lot of people are excluded from clinical trials because they have a history or family history of certain conditions, and they don’t have access to therapy at all, so this could be a very good thing.

Question 6. Any additional thoughts on neuroplasticity and psychedelics ?

Bear in mind that neuroplasticity can be stimulated by other means, such as taking good care of yourself, engaging in physical activity, meditation, eating healthy food and getting enough sleep. All these can be beneficial and contribute to positive treatment outcomes. We also want to be cautious here, because we don’t know when neuroplasticity stops being a good thing. I believe everything is about balance, so it is good to remain critical. As my colleague Erwin Krediet once said to me: “A plant doesn’t survive when you give it fertiliser every day, it’s too much.”

References:

1. Griffiths, R. R., Richards, W. A., McCann, U., & Jesse, R. (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology, 187(3), 268–292.

2. Griffiths, R. R., Johnson, M. W., Richards, W. A., Richards, B. D., McCann, U., & Jesse, R. (2011). Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology, 218(4), 649–665.

3. Carhart-Harris, R. L., Bolstridge, M., Day, C., Rucker, J., Watts, R., Erritzoe, D. E., Kaelen, M., Giribaldi, B., Bloomfield, M., Pilling, S., Rickard, J. A., Forbes, B., Feilding, A., Taylor, D., Curran, H. V., & Nutt, D. J. (2018). Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology, 235(2), 399–408.

4. Johnson, M. W., Garcia-Romeu, A., & Griffiths, R. R. (2017). Long-term follow-up of psilocybin-facilitated smoking cessation. The American journal of drug and alcohol abuse, 43(1), 55–60.

5. Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A., Wilcox, C. E., Barbosa, P. C., & Strassman, R. J. (2015). Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. Journal of psychopharmacology (Oxford, England), 29(3), 289–299.

6. de Vos, C., Mason, N. L., & Kuypers, K. (2021). Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. Frontiers in psychiatry, 12, 724606.

Illustration modified version of Milad Fakurian on Unsplash

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.

Author: Maxim Siegel
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.

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. https://doi.org/10.3233/JAD-150520

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. https://doi.org/10.1016/j.jad.2018.01.006

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. https://doi.org/10.1080/00952990.2021.1910830

The Netherlands should be ‘at forefront’ of psychedelic research, says Dutch government

‘The Netherlands can play a pioneering role in developing the right frameworks, limiting potential risks, and designing training programs,’ the Dutch health minister said.

Author: Stephan Tap

Ernst Kuipers, the new Dutch Minister of Health, Welfare, and Sports, has given his green light to more research in psychedelic therapy, citing “promising results” for typically difficult-to-treat mental illnesses through psychedelics-assisted therapy. His endorsement came in response to questions from three members of parliament from the Dutch political party D66. Kuipers summed up his stance on psychedelic research in a letter directed to the Speaker of the Dutch House of Representatives, and its content is factual and amenable to recent scientific results.

This is a departure for the Dutch government, which in recent years produced more prohibition-focused or avoidant language when it came to issues surrounding psychedelics. The new government has also announced that a state committee will look into the medical use of MDMA – a political compromise arising from the ongoing discussion in the Netherlands about the possible legalisation of MDMA for recreational use.

The new government’s health minister demonstrated conviction about the prominence psychedelic therapy will gain in global healthcare in the coming years, and envisions how the Netherlands could become a leader at the forefront of psychedelic research: “It is paramount that these and other potentially innovative treatments are safely accessible to the target population,” the minister writes. “The Netherlands is one of the leading countries in research into psychedelics in mental health care. In addition, the Netherlands can play a pioneering role in developing the right frameworks, limiting potential risks, and designing training programs for therapists. I am in favour of sharing earned knowledge with parties in the field across different countries.”

The Netherlands at the forefront of psychedelic research

Apart from MDMA, other psychedelic substances – such as psilocybin1 and ketamine2 – have also demonstrated promise. Kuipers strikes a more cautious tone when speaking about these compounds, affirming the need for more research due to the preliminary nature of current results: “Most of these substances are still in the investigative phase of research. […] It is up to the relevant field parties to follow up on these results. This concerns conducting the necessary research, completing the step-by-step registration process for approval of the substance, and the development of guidelines and protocols necessary for treatment.”

Kuipers further stresses the need for extensive education, the training of psychedelic therapists, and the need to better understand individuals engaged in self-experimentation. He adds that he is “willing to play a facilitating and advising role” in implementing psychedelic research and that his ministry has recently conducted exploratory meetings with researchers and mental healthcare institutions.

He envisions the Netherlands as playing a major role internationally in the coordination and promulgation of psychedelic research, writing that “[t]he Netherlands can stimulate cooperation in a European and international context. In addition, the Netherlands can draw attention to removing barriers in conducting research. In the framework of the United Nations Commission on Narcotic Drugs, I continue to advocate for the removal of barriers to therapeutic use and research into substances on United Nations drug convention lists.

New Research

According to Kuipers, an estimated 1.2 million Dutch citizens currently seek curative mental healthcare each year. Another 215,000 citizens suffer from severe psychiatric illness, a segment of the patient population that is very difficult to treat with current therapies. Kuipers has announced he will allocate 35 million euros to mental healthcare research over the next four years, made available through the Dutch grant organisation ZonMw. Grants will support multidisciplinary studies focused primarily on clinical applied research.

The availability of these funds presents psychedelic researchers with a rare opportunity. Results from these new studies could further elucidate the therapeutic mechanisms by which psychedelics function, thereby putting their clinical application on firmer scientific footing.  Ultimately, Kuiper’s initiative offers the promise of advancing the field beyond its “investigative phase” and imagines a not-too-distant future in which psychedelics are used as legitimate therapeutic agents in clinical contexts, offering hope to the millions who suffer from severe psychiatric illness around the globe.

Barriers to breakthrough therapy status

The three representatives of D66 asked further questions surrounding the current “breakthrough therapy status” of certain psychedelics in the United States. A breakthrough therapy designation is granted to a drug that treats a serious or life-threatening condition, where preliminary clinical evidence indicates that the drug might demonstrate substantial improvement on clinically significant endpoints over available therapies.

Recently, the American Food and Drug Administration (FDA) granted ‘breakthrough therapy status’ to psilocybin for treatment-resistant depression and to MDMA for PTSD. Kuipers explains that a similar status within the Netherlands and other countries in Europe can be attained through organisations such as the European Medicines Agency (EMA).

The minister acknowledges the barriers that still exist for psychedelic research, like “a lack of financial resources for doing the necessary clinical research and developing an approved product for the patient. In addition, psychedelics are substances that are generally non patentable and thus do not fit the ordinary development and revenue model. The potential high costs for the therapeutic treatment with these substances (due to the large amount of hours therapists dedicate to patients during treatment) might also impede incorporating psychedelics as a standard treatment.” 

The issue of the relative expense of psychedelic therapy bears further scrutiny. How, for instance, would the cost of psychedelic therapy compare to that of treatment as usual (TUA) if we take into account factors such as the economic burden of different psychiatric illnesses and/or disability-adjusted life years (i.e,. the number of years lost due to an illness)? To resolve the issue of financial expenditure, cost-effectiveness analyses of psychedelic therapy should be conducted, such as that performed in 20203. This study found that MDMA-assisted psychotherapy versus TUA per 1,000 patients produced savings of up to $103.2 million over 30 years including costs, and surmised that “third-party payers are likely to save money within three years by covering this form of therapy [MDMA].” This, however, is just the conclusion of one study, and the issue of financing deserves further investigation.

Central management and the Netherlands

Kuipers acknowledges the risks involved in the lack of central management of psychedelics. Possible risks include personal experimental use of psychedelics and the development of  commercially exploitative practices that fail to the interests of patients first. Kuipers emphasises the urgency with which these questions need to be answered, and references the Dutch researchers and clinicians who authored Therapeutic use of psychedelics4: “[…] they can develop a framework for this new form of treatment by means of high quality guidelines, standards, and protocols.”

Finally, the new government of the Netherlands has called for more research into MDMA and the possible legalisation of it in the near future. Kuipers mentions that there will be a state committee specifically for MDMA. The state committee will “investigate the status of MDMA in the context of public health and provide advice surrounding the pros and cons of medicinal use by adhering to a multidisciplinary analysis, which takes into account potential risks for health, prevention, and the European context and its relevant treaties.” Kuipers expects to inform the House of Representatives of the committee’s findings in the second quarter of this year.

References:

1. Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., … & Griffiths, R. R. (2021). Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA psychiatry, 78(5), 481-489.

2. Nieuwsuur (2022). Keta kan ‘revolutionair’ middel zijn tegen depressie, maar er zijn ook zorgen.  Consulted on 27 March 2022.

3. Marseille, E., Kahn, J. G., Yazar-Klosinski, B., & Doblin, R. (2020). The cost-effectiveness of MDMA-assisted psychotherapy for the treatment of chronic, treatment-resistant PTSD. PloS one, 15(10), e0239997.

4. Universitair Medisch Centrum Groningen. Manifest therapeutische gebruik van psychedelica. Retreived March 20, 2022.

’Psychedelic professors’ on the rise as universities expand courses on psychedelics

If you attended university or college and didn’t have an option to take a course on psychedelics – that was because they were practically nonexistent until very recently. Up to the beginning of this century, getting educated about psychedelics meant researching on your own, learning from elders, attending the few conferences that existed, reading available journal articles and books, or maybe joining secret psychedelic societies (in person or on the internet).

But today we are simultaneously experiencing a rise in international psychedelic research and an international acceptance of this field as a genuine, revived field of science. As a result, there is an emergence of university courses. And not just in a few places, but in some very prominent universities.

The psychedelic professors

The relative novelty of this educational endeavor spiked our interest: What are the types of courses offered? How are they organized and taught? What type of students are taking them? And what are the biggest challenges in teaching about psychedelics? We’ve interviewed three professors of current psychedelic courses at prominent research universities, who can rightfully call themselves psychedelic professors: Kim Kuypers (Maastricht, NL), Gianni Glick (Stanford University CA, USA), and Brian Pace (Ohio State University, OH) 

Kim Kuypers, PhD, is an Associate Professor of Psychology and Neuroscience at Maastricht University in the Netherlands. Dr. Kuypers focuses on “Me We Biology”, trying to understand the biology of mental well-being. She researches psychedelics and their effects on cognition, creativity, hormones, and the mechanisms underlying these effects. Dr. Kuypers will be a speaker at this year’s ICPR conference

Giancarlo “Gianni” Glick, MD, is a 3rd-year psychiatry resident at Stanford whose psychiatric focus is on the interdependence of emotional and physical well-being for his patients. He is also the organizer of the Stanford Psychedelic Science Group.  

Brian Pace, PhD, is an affiliate scholar with the Centre for Psychedelic Drug Research and Education in the College of Social Work and a lecturer in the Department of Plant Pathology at The Ohio State University. Trained as an evolutionary ecologist, Brian studied agroecology, climate change, and ethnobotany. He is the Politics and Ecology Editor at the 501c3 psychedelic watchdog Psymposia and is currently a part of the team organizing Psychedemia, an interdisciplinary psychedelics conference scheduled for August of 2022 at Ohio State.

Here is what they teach, how they teach it, and why it is important they do it. 

Q: Which courses on psychedelics do you teach?

A: Kuypers (Maastricht) “Psychedelic Medicine” is an 8-week long elective course for third-year bachelor’s students which is housed in Maastricht’s department of psychology. I also teach a first-year elective course in the same department, called “Drugs in the Brain”. This is for first-year students and is only 4 weeks long. This helps to serve as good preparation for those who will take the psychedelics class. 

A: Glick (Stanford) “Introduction to Psychedelic Medicine” is a 10-week course, housed in the department of psychiatry at Stanford Medical School. This semester we have 187 students enrolled. It is an elective course and the make-up is about 70% undergraduates and the rest are graduates of all kinds. We also have many auditors ranging from neuroscience postdocs to attending psychiatrists. This makes for a huge range of expertise and familiarity with psychiatry. 

A: Pace (Ohio State) “Psychedelic Studies: Neurobiology, Plants, Fungi, and Society” is a 14-week/one-semester course and it is through the Department of Plant Pathology. The course is for undergraduate bachelor’s students, without any prerequisites, but I frequently have graduate students as well. The majority are third and fourth-year students. There is also a new course being taught in our department called “Psychedelic Bioethics,” taught by my colleague, Dr. Neşe Devenot.  

Kim Kuypers teaches “Psychedelic Medicine” at Maastricht University to third-year bachelor’s students. She is also a speaker at ICPR 2022.

Q: What are the key learning outcomes for your students?

A: Kuypers (Maastricht) I want the students to know about the rich history of psychedelics and to be educated on both the positive and negative aspects of these substances. I place a major focus on how to properly read a scientific article: reviewing the research methodology, analyzing the results, and having a critical mind about it.  I see this course as really the first way of getting the students acquainted with psychedelics and from here they should be able to navigate the future research that comes out with a better eye, and maybe also be inclined to get into the research and/or work in psychedelic-assisted therapies themselves. 

A: Glick (Stanford) This question keeps me up at night, but I hope for a good cause – there are so many decisions about what to present, how to engage, what sequence of information makes the most sense. Ultimately, I want to prepare students to critically interact with everything they hear in the media and in the scientific literature about psychedelics. This course covers the foundational principles, history, and context for these students to then ask more questions and hopefully contribute to the field of psychedelics, themselves. I think one of the first questions we try to ask is: What does it even mean to call psychedelics medicines? And in doing so understand that we are applying a particular frame to it, specific to this pre-FDA-approval moment in time and space. While it’s nicer pedagogically to stay focused on psychedelics as a medicine, we also tell them that psychedelics can be many other things: sacraments, recreation, and so on. But for this course, we focus on them as medicines.

A: Pace (Ohio State) As the instructor of a course on psychedelics it is my job to prepare students to engage intellectually, become better communicators, and to have better conversations around a controversial topic that is rapidly taking center stage. Frankly, there are a lot of grifters in the psychedelic space, people who are attempting to own the space, and so part of my responsibility is to provide students with tools to critically evaluate psychedelic science and health claims, the job market they may enter, and to hopefully have these students make informed choices.

Q: What is the greatest challenge in teaching your course on psychedelics? 

A: Kuypers (Maastricht) I haven’t had too many difficulties in teaching this material. I did have an incident where I was teaching about animal research that was done with MDMA to investigate neuronal death, and in doing these studies I discussed the methodology which included decapitation to further look at their brains. As a result of saying so I had a student who left the room because they could not bear to hear this type of work. Though not directly related to in-class learning itself, I have had emails sent to me from parents of children who have abused drugs who question whether I am being too positive about these compounds, even going so far as calling me the devil. But in the 4 years of teaching this course, I have not faced many challenges from students. 

A: Glick (Stanford) Trying to figure out – what are the first principles of psychedelic medicine?  Where do you start?  How to strike a balance between asking big, zoomed-out, philosophical questions of human life and suffering (which I think is what this is really about), while staying in close contact with the data, the practice of medicine, counterpoints to my own views, and a sober take on all of this. How to teach students a kind of big picture schema that new ideas and facts and questions can fit into.

A: Pace (Ohio State) Psychedelics are inherently interdisciplinary. I’m not a psychiatrist. I’m not a social theorist. I’m not a political scientist. Yet these topics are as necessary to address as botanical, mycological, or neurochemical considerations–even though more broadly they may exceed the scope of my expertise. This can be challenging at times, but manageable. What is truly challenging is that issues like colonialism, addiction, and traumatic experiences are discussed in my course, and the reality is that some of the mental health distress faced globally is experienced personally by some of my students. Real injustice never gets easier to talk about, especially with those who are directly impacted by it.

One early psychedelic professor is Dr. Neşe Devenot – now an Affiliate Scholar at the Center for Psychedelic Drug Research and Education at Ohio State University.
She advocated for Psychedelic Studies courses for years, formally so in an essay in 2011 entitled “A Declaration of Psychedelic Studies”. Her first class, “Poetic Vision and the Psychedelic Experience,” ran from 2011 to 2012. A later class called Drug Wars had a focus on psychedelics and featured guest lectures from Matt Johnson and others working in the field. Her “Higher Dimensions in Literature” class in 2014 read McKenna and Castaneda. She went on to teach Psychedelic Studies at the University of Puget Sound from 2015 – 2018.

Q: What pedagogical tools do you use in your course? 

A: Kuypers (Maastricht) For both the “Psychedelic Medicine” 8-week course and the 4-week “Drugs of the Mind” course I use Problem Based Learning (PBL). This pedagogy works by bringing real-world problems to the class which functions as vehicles for students to have to look up things they don’t know, synthesize an answer based on their research and these problems are generally guided, often providing one part of a problem at a time.  An example of the last PBL assignment was a problem evaluating the positive and negative of the field of psychedelic medicine. In terms of course materials, I developed a course manual and we also use recent research articles for the “Psychedelic Medicine” course. In the 1st year course “Drugs of the Mind” course we use David Nutt’s “Drugs Without the Hot Air”.  I do most of the lectures but some of my colleagues help as well. We have a limited amount of time in these courses so we provide additional resources online for students to read and watch on their own. 

A: Glick (Stanford) Two years ago the course started as a lecture series, with a different speaker each week presenting on their area of expertise.  We updated the second iteration (last year) to have a more coherent through-line and progression of topics, with added small group discussion. And this year we tried to improve that further, so we spent the first third laying the foundational principles, the second third hearing from serious experts in the field (Brian Anderson, Jennifer Mitchell, Robin Carhart-Harris), and the final third weaving everything together.  The best session is always the last one when students give 5-minute presentations to the class on any topics or psychedelics subgenres they found interesting.  This year they taught us about psychedelics in China, the Eleusinian mysteries, research in psychotic disorders, and a bunch more.

A: Pace (Ohio State) This is a lecture-based course accompanied by reading articles and watching videos that conclude with 30-minute discussions each class. Since it is a course goal is to get students to have better, evidence-based conversations around psychedelics, students write weekly reading reflections showing that they are considering the material and reflecting on how they feel, and how these topics may connect to their life. Students also do presentations which are evaluated in part by peer review. From day one I am walking students through difficult, yet respectful conversations; you can’t understand psychedelics without touching on topics like consciousness, perception, religious experiences, and criminalization. 

Q: What do you believe is the ROLE of university courses in the psychedelic renaissance? 

A: Kuypers (Maastricht) It is incredibly important to have these available. I get requests from therapists and psychiatrists who did not get these types of courses in the curriculum of their educational training. Some of them also tell me of the cost for psychedelic-assisted therapy training from private institutions that can cost upwards of 20,000-25,000 Euros, which is crazy. Instead, this type of education should be embedded within all levels of university education from bachelor’s, graduate, and medical education. We definitely need psychedelic-assisted training for therapists in the universities (instead of the private organizations). 

A: Glick (Stanford) Similarly to how Johns Hopkins, NYU, and UCLA have stewarded the research through this kind of rigorous academic environment, there is this similar way that universities may offer a credible education, with a kind of peer review process, with a set of checks and balances where you can’t just teach anything. Secondly, doctors should know about this. For medical students and psychiatry residents to be competent about medicines their patients are in some cases already using and that may soon become legal, this should be part of the curriculum.

A: Pace (Ohio State) Psychedelics were abandoned by institutions following the Controlled Substances act in 1970. The new-agey, cultish stuff we see around psychedelics now, with tuning your chakras and merging souls or whatever: that is our fault. That’s an abdication of the responsibility to investigate interesting questions and to chase down data: to find out how things work.  So where we are now is a very timid and late re-entry to the subject, more so for education than research.  Psychedelic research didn’t end when the universities and governments abandoned it. It continued in the underground. The role of the university courses on psychedelics is to identify and evaluate high-quality information on the topic. We have a lot of catching up to do and I think that should be done with humility.

Addendum: The author of this article, Dr. Joey Lichter, is a volunteer for OPEN and ICPR, but also a chemistry professor who teaches a course titled “The Psychedelic Renaissance” at Florida International University in Miami, FL USA, thereby also qualifying as another psychedelic professor.

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

Truffle therapy in the Netherlands is running ahead of the science

The promising results of psychedelic treatments in small scale clinical trials are feeding an emergent health and wellness industry around these substances. The Netherlands, where psilocybin truffles remain unregulated, has become fertile ground for entrepreneurs aiming to position themselves at the cutting-edge of the psychedelic medicine market. Even though most of these psychedelic retreats cater to healthy participants, an increasing number of companies are planning to offer truffle sessions as psychedelic therapy to psychiatric patients. At the current stage, when scientific evidence proves promising but not yet conclusive, researchers are worried about the risks of commercial providers running ahead of the ongoing research. Should companies tread more carefully and let clinical researchers take the lead in the development of psychedelic therapy?

Psilocybin in the Netherlands

Psilocybin is a controlled substance in the Netherlands and the possession and sale of any species of psilocybin containing mushrooms is forbidden. However, this regulation does not apply to truffles, given that these are not strictly mushrooms but a different part of the fungus. This legal loophole has allowed the spread of psychedelic retreat centers offering truffle ceremonies for self-development or spiritual purposes.

Even though truffles qualify as a legal food in the Netherlands, they cannot be advertised as a medical treatment. The Dutch Health and Youth Care Inspectorate (IGJ) states that truffles may fall under the regulatory scope of the Medicines Act if medical claims are made. “In that case, we qualify the truffles as a medicine, for which no trade permit has been granted in the Netherlands”, an IGJ spokesperson declared.

Most entrepreneurs, aware of the existing regulation, avoid making explicit medical claims when advertising their services and try to use terms like “inner healing” and “personal development” instead. Many also warn that their ceremonies are not meant to substitute medical or psychotherapeutic care and make an effort to exclude clients with mental diagnoses and possible physical risks from participating through careful health screening.

This is, however, not always the case. The clinical director of a new truffle clinic recently declared to Dutch media: “We administer truffles to people in order to make them feel better and to overcome psychological disorders such as depression, anxiety and stress”. Others openly claim to provide “psychedelic-assisted therapy” on their websites and display the available scientific evidence to illustrate its efficacy in the treatment of depression, addiction or PTSD. We asked Nick (whose real name is not disclosed) about the apparent targeting of mental health patients on his retreat center’s website. “We are not pretending to treat or cure PTSD”, he assured, “we are acknowledging that there are people who have PTSD and that those clients that we have received (and not targeted) had very beneficial experiences”.

The hype around psychedelics is sparking a race among startups to become pioneers of a new therapeutic or wellness market, the boundaries are not always clear. But the emergence of truffle therapy is not just about opportunistic entrepreneurship. The mainstreaming of psychedelics is also bringing some of the underground therapists to the surface and from their perspective, there might not be meaningful reasons to wait for approval and regulation. Peter (whose real name is not disclosed) has conducted truffle therapy for the last eight years and more recently decided to start advertising their services online. “Back then we also thought we were moving too fast but people were really searching for this. We just couldn’t wait. Regulation can be helpful, but for a lot of us who already walked that path it’s not that great, especially for the ones who believe more in alternative therapies”.

The lack of formal regulation governing the profession has led some psychedelic guides in the Netherlands to found the Guild of Guides. This professional association is developing its own ethical codes in order to ensure best practices during psychedelic sessions. Peter also acknowledges the importance of the guild in the self-regulation of psychedelic facilitators. When it comes to offering therapy, however, their guidelines are unequivocal: “Guides do not claim to be psychedelic therapists nor offer ‘therapeutic’ services when they lack the appropriate accreditation.”

Scientists’ call for caution

A number of Dutch researchers and therapists are currently working on trials investigating the safety and efficacy of psilocybin for patients with treatment-resistant depression. They are concerned about commercial providers rushing to open up the market even before the scientific evidence is established. Clinical psychologist Jan Mars, therapist at the University Medical Centre Groningen (UMCG), says: “I am not a supporter of this practice because we are still doing research right now and you don’t want to run ahead of the science”. Joost Breeksema, researcher at the UMCG and director of the OPEN Foundation, echoed similar concerns: “The main problem is that we don’t know yet if this can be done safely and if so, which patients might benefit and which may be more at risk. And we’re only talking about the treatment of depression, where clinical research with psilocybin is relatively advanced. Offering psilocybin truffles to treat PTSD is even more problematic, not just because of the nature of this disorder, but also because we lack solid research. I understand the need for better treatments, and the impatience of patients who’ve sometimes suffered for decades, but it’s unethical, unwise and irresponsible to experiment blindly with these powerful treatments.”

It is important to remark that most scientists and therapists see no harm in conducting truffle ceremonies with experienced guides outside the medical realm. Renske Blom, psychiatrist at GGZ Centraal and therapist at UMC Utrecht, noted: “Truffles are legally available in the Netherlands so they can be and are being offered for spiritual care, wellbeing and self-improvement”.

While there are signs to be hopeful about the potential of psychedelics for the future of mental health treatments, research has not yet offered conclusive evidence that would warrant safe and efficacious provision of psilocybin therapy. Two psilocybin trials so far have shown significant and long-term improvements for depression. However, these trials lacked placebo controls and the samples were pretty small. Several ongoing multisite trials with hundreds of participants will be able to give more reliable evidence about the therapeutic value of psilocybin. Nonetheless, these studies have not yet been completed and experts warn that it is precisely at this stage of drug development where most new pharmaceuticals fail. In the case of PTSD, larger studies are proving that MDMA-assisted psychotherapy may be useful, but not a single clinical trial has investigated psilocybin for this indication yet. In general, there are still a number of incognitas around safety, short- and long-term efficacy, relapse rates and the optimal amount of integration sessions.

Janis Phelps on training the first psychedelic therapists

One of the main concerns of researchers relates to the qualifications and therapeutic experience of these truffle providers. This is a complicated issue given that clinicians and researchers are still debating the adequate standards and training requirements for the certification of future psychedelic therapists. Some companies currently offering truffle therapy have a team of professionals with a background in mental health. In other cases, the psychotherapeutic and medical credentials of guides and their experience with disorders such as PTSD or depression are dubious.

The exposure of these sensitive populations to the intensity of the psychedelic experience can be risky if guides are not able to respond to the particular needs of psychiatric patients. In working with depression and psychedelics, Jan Mars emphasizes that “supporting a psychedelic journey is a humbling experience. You don’t know what is going to happen during the session. You can expect anything to happen,” and therefore, he adds, “It’s important that therapists know how to provide a safe environment. We still need much more experience and knowledge about how to work with patients who suffer from chronic psychological conditions. Trauma often lies beneath the surface and pops up during a session with psychedelics”. In regard to trauma therapy with these substances, Joost Breeksema adds: “Patients may relive traumatic moments, completely dissociate or become overwhelmed with fear and anxiety. This can be hard to handle even for an experienced therapist. Now imagine what happens with well-intended, but under-qualified and unprepared guides”.

Although these treatments are known to be generally safe in terms of toxicology and no serious adverse events are commonly reported in trials, their safety profile resides precisely in the close psychotherapeutic support and monitoring performed before, during and after psilocybin administration. Jan Mars hopes that in future clinical practice, “psychedelic journeys will be embedded in a safe and trusting therapeutic environment. These journeys are no magic bullets.”

In general, truffle providers understand the concerns of scientists, but they feel that the benefits of psilocybin treatment outweigh its risks. According to the clinical director of a truffle clinic, clients with depression may be thinking: “Damned! Science says that this can help me. It is not yet approved but there are places where it can be done safely so I am going to try”. From his own experience guiding sessions, Peter concluded that: “It all comes down to a balance between safety and effectiveness. We are all trying to find out, but at the moment psychedelic sessions do more to help people than to harm them”.

For psychiatric patients for whom other treatments have failed, this call for patience and caution may be difficult to accept. At the same time, they should be able to make informed decisions. Given the current exclusion criteria in psychedelic trials, researchers discourage patients with a history of personality or psychotic disorders from seeking these treatments at all. Jan Mars sends a piece of advice to those other patients without complex comorbidities who, despite potential risks, decide to seek truffle therapy: “Involve a loved one in the journey that you are about to embark on, for support before and after. Do some research on who is guiding it, what the setting will be like and whether there is enough time dedicated to the preparation of the session. Make sure that you feel you can trust the guide. If you have doubts, then there is probably a good reason for it, and it might not be a good idea.”

The relation between retreat and research

Truffle therapists in the Netherlands definitely have clinical research on psilocybin as their reference of best practice. Nick explained: “We frame it in a therapeutic setting to optimize positive outcomes and keep clients safe”. Nonetheless, researchers remain sceptical about the degree to which truffle providers actually manage to screen out participants with mental diagnoses or maintain high standards of care. To be fair, even some research protocols could be criticized for including the minimal amount of preparation and integration sessions.

The biggest challenges for psychedelic science today

Besides the potential harm to patients, researchers also seem to be worried about the future of research itself. The controversial history of the field has made psychedelic scientists generally cautious about avoiding any kind of social backlash. An unfortunate incident with a patient could set back the progress made in the last years. Renske Blom added: “If a major incident happens in the context of these therapy sessions, inside or outside clinical trials, it could influence upcoming research as well”.

While acknowledging the importance of further research, Nick also stressed that “truffles were never researched. They cannot say that psilocybin session guides are too early. Actually, the research is late because more people trip on naturals than on lab-grade psilocybin”. Bearing in mind the likely pharmacological difference between the synthetic compound and whole truffles, the current research agenda may not represent the interests of truffle therapists. In other words, it is unclear whether research with pure psilocybin would ever be considered valid evidence to justify their practice. Joost Breeksema said: “We don’t really know what truffles contain because they haven’t been standardized or analyzed in the laboratory, but I do think that if psilocybin goes through the approval process, it is likely that people and investors will get interested in the whole product as well.”

Despite the rather marginal position of truffles in current research, some investigators have realized the potential role that the retreat ecosystem can play in psychedelic science. In collaboration with retreat centers, several research projects have administered questionnaires to participants to learn more about the effects of these substances and their ritual use on healthy people. These centers could also become a place where all kinds of alternative models of psychedelic care can develop. The rigid regulatory and scientific frameworks within which researchers operate may limit the possible treatment conditions. In contrast, retreats offer the chance to explore new experimental protocols such as group sessions or natural settings. Joost Breeksema said: “The retreats may offer an infrastructure that is better suited to the psychedelic experience than clinical hospital settings”.

Nick is enthusiastic about future collaborations: “We want to set up research at our centers and we would love to count on scientific organizations, so we can actually build up the science needed and move beyond this internal dialogue about truffle therapy.” Joost Breeksema adds: “If they do proper data collection and analysis, they can contribute to the body of knowledge about the potential effects and risks of psychedelics. There are definitely options for collaboration but it has to be done judiciously and cautiously.”

The medicalization of psilocybin appears to raise tensions among different stakeholders in the psychedelic field. In the eyes of researchers, the underground therapy scene and the booming industry around psychedelic medicine may entail risks for patients and for the public image of ongoing research. Hopefully, future collaborations between retreat centers and research teams may offer a way forward to generate the evidence needed for an eventual regulation of the medical, as well as the non-medical uses of psilocybin truffles. However, at this stage, the open commercialization of psychedelic therapy to potentially vulnerable patients may be an unwise step ahead.

Written by Alberto Cantizani López
Art by Anna Temczuk
*The names of all informants involved in the commercial provision of truffles as therapy have been omitted or replaced by pseudonyms

The Legitimation of Psychedelic Science: An interview with Danielle Giffort

“I am proud to have ‘killed’ government-authorized research on psychedelics.”
Timothy Leary, 1992

Most stories about the early psychedelic research in the 1960s tend to converge towards a common narrative: Timothy Leary, a rogue researcher turned LSD prophet, triggered the social backlash that would ultimately condemn psychedelics to decades of prohibition. In her book “Acid Revival”, sociologist Danielle Giffort explores the history of psychedelic science and how the controversial figure of Leary has shaped the path towards legitimacy for contemporary researchers. In this interview, we discussed Leary’s responsibility for the demise of the first wave, as well as the history of self-experimentation, controlled methodologies and spirituality in psychedelic science.

Dr Danielle Giffort – Assistant professor of Sociology at St. Louis College of Pharmacy

How did you become interested in the history of psychedelic science?
I have always been very interested in Science & Technology Studies (STS) work on non-knowledge or what’s sometimes called “scientific ignorance”, not in the sense of studying public ignorance of science but in the sense of studying what kind of knowledge is not produced in science and why is that the case.
Psychedelic science offered a really good case to study how a group of scientists rallies to bring their field back to life. I wanted to trace the trajectory of psychedelic science to understand its ebbs and flows from knowledge to nonknowledge and back again.
When I started this project, as a sociologist, I thought I would be writing a broad institutional story about how governments, science, and the media shaped this field. But as I interviewed the researchers doing this work, listened to their presentations at conferences, and read their published commentaries and research, I found that their explanation for what happened to their field was very different. They told me that Timothy Leary, the infamous Harvard psychologist turned countercultural guru, caused the demise of this field. The consistency with which he came up in my data was such that I ended up organizing my whole book around the story.
In your book, you argue that Leary represents the figure of the “Impure Scientist” for contemporary researchers. Can you elaborate on what you mean with this concept?
I argue that the researchers are not necessarily just talking about Leary in their stories but that he comes to symbolize a larger figure in the field. The impure scientist is a person who defies the norms and the boundaries of science. In each chapter, I show how Leary crossed different boundaries in ways that caused all sorts of problems for the field of psychedelic science. First, there’s the boundary between science and pseudoscience. In other words, I’m talking about the legitimacy of the methods researchers are using. Second, there’s the boundary between objectivity and subjectivity in science; in the case of psychedelic science, this boundary has to do with whether a researcher has personal experience with these substances and whether that spoils, so to speak, their objectivity. Third, I discuss the seemingly irreconcilable gap between spirituality and science, which comes up again and again in psychedelic therapy with its recurrent focus on mystical experiences. Finally, I cover the boundary between “mainstream” society and the counterculture.
But I also found evidence of other researchers that did quite similar things during the first wave of psychedelic science. That’s why I say Leary, as the impure scientist, is a figure. Even though many other researchers could be accused of the same behaviors, Leary becomes the fall guy because he is this easily identifiable person that they can all point to and say: “He did it, he crossed these boundaries and polluted the whole field”. Leary represents a bad expert that current researchers are really trying to push away from. Ostensibly, they do that by being the opposite of what the impure scientist was, what some have even dubbed the “Anti-Leary.”
You stress that the goal of the book is far from reassessing the historical responsibility of Leary in the failure of the first wave of psychedelic research. At the same time, after reading your book, readers may wonder what criticism he rightly deserves for his behavior.
I am explicit, as you said, about how the point of the book is not to ask whether this story is true. That is, whether Leary is really to blame or not. In the book, I am  more interested in studying how people use these subjective narratives and their accompanying performances to make sense of their situation and take action. So I asked myself, if psychedelic researchers are using this idea of the impure scientist to make sense of the situation, regardless of its truth, how does that interpretation influence what they do? 
Ultimately, I am not blaming Leary nor exonerating him because the reasons why psychedelic science became forbidden knowledge are multifaceted. If Leary had been a bit more reserved, would it have caused such a media spectacle and subsequent public backlash against psychedelic drugs? The stories suggest that might be the case, but the fact that there were other researchers at the time who were doing similar things, even before Leary came on to the psychedelic scene in 1960, also suggests that what happened to this field is not all about him. He was a part of it, for sure. But Leary, the government regulations, the media coverage, the scientific expectations, the cultural panic; they all contributed to what happened with psychedelic science.
In the end, the focus on Leary does serve a strategic purpose. Instead of blaming institutions like the FDA or DEA (in the US), which are necessary for this research to happen, the story blames an individual. While the narrative avoids making a more direct critique of institutional systems of power, at the same time it still allows researchers to get work done within the system, potentially making change from within, for example, getting psychedelic drugs rescheduled. 
You dedicate one chapter to the topic of objectivity and scientists’ self-experience with the drugs they study. This is still a contentious issue today when it comes to whether therapists should have personal experience with psychedelics to guide patients. Can you elaborate on this method of drug self-experimentation and how it has played out in the history of psychedelic science?
One of the first recommended uses for LSD was self-experimentation. The idea was that psychiatrists who took the drug themselves could understand what their schizophrenic patients were feeling because, at the time, LSD was thought to mimic endogenous psychosis. As such, it offered a tool for healthcare professionals to develop empathy towards their patients and a shared understanding of their mental health problems.
As many LSD researchers moved away from this “model psychosis” framework towards studying potential therapeutic uses, some investigators said that it was also important for therapists to take the substances themselves. The thinking was that if you have had a psychedelic experience, you can develop a kind of tacit, embodied knowledge that can help you as a healthcare provider know when to step in and offer support for your patient or when to back off and let them be. Here, self-experience was once again about empathy but also about patient safety. 
Not everyone self-experimented because it raised questions about objectivity. Some argued that if the researcher has had a psychedelic experience, it will  influence how they interpret their data or how they guide their participants through a psychedelic therapy session, potentially in a way that leads to a particular outcome.
Personal experience with psychedelic drugs continues to create dilemmas for researchers because objectivity is synonymous with legitimate science. The public wants you, the researcher, and all your values and opinions, to be detached from what you are studying so that I, as the consumer of knowledge, know that the knowledge produced from your research is credible. That is the public imaginary around science. So there is a desire among many psychedelic researchers to keep hush-hush about any personal experiences with these drugs to avoid accusations of being biased or being like Leary, but at the same time, these experiences are very meaningful for those who have had them. Like their predecessors, the researchers I spoke with agree that, although not strictly necessary, self-experimentation is important for patient safety and empathetic interactions. 

Should psychedelic guides keep spirituality out of the therapy room? – Interview with Daan Keiman

Spirituality has featured prominently in psychedelic research throughout its history. How would you evaluate the relation between spirituality and science in the field of psychedelic research?

Since the early days, spirituality has also been controversial in psychedelic therapy. Some people believed that spirituality wasn’t compatible with scientific inquiry. It would bring up questions, such as, “How do you objectively quantify a psychedelic-induced spiritual experience?” which then brings up larger scientific issues surrounding conceptualization and operationalization. In other words, how are we defining what we are studying and how are we measuring it? Answering these questions has been key to demonstrating scientific objectivity.

Despite such obstacles, we see this mystical discourse popping up again in the revival. Some research teams, like the group at Johns Hopkins, have embraced this approach, and they have worked to validate mystical experience questionnaires that they use to assess people’s experiences and outcomes. Neuroscientists are also using  brain scans to study the spiritual experiences induced by psychedelics, although some groups, such as the team at Imperial College in London, prefer the language of “ego dissolution” to describe them. If scientists can actually uncover these processes happening in the brain, then they can make the case that what happens when people take psychedelics is not simply a subjective experience. They can back up patient accounts with quantified questionnaires and brain scans. That kind of evidence could help legitimate psychedelic treatments further, as numbers and neuroscience hold a lot of weight in today’s scientific environment.
So far, it doesn’t seem like people are totally against the idea of mystical experiences in psychedelic science. Research on this exact topic is getting published in mainstream scientific journals, getting approval from advisory boards, and getting a lot of positive attention in the media. So, although it continues to create dilemmas for researchers on their road to legitimacy, I see this intertwining of spirituality and science unfolding a bit differently than it did in the first wave.
Findings from LSD research in the 60s are often dismissed because of the lack of rigorous methodologies. In the book you say that questions about aligning psychedelic therapy with the method of randomized controlled trials (RCT) remain in the renaissance. What methodological lessons do you think contemporary researchers have learnt from the first wave?
They learned that to be seen as legitimate researchers, they need to use controlled methodologies.The US-based researchers I spoke with regularly shared with me the arduous process of getting FDA approval, and how they need to submit proposals that include an experimental group, a placebo, and so on. So RCT methods have been legitimated institutionally, not just within scientific cultures. Looking at the past, researchers learned that they need to play that game for their studies to get approval, get funding, and get published.
But I think that today’s researchers are also careful to avoid past mistakes that happened when researchers who didn’t have a lot of experience doing LSD therapy focused too closely on sticking to the RCT model. The poor treatment outcomes observed in some of the studies of LSD therapy for alcoholism in the 1960s were not necessarily because the treatment didn’t work, but because researchers failed to optimize set and setting. One group of researchers, for example, gave LSD to patients, strapped them to a hospital bed and left them alone for hours. Based on what we know about the interactive effects between drugs, the mind, and the physical and social environment, it is not surprising that these patients consistently reported terrible LSD trips and that the drug was deemed not therapeutic by some researchers.
So I think that today’s researchers learned that controlled methodologies are legitimate and they need to use them, but at the same time, they recognize that an excessive focus on that step-by-step process isn’t a good fit for psychedelic therapy. That is why you see this merging of set and setting, such as preparing the treatment room and the patients to optimize the experience, while also having placebos and control groups, in much of today’s psychedelic research protocols.

The influence of society on the psychedelic experience – Interview with Ido Hartogsohn

At the OPEN Foundation, we try to foster interdisciplinary dialogue between the social and the medical sciences. How do you think that psychedelic researchers may benefit from reading your book?
I still can’t decide if I want to be a historian or a sociologist. But here is where my historian side comes out. Delving into the past can be very important for helping us understand how people act in the present. Regarding psychedelic research in particular, this means understanding not just cultural narratives about Leary or figures like him, but understanding, for instance, the institutional regulations in the first wave regarding scientific methods that changed how clinical research gets approved, conducted, and hence, legitimated. Knowing these contextual influences can change what researchers  do in the present in ways that can help them make this work happen.
From a sociological perspective, I hope that the book helps researchers and readers think about science not as insular but very much as a social endeavor. The production of scientific knowledge does not exist in a vacuum, and psychedelic science is a great example of this. As Ido Hartogsohn shows in his book “American Trip”, for example, in developing protocols for psychedelic therapy, researchers  not only have to take into consideration the setting of the therapy room itself, but the broader environmental factors that are shaping this research in the first place. They must navigate different social obstacles and opportunities, such as government regulations for clinical drug trials or public preconceptions about psychedelic drugs. Thinking sociologically about science and psychedelic drugs helps us take into consideration larger social factors that potentially affect this work, both in ways that can help and in
ways that can hinder psychedelic research.

Danielle Giffort: Author of Acid Revival: The Psychedelic Renaissance and the Quest for Medical Legitimacy (2020)
Art taken from the front cover of Acid Revival
Interview by Alberto Cantizani López

Should psychedelic guides keep spirituality out of the therapy room?

While the use of psychedelics has been closely entwined with spiritual practice, prominent voices in psychedelic research have called for the demystification of these substances and the adoption of more secular approaches to psychedelic therapy. I sat down with OPEN Foundation collaborator and psychedelic chaplain, Daan Keiman, to discuss the ethical issues that have been raised around the introduction of spiritual frameworks in psychedelic therapy sessions. From his experience facilitating psilocybin truffle ceremonies at one of the many legal psychedelic retreats in the Netherlands, he thinks that rather than secularize psychedelic guidance and integration, we should tackle these concerns through an interfaith approach. If therapists acknowledge that they are not “existentially neutral” about the nature of the psychedelic experience and its meaning, they should therefore reflect honestly with patients on their therapeutic relation and their respective existential views.
 
The risk of imposing religious beliefs
In a recent viewpoint article about the pitfalls of psychedelic medicine, researcher Matthew Johnson has raised concerns around the possibility of imposing religious beliefs on patients undergoing psychedelic therapy. Johnson warns therapists about the risks of using concepts from Eastern or indigenous spiritualities in integration sessions or even displaying particular religious icons in the therapy room. In his own words, “in addition to other concerns about conflating religious beliefs with empirically based clinical practice, the introduction of such religious icons into clinical practice unnecessarily alienates some people from psychedelic medicine, e.g., atheists, Christians, and Muslims. It will ultimately interfere with the mainstream adoption of these treatments.”
Daan shares some of these concerns given that psychedelics may put patients in particularly vulnerable states that must be handled with care and responsibility. “Under the effects of psychedelics, the suggestibility goes up significantly and we know that people often have noetic experiences: a feeling that something is being revealed to them that is incredibly true.” Although we know that these experiences are deeply mediated by the context in which they are used, their noetic quality feels as unmediated, as completely independent from the set and setting.
Therapeutic work with this kind of deeply felt experiences of truth is proving challenging for psychedelic researchers concerned about the ethics of inducing or validating profound metaphysical beliefs in patients. They worry that such revelations facilitated by the combination of drug and setting may turn psychedelic therapy into a form of non-consented spiritual conversion. Therefore, as Johnson argues, researchers and clinicians should adhere to a secular approach and refrain from introducing any “non-empirically verified beliefs” into their therapeutic protocols.
Daan agrees with the difficulties of introducing elements from particular spiritual traditions in pluralistic settings such as the truffle retreats that he facilitates. In fact, the Buddhist teachings and stories that he used to share with participants in preparation for their ceremonies did not always resonate with everyone’s worldviews. In one of these stories, the Buddha is seduced by the demon god Mara during meditation and, instead of ignoring his calls, he accepts them and invites the demon to tea. With this story, Daan would encourage psychedelic journeyers to confront challenging experiences: “invite your demons to tea, and see what you can learn from them”. However, he recounts an occasion on which a couple of Christian retreaters felt incredibly uncomfortable with the idea of inviting their demons to tea.
“Although I had been trained as an interfaith spiritual caregiver, I had wrongfully assumed that the prevailing clinical and therapeutic best practices, those underlying the Buddhist story, were universally applicable. The incident made me realize that they can come with ontological or theological assumptions”.

Daan Keiman, MA

Empirically verified frameworks of meaning
While discarding religious iconography and language appears as an easy solution, the distinction between belief and empirically based clinical practice is not always so straightforward. As Daan shows, the main psychotherapeutic frameworks used nowadays in psychedelic research are shaped by spiritual beliefs and practice. “If we look at ACT and other third-generation behavioral-cognitive therapies, we see that they are based on mindfulness. A lot of Buddhist insights deeply inform the ways people are encouraged to go into psychedelic experiences”. Transpersonal psychology and existential psychotherapy are other examples of how psychedelic therapy draws from traditions that have their own ontological assumptions.
Some in the psychedelic community have expressed their criticisms to Johnson’s article. “Something that a lot of people take issue with,” explains Dann, “is what comes across as yet another white man pretending that his secular psychotherapeutic perspective is the position of no-position; as if it is neutral, as if it doesn’t come with its own baggage and its own set of assumptions which are not empirically verified.” Daan acknowledges that Johnson is actually much more nuanced than how he is depicted by critics. However, he also thinks that secularizing psychedelic therapy might not be the best solution.
 
There are good reasons to be careful when introducing spiritual frameworks as meaning-making tools in integration sessions.  Yet ruling them out completely due to the lack of evidence to support them seems premature. Daan adds: “Let’s not pretend that psychotherapeutic approaches are neutral. They are deeply informed by certain assumptions. The interesting thing is that currently accepted approaches, like mindfulness-based cognitive therapy or Internal Family Systems, were not empirically verified before they were put into practice and researched. They were met with scepticism, and it took effort to research them and show their validity.”
Excluding all spiritually oriented elements from therapeutic and research protocols would only perpetuate their non-empirical status. Instead, perhaps more research should be dedicated to questions about the ideal therapeutic setting and the necessary competencies to accompany the meaning-making process of patients of diverse existential orientations. 
In regards to such questions, Dann believes that “spiritual traditions, alongside with the richness of shamanic approaches and their accompanying ontologies, might provide fruitful and wholesome insights, and could inform contemporary psychedelic-assisted psychotherapy; as long as they are presented as exactly that: spiritual narrative or practice, not ultimate truth.”

The influence of society on the psychedelic experience (Interview with Ido Hartogsohn)

In contrast to this proposal, Johnson’s article seems to “naively suggest that if we just wear a white coat and strip our protocols of anything that remotely smells like meaning, we will be fine”. However, meaning pervades every element of the therapeutic protocols, from psychometric tests to music playlists, driving the psychedelic experience in subtle ways. This is something that researchers are still struggling to deal with.
Current research about the psychological mechanisms of action of psychedelics is running into the problems of shaping people’s expectations as they prepare for a trip. Along these lines, Daan wonders “to what extent the flight instructions are not some sort of descriptive tool but actually a primer for the experience”. Yet, rather than a mere source of confusion, these feedback loops may help us better understand the interplay of drug, set and setting that determines psychedelic effects.
“We need a deeper understanding of how everything we do is endowed with meaning. Therefore, it is more useful to be transparent, reflect on the meaning of what we do and work towards a more patient-centered approach based on informed consent.”
 
From secular neutrality to interfaith positionality
Psychedelic researchers agree that therapists should empower patients to make sense of the metaphysical aspects of their experiences by themselves. “I am not against that idea,” says Daan, “but as a spiritual caregiver trained to talk about existential questions, I think you need particular competencies to discuss these issues with patients.”
Daan advocates the figure of the psychedelic chaplain, a guide who is fully equipped to help patients with the ontological shock that may be triggered by intense psychedelic experiences. In his view, “to have a psychotherapist helping you interpret those experiences from a purely secular standpoint might become very difficult and could actually harm the existential or spiritual integrity of the client.”
Instead of secularizing psychedelic therapy, Daan suggests  working within an interfaith approach that emphasizes the positionality of both therapist and patient. Deep awareness about the spiritual integrity of the patient and a clear agreement about the framework within which the therapist will guide the patient, therefore, become central in establishing trust in the therapeutic alliance. “Before you start to work with me, I am going to be honest about the fact that I am a Buddhist psychedelic chaplain. Even though I work with a client-centered interfaith approach, there are things that I am bringing into the psychedelic context which I cannot erase and which will influence your journey. If you are uncomfortable with this situation that we call “Daan”, then I might not be the right person to guide you.” 
This notion of positionality that Daan borrows from anthropology is aimed at promoting self-reflection and ensuring transparency in face of the potential ethical issues that may arise in situations where being neutral appears as a naive ideal. To Daan, this self-reflection is very much needed in psychedelic therapy given the position of power and authority that therapists and guides often hold in relation to their patients.
“It is very important that psychedelic psychotherapists are honest about the baggage that they carry in a much deeper way than just in terms of spirituality and ontology. Race, sex and gender play crucial roles in the power disparities between the guide and the person being guided. In the same way that Mathew Johnson identifies the risks of the spiritual orientations of therapists, we also need to become aware of the risks inherent to these power relations, by elucidating them, by articulating them and by reflecting on them with peers and supervisors.”
Should psychedelic therapists then keep their spiritual beliefs away from patients? Perhaps, a self-reflecting interfaith approach is better attuned to cultivate meaningful therapeutic encounters. Patients should have the last word about this.
Written by Alberto Cantizani López
Art by Anna Temczuk

Treating drug addiction with psychedelics looks promising

Although controversial only a few years ago, there is ample evidence that psychedelics can help in the fight against addictions (use disorders). Over the past decades, there have been multiple studies looking into the workings of psychedelics in the field of addiction. Multiple trials have concluded that there are indeed possibilities to develop psychedelic-assisted treatments towards treating multiple drug addictions. Below we list just a few promising areas which include LSD for alcoholism, psilocybin for smoking cessation and alcoholism, and ibogaine for opioid addiction.
Back at ICPR2012, researchers from Norway presented a meta-analysis of randomized controlled trials using lysergic acid diethylamide (LSD) for alcoholism. Researchers Krebs and Johansen had found six trials done in the 1960s and 1970s that included a total of 536 participants. The researchers concluded that “A single dose of LSD, in the context of various alcoholism treatment programs, is associated with a decrease in alcohol misuse.” The results of the meta-analysis were published in the Journal of Psychopharmacology that same year and made it to mainstream media.
Contemporary addiction research has focused on using two compounds in particular: psilocybin and ibogaine. LSD is less researched, perhaps because of stigma or the long active duration of the psychedelic effects of LSD. Ketamine and MDMA are also researched and covered in this year’s online conference. Preliminary studies suggest that these compounds may help with the treatment of drug-related disorders. However, it is still not completely clear how their mechanism of action results in the observed outcomes.
At Johns Hopkins School of Medicine, Professor Matthew Johnson conducted a study with psilocybin and tobacco smokers. Twelve of the 15 participants managed to quit tobacco smoking, and importantly: maintained their decision to quit. Although it was a small sample group, a success rate of 80% was enough to warrant studies with larger groups.

Image
Johnson, who is currently the President-Elect of the International Society for Research on Psychedelics, will give a talk at our Psychedelics in Psychiatry and Psychotherapy Symposium on the working mechanisms of psychedelics used in clinical research.

What could be the mechanism of action that helps people kick their addiction when treated with psychedelics? I an interview we did with Prof. Johnson in 2015 he stated that: “evidence suggests that there are psychological mechanisms of action at play. For example, people endorse that after the psilocybin sessions, it was easier for them to make decisions that were in their long-term best interest, and they were less likely to make decisions based on short-term, hedonistic desires.” They also seemed to feel more in control of decisions about their behavior, and Johnson says “they also reported an increase in their self-efficacy, their confidence in their ability to remain quit.”
Another area where psilocybin seems promising is in treating alcoholism. Addiction researcher Michael Bogenschutz at New York University has been interested in alcohol-related treatments and is now conducting studies using psilocybin: “I’m interested in addiction in general but for me alcohol, which is a very common, devastating addiction throughout the world, was a logical place to start. As I learned when I started investigating the topic, a considerable amount of research on the use of psychedelic treatment (mainly LSD) and alcohol had already been conducted in the late 1950s.”

Elizabeth M. Nielson, PhD, CASAC - Psychedelic.Support
At ICPR2020 Dr. Elisabeth Nielson will present the historical context and current clinical research on Psilocybin-Assisted Treatment of Alcohol Use Disorder.
In addition, at the upcoming International Symposium on Psychedelics in Psychiatry and Psychotherapy (ISPPP) there are several presentations about clinical application for psychedelics in alcoholism, including the Bristol Imperial MDMA in Alcoholism Study (BIMA) which is an open label within-subject feasibility study in 20 patients with Alcohol Use Disorder who have recently undergone detoxification. The study is conducted by Ben Sessa, MD, one of the ICPR2020 speakers, and its principal investigator is Professor David Nutt.

A less known psychedelic compared to psilocybin and MDMA is ibogaine, which is derived from the African plant Tabernanthe iboga. Ibogaine was a hot topic at this year’s World Economic Forum which included positive reports on ibogaine’s potential role as an addiction interrupter for opioid addiction.
In the Netherlands, researchers at the Radboud University have been investigating the use of ibogaine for addiction. During ICPR2016, researchers from Radboud shared some promising pre-clinical evidence for the efficacy of ibogaine in treating addiction and shared some of the challenges of conducting psychedelic research in the Netherlands.
Currently there are several clinical research projects recruiting participants for psychedelic research in the Netherlands and Europe.
Luís Fernando Tófoli, who is a Professor of Psychiatry at the Faculty of Medical Sciences of the University of Campinas, Brazil, gave a fascinating review at ICPR2016 about brain imaging studies on psychedelics and their relation to addiction studies. Reviewed results point to effects in the medial prefrontal cortex, the anterior and posterior cingulate cortex and the precuneus. Psychedelics also seem to affect limbic structures (e.g. amygdala), insula, occipital lobe and, less frequently, thalamus and they have been associated with a deactivation of the default mode network. Psychedelics have a relatively modest impact on dopaminergic circuits associated with addiction, but they affect structures implicated in cue processing and decision-making in drug-seeking behavior.
At ICPR2020, Prof. Tófoli is returning, this time discussing the role of integration in psychedelic experiences, including in the treatment of addiction with ibogaine in biomedical clinics.

What is the future of legal MDMA?

There has been a renaissance in the research of psychedelics, and much of it has been led by promising studies over the past two or three decades. Aside from the discussion of whether MDMA is a true ‘psychedelic’, it is clear that recent studies have created momentum to reconsider these substances as medication for severe mental health problems such as depression, anxiety or addiction.
MDMA’s application to trauma therapy has become one of the central priorities of psychedelic researchers. So what is the current state of knowledge and where do we stand in the regulatory process? According to MAPS-founder Rick Doblin, MDMA will be legal soon if the hard work continues. “I keep saying it’s going to be 2035”.
MDMA Treatment
Victims of war or sexual assault are prone to develop anxiety and avoidance behaviors as a result of these tragic experiences. Some of them may be diagnosed with Post-Traumatic Stress Disorder (PTSD), a condition characterized by severe feelings of fear and distress in response to trauma-related details. The increasing prevalence of PTSD is aggravated by the lack of treatment options.
Current trauma-focused psychotherapies, such as exposure and cognitive-behavioral therapy, have important problems of access for certain high-risk populations, as well as high dropout rates. In regard to efficacy, some reviews have found that up to 70% of patients retain their PTSD diagnosis after treatment.
The only two pharmaceuticals with FDA approval also seem to be inefficient for many. One third of all PTSD patients are estimated to be treatment-resistant. This diagnosis is given when several different treatments fail to improve symptoms.

MDMA trials have focused on this specific population because of strategic reasons. It is easier to get permission to test a new drug on patients for whom everything else has failed. Psilocybin trials have taken a similar approach by focusing on treatment-resistant depression or anxiety related to the end of life.
Current clinical research employs a hybrid treatment model that combines the administration of 75 to 125mg of MDMA with therapeutic support provided in preparation and integration sessions. During the drug sessions, therapists monitor the patient and adopt a non-directive approach that allows the person under the effects of MDMA to dive into the experience with minimal interruptions. This model of psychedelic-assisted psychotherapy entails a groundbreaking paradigm in psychiatry that goes beyond mere medications and talk therapy.
A long path
It has taken a while before these modern trials were set up. MDMA is an amphetamine derivative first synthesized by Merck Laboratories in 1912 and later rediscovered by chemist Sasha Shulgin in the 1970s. At the time, psycholytic therapy was being developed with LSD and psychiatrists saw a new potential tool for psychotherapy in MDMA and its empathogenic properties.
Unfortunately, the increasing popularity of “Ecstasy” in recreational contexts and the ensuing anti-drug propaganda soon led to the classification of MDMA as a Schedule 1 substance in 1986, which introduced immense obstacles to scientists investigating its medicinal application.
Ever since, the Multidisciplinary Association for Psychedelic Studies has been working for the approval of MDMA as a therapeutic treatment in mental health and to remove the immense barriers that were thrown up for the potential medication.
Although preliminary investigations by Charles Grob had successfully proved the safety of administration of MDMA to healthy subjects in the 1990s, the first MAPS-sponsored trial for PTSD conducted in Spain by José Carlos Bouso was shut down because of political pressure from the Spanish authorities.
Placebo challenges
So far, six phase-2 clinical trials have been completed, and despite the small samples and the methodological limitations, the results are very promising. The first randomized controlled trials with PTSD patients began to take place in the late 2000s, and resulted in a landmark paper from 2011 by Michael Mithoefer, Mark Wagner, Ann Mithoefer, Lisa Jerome, and Rick Doblin. It concluded that ‘the rate of clinical response was 10/12 (83%) in the active treatment group versus 2/8 (25%) in the placebo group’.
One year later, most of these patients for whom all other treatments had failed still showed a persistent and significant improvement. More importantly, the lack of serious adverse effects pointed at the safety of MDMA in a clinical context and paved the way for more trials.

Skeptics pointed at the methodological weaknesses of this first trial. They criticized the use of lactose as placebo and the difficulties to blind the effects of MDMA to patients and investigators, a common problem in psychedelic therapy trials. An attempt of replication in Switzerland by Peter Oehen which circumvented the blinding problem with an active placebo group (25mg MDMA) showed good results, but were not statistically significant.
Researchers suspected that differences in the work and style of the Swiss therapists might have been behind these suboptimal results, which raised the question of how to standardize the psychotherapeutic part of the treatment. In subsequent trials, MAPS developed an adherence rating system in order to ensure that therapists stick to the standard guidelines of their therapeutic model.
In 2018, Michael Mithoefer published the first dose-response study, which compared the efficacy of three different doses of MDMA: 30mg, 75mg and 125mg. The groups with middle and high doses showed significant remission of PTSD with respectively 86% and 58% of each group’s sample not meeting the diagnostic criteria anymore after treatment, improvements which persisted in the one year follow-up. Shortly after, a similar study by Marcela Ot’alora replicated the results with 76% of patients not meeting the diagnostic criteria for PTSD one year after the treatment.
A Path Towards Regulation
Given these promising results, the FDA accelerated the approval process of MDMA with the Breakthrough Therapy designation in 2017 and allowed the early compassionate use of MDMA-assisted psychotherapy for treatment-resistant patients in 2020.
Two ongoing multi-site phase-3 trials sponsored by MAPS are currently assessing the efficacy of MDMA in around 200 participants from the US, Canada and Israel. Recently, MAPS’ interim analysis of the first phase-3 trial suggested that their results will probably reach statistical significance, and if nothing goes wrong, MDMA could be approved for the treatment of PTSD by mid-2022.
In the meantime, more phase-2 trials are starting to take place in Europe for PTSD and other conditions such as alcoholism. With the first psychedelic substance on the verge of approval, many questions remain in the air:

All these questions will require years of additional research, which needs to be done by current and future doctors, researchers and policy makers. But the direction and ambition of all this research is clear: to turn the hard facts of well-researched trials into a regulatory model, so that MDMA will be a legal future medication to help many.