About six months ago, the Dutch minister of Health, Ernst Kuipers, wrote an official response towards the Dutch parliament after receiving a report on psychedelic-assisted therapy (PAT). This report was commissioned by the Dutch funding organisation ZonMw. It provided a first overview of the current state of affairs of PAT in the Netherlands. According to Kuipers in an earlier blog post, the ZonMw report provided “a significant contribution to the conversation about PAT and decisions about future steps.”

Kuipers exhibited a healthy dose of enthusiasm towards PAT as a potential innovative treatment for treatment-resistant psychiatric disorders. But he also recognised various challenges when moving towards the ultimate legislation of psychedelics as medicine. Kuipers was not alone in this. Indeed, four political parties of the Dutch House of parliament, in particular VVD, D66, CDA, and PvdA/GroenLinks, responded to Kuipers’ letter and raised several questions.

Psychedelics as Medicine

PvdA/GroenLinks, for example, were happy to see that the minister was positive towards future research of PAT and its ultimate implementation. In addition, PvdA/GroenLinks understood from reading Kuipers’ response that he was “encouraging university medical centres and special health care institutions to work together within a national cooperation to conduct the necessary scientific research.” Such an endeavour would allow for the collection of information in a structured and coordinated manner that could in turn evaluate the quality, efficacy, and safety of PAT. However, the party members of PvdA/GroenLinks did wonder what this “encouraging” essentially means by asking “in what way the minister is going to support this?”

In response, Kuipers announced that he will provide 1.6 million euros for future research on PAT in the Netherlands. This will be a grant proposal within the Dutch grant organisation ZonMw. Kuipers: “The program is targeted at the development of new medications and, in the event of positive results, to the registration of one or more medications. Funding will be used to set up an overarching partnership, draw up a development plan by the partnership for registering and marketing one or more medications and/or indication areas. The program will primarily be focused on carrying out clinical research.”

Hopefully, the clinical research studies will also determine the potential long-term effects of PAT. Indeed, political party VVD already raised concerns about this unknown in their response to Kuipers’ letter and wanted to know “which studies are already being conducted on the long-term effects of PAT.” Kuipers responded to this question by referring to the websites of CCMO and ClinicalTrials.gov where all scientific research is listed. In addition to this, I highly recommend the Atlas of Psychedelic Research where you can find any current study on PAT filtered by phase, topic, and psychedelic substance.

On the Taboo Against Knowing What Psychedelics Are

Now all of this is great news of course. But some parties also recognise the multitude of barriers scientists have to confront when trying to conduct clinical research on PAT. According to D66, for example, there still rests “a taboo on psychedelics” that can have “a negative effect on the potential for developing new treatments.” Not surprisingly, D66 raised the question to Kuipers “what plans the minister has to diminish this taboo?” and whether he could “present an overview of which conversations or campaigns are taking place or in what other way information is provided to combat this taboo?”

The round table discussion about PAT, which took place within the Dutch parliament on October 13^th, 2022, is one example given by D66 that provided a lot of new information and potentially led to more understanding of PAT. Kuipers agrees that “increasing the amount of knowledge can contribute to the acceptance of these new types of treatments” and adds that “it is important that in the future psychedelics are seen as medical applications, not as drugs, and that this view is shared amongst professionals, patients and the general public.” The research program within ZonMw can be a first step in diminishing the taboo on psychedelics, says Kuipers.

Kuipers continues that there are a lot of substances that are on the so-called Dutch ‘Opiumwet’ but are used as medicines. These include opioid medications for individuals struggling with pain or the use of Ritalin for ADHD. “Psychedelics are no exception in this”, says Kuipers. Yet, because psychedelic substances are illegal and on the list of the ‘Opiumwet’ remains a problem for researchers. Indeed, to do any clinical research at all, you have to receive an exemption from the Dutch government with a decision period of approximately three months. And if you manage to do this, you then must face the next hurdle at the CCMO and apply for ethical approval that can take up to one year (if you’re lucky!).

Finally, the political party CDA wondered “if research using psychedelics as medicine were promising, wouldn’t there be full commercial interest in financing?” Indeed, authors from the aforementioned ZonMw report already indicated that there are problems with the funding of psychedelic research because of the lack of commercial interest. I have asked this question myself many times and was happy to see a Dutch political party came to the same conundrum. Kuipers clear in his response and stated that “pharmaceutical companies have little incentive to focus on this market, partly because most drugs can no longer be patented. Only through chemical modifications or new methods of administration is it possible to obtain a patent, such as with Janssen’s esketamine nasal spray.”

Don’t Believe the Media Hype

Across the political spectrum, Dutch political parties raised their concerns regarding the potential self-experimentation with psychedelics due to increased media exposure. VVD, for example, highlighted that “increased media attention can lead to an increase in non-medical use. The hype that raises too high expectations regarding PAT and that people with a mental illness do not want to wait for PAT to be approved and start experimenting themselves is something that worries the members of the VVD faction.” Similarly, D66 recognises “the danger of self-experimentation with psychedelics and acknowledges this as a political signal to get psychedelics within regular healthcare as fast as possible, while simultaneously maintaining caution.” Both parties CDA and PvdA/GroenLinks shared similar concerns and acknowledge the risk of new groups of users with severe psychological issues that essentially require education, prevention, and the improvement of harm reduction measures. After all, psychedelic substances, let alone their therapeutic use, remain out of reach for a lot of patients who are in dire need of treatment.

Kuipers general response is that the ZonMw of 1.6 million euros should help mitigate these concerns, in particular regarding the urgent need to register psychedelics as a medication. In addition, Kuipers has commissioned both ‘Stichting Mainline’ and the ‘Trimbos Instituut’ to conduct an investigation that is aimed at obtaining more insight into the various (new) user groups of psychedelics and reasons for (non-medical) use. What is more, this investigation includes an evaluation of whether the current education is not already appropriate for these groups, but also to develop new (online and offline) information material about psychedelics together with prevention of risks and limitation of harm when these compounds are used. Kuipers concludes that “this investigation will be completed before the summer of 2024 and a report will be send towards the Dutch parliament.” It would be interesting to see whether the results from this investigation also shed light on the ‘imprinting’ phenomenon, where environmental influences from the past are able to shape the psychedelic experience.

In any case, the fact that there is already a lot of information available on the internet is hopeful. For example, Kuipers refers to the website of the Trimbos Instituut that has “released a factsheet [of 26 pages] about PAT that details the various mechanisms of psychedelics and the potential risks.” In addition, Kuipers mentions the website www.drugsinfo.nl which has added four pages all dedicated to the inner workings of PAT. And, last but certainly not least, the National Drugs Monitor of the Trimbos Instituut will monitor the non-medical use of psychedelics in the Netherlands. Here, Kuipers mentions in brief that “the recreational use of psychedelics is below 1% and for MDMA/ecstasy this was 3.9% in 2022.”

Building the Infrastructure of Psychedelic-Assisted Therapy on Rock ‘n Roll

Another concern was raised by both the VDD and PvdA/GroenLinks regarding the infrastructure of PAT. For example, VVD said mentions that “the minister stated [in the ZonMw report] that there is no infrastructure for PAT training yet and that he is in consultation with the Dutch Psychiatry Association (NVvP) about this.” This is a good sign, but VVD was left with some questions: “How does the minister include the NVvP in the entire process to provide training regarding PAT? When will there be more implementation? Are others involved in the training?”

The political party PvdA/GroenLinks first announced that they “are happy with the ‘Platform Psychedelica’,” which was founded to accommodate the discussion about the possible applications of PAT within the NVvP. Similar to VVD, the political party wondered “what additional steps the minister is going to take in creating an infrastructure for training for PAT as was already recommended by the authors of the ZonMw report?”

To both questions, Kuipers reiterates that “it is up to the NVvP to develop and implement training requirements for additional training in PAT in collaboration with other parties. The Dutch ministry of Health, Welfare, and Sport has an advisory role and, where necessary, facilitates with other parties. This includes the Dutch Institute of Psychologists (NIP) and patient associations.”

On the Varieties of Ketamine Formulations

There were also some questions about the atypical psychedelic ketamine. VDD, for instance, asked whether Kuipers is able to provide “an overview of the different types of ketamine and for which treatments they are and are not registered?” to which Kuipers simply referred to the website Medicines Evaluation Board (CBG/MEB) that contains all registered medications in the Netherlands.

The party of VVD agrees that “compassionate use is subject to strict rules, but also notice that oral ketamine is currently applied as off-label while a registered variant is already available.” This variant that the VVD is referring to is Spravato, which is a nasal formulation of ketamine approved for treatment-resistant depression. The off-label use of oral ketamine, however, is not yet registered, but can be used in this way “as long it meets the criteria for off-label use” says Kuipers. These criteria that ‘compassionate use’ has to meet are set up by the CBG/MEB. At this moment, Kuipers mentions that “the funding program ‘veelbelovende zorg’ subsidizes research into the (off-label) oral formulation of esketamine for the treatment of patients with severe, non-psychotic, treatment-resistant depression.”

In addition to oral esketamine, PvdA/GroenLinks were also curious about “the current status and availability of the nasal formulation of esketamine (Spravato) for patients with a severe treatment-resistant depression.” In particular, the party wanted to know “how many actual treatments there currently are with Spravato?” and whether “the contracts between healthcare providers and health insurances are well set up?” Kuipers responded by presenting the current state of affairs in the Netherlands. “Currently, there are 17 active locations centres in which nasal esketamine is provided. Kuipers expectation is that there will be 4 extra centres in the upcoming months. As of 2023, there were more than 30 healthcare providers with a contract, but within the budget only 12 of them have made an invoice. Organizing the healthcare of providing esketamine nasal spray for treatment-resistant depression takes time, because the criteria must be met in terms of facilities, staff, and participation in national research. This means that some centres have been contracted but are not yet active. A careful approach to implementation and good coordination with centres that are already operational and have thus gained experience are considered valuable.”

A First Step towards the Legislation of Psychedelic-Assisted Therapy 

As stated almost two years ago by Kuipers, the Netherlands should be at the forefront of psychedelic research. Indeed, D66 recognises that the Netherlands “is in an excellent position to play a leading role internationally in research and implementation of PAT” but is also somewhat concerned. At the same time, D66 “sees that developments are happening very quickly in other countries” and wonders whether “the Netherlands risks to walk behind other countries? What is needed to actually capitalize on that leading role?”

Kuipers confirms that on a global scale “there have indeed been many developments in the field of research, but so far PAT has not yet been accepted as a registered treatment by pharmaceutical authorities.” However, there are countries, such as Australia and Switzerland, that provide PAT on a limited scale through a form of compassionate use. Moreover, in three states of the US the use of psychedelics is regulated within a therapeutic setting. Other developments from the past year come from Canada, where the government has invested nearly 3 million dollars in clinical research of PAT involving psilocybin for the potential treatment of alcohol use disorder, treatment-resistant depression, and end-of-life distress in cancer patients.

Essentially, Kuipers agrees with D66 that “the Netherlands has an excellent starting position to play a pioneering role alongside these other countries. The Dutch mental health care system has the infrastructure for this with highly trained professionals and the high-quality amount of research that is being conducted. More investments have to be made in a coordinated approach to research and implementation.”

One week following this back and forth between Dutch politicians, minister Kuipers wrote an official letter to the chair of Dutch parliament on December 19^th. Specifically, the minister reiterated his concerns regarding the unmet medical need in a large group of patients that are currently unable to receive treatment. This is simply due to a lack of availability in effective medications for this particular group. Accordingly, Kuipers states that he “wants more control on medicine development.” This claim to responsibility and research policy is partly in response to an earlier research rapport concluding “that a drug’s expected financial return ultimately determines whether it is developed up to launch.” According to Kuipers and another study, “psychedelics are the most promising” for meeting the unmet medical needs of patients with depression, but that “pharmaceutical companies lack interest for this market because most substances cannot be patented.”

Ultimately, the ZonMw grant of 1.6 million dollars will aid Netherlands’ pioneering role and to establish a national cooperation for conducting coordinated clinical research. This will bring us one step closer to the registration of psychedelics as medicine and the implementation of PAT within general healthcare.

_{Image credit: D66.nl}

The Mystical Entropy workshop consisted of a three-day event with various academics and scholars from around the world. They sought answers to the calling question of whether we can use the concept of ‘entropy’ to characterise key ideas from mystical traditions, and how this would facilitate scientific research into mystical practices and experiences.

The Mystical Entropy workshop consisted of a three-day event that was organised by Michiel van Elk (cognitive neuroscientist at Leiden University and board member of the OPEN Foundation), Aidan Lyon (philosopher at Leiden University) and hosted by Anya Farennikova (philosopher at University at Amsterdam).  The event took place on October 12-14 at the IJ-kantine in Amsterdam and was attended by a highly interdisciplinary group of individuals coming from every corner of the world. As a result, I had the pleasure and good fortune of engaging in deep conversations with cognitive neuroscientists, physicists, computer scientists, philosophers, religious scholars of Judaism and Sufism, meditation teachers, yoga teachers, a lawyer, and to top it all off, a Buddhist monk who practices in a monastery in the Hollywood Hills.

If this was not already the perfect recipe for facilitating information-rich, and sometimes highly entropic (uncertain and disorderly) conversations, the Mystical Entropy workshop adhered to a so-called Open Space Technology (OST) methodology. Rather than using a top-down approach where the organizers choose the various topics of interest prior to an event, the OST methodology comprises a bottom-up approach in which the participants get to pick the various topics of interest and set up the agenda for the day.

Naturally, this occasioned some entropy (‘uncertainty’) in some of the participants during the opening and introduction on the first day. But I imagine this to be the case for the organisers Michiel, Aidan, and Anna in particular. Then again, the OST approach also brought with it a certain meta-vibe and essentially seemed like a perfect fit for the topics at hand. Indeed, what better way to organise and conduct a three-day workshop about entropy and mysticism – concepts that are by themselves already elusive – than to create a container in which both the setup and outcome are somewhat entropic. And all this to seek out the calling question of how we can use the concept of ‘entropy’ to characterise key ideas from mystical traditions, and how this would facilitate scientific research into mystical practices and experiences.

Origin Stories

The workshop was initiated by Aidan, Michiel, and Anya by giving an introductory talk on how this workshop came to be. Aidan was introduced to the topic of ‘entropy’ by one of his professors whilst still a student of mathematics. He became immediately enamoured by the subject, read as much as he could, and ended up bugging his professor with tons of questions until his professor gave up and grew tired of him by responding: “Aidan, this is ultimately a philosophical question!” This led Aidan to study and pursue philosophy to gain a better understanding of entropy.

Michiel, on the other hand, grew up in a very religious town near Amsterdam. As a young boy, he attended various ceremonies in church where he witnessed individuals becoming cured from the most extreme forms of diseases and how they were freed from the devil. These early experiences with the ‘ecstatic’ imbued in him a fascination with the topic of mysticism. Together with his natural curiosity, he became an academic in cognitive neuroscience to better understand these types of religious and mystical experiences.

Anya also made an encounter with the mystical at a very young age, except through something entirely different. She shared a personal story during her introduction of how she was born in Belarus when it was still part of the Soviet Union. When it declared its independence on August 25, 1991, this meant that Anya was finally able to view cable television instead of three national channels, was allowed to wear denim jeans, and could listen to a wide variety of music genres. But the memory that stuck with her the most was her first piece of bubble-gum of the so-called brand ‘Love is…’ which, after eating it for the first time, seemed to have given her a full-blown mystical experience. Fast forward to somewhere in the year 2018, all three thinkers met up due to their mutual fascination with these subjects, thereby converging the fields of philosophy and cognitive neuroscience, and the Mystical Entropy workshop was born.

The Marketplace of Open Space Technology

Anya then explained to us in more detail the setup and potential merits of OST. But before we continued, we had to get up of our chairs, touch the ceiling, then touch our toes, and roll around our shoulders for a few minutes. Only then were we thrown into an entropic state that was going to last for the upcoming three days.

As mentioned previously, OST requires input from the participants to set up the agenda for the day and to create a marketplace of ideas. This allows for the option of merging workgroups and relocating them if there seems to be a considerable overlap between topics. Another responsibility was that each workgroup ‘leader’ had to write a report on what was discussed during the session. At the end of the day, other participants could read this report and provide feedback or ask for clarification.

Naturally, there was some trepidation from all the participants following Anya’s presentation, but as the Dutch saying goes: “when one sheep crosses the dam, more will follow!” Indeed, before we knew it, the agenda for the first day was set after only 15 minutes.

^{The Mystical Entropy workshop agenda for day 1 (sessions 1 and 2) using Open Space Technology}

Humble Beginnings: embracing uncertainty, disorder, and information

To say that the three days of the Mystical Entropy workshop were engaging is definitely a huge understatement. As I already mentioned, the group that showed up at the workshop was highly interdisciplinary. Consequently, the various discussions I participated in resulted in some of the most interesting, deep, but at several times also very challenging, conversations I have had in my entire life and early academic career. Naturally, to summarize what was discussed one week following the workshop is nothing short of an insurmountable task. What follows represents a rough impression of what I experienced during these three days and the main current challenge. 

Most of the workshop sessions I attended were oriented towards the measurement of the mystical experience and, to a lesser degree, how the concept of entropy might be used to conceptualize such an extraordinary, altered state of consciousness. Topics here varied from potential tools we can use from cognitive neuroscience to better understand the mystical experience, whether (informational) entropy can be used to clarify mystical experiences of unity or ego-dissolution, the potential problems with the conceptualizations and operationalizations of the mystical experience, and novel conceptual frameworks such as Cusp Catastrophe Theory to describe the dynamics of conscious states during mystical experiences.

The workshop session hosted by Josjan Zijlmans on the second day stuck with me the most. Josjan already caught my attention a few years ago when he co-authored the paper Moving beyond Mysticism with James Sanders. This paper proposes to demystify psychedelic science and to use unambiguous secular frameworks with alternative questionnaires, as opposed to the widely used Mystical Experience Questionnaire, to predict the (psychedelic) experience of interest and potential clinical outcome(s).

This paper received a response from Joost Breeksema and Michiel van Elk in which they argue that psychedelic science should embrace the study of mystical experiences, not only because of their clinical significance, but also because these experiences have a long and rich history in religion and have been extensively studied by several religious scholars. For the interested reader, I highly recommend the journal club from the Amsterdam Psychedelic Research Association where all authors were invited to debate this question.

This session particularly grabbed me because, as it turns out, it is extremely hard to talk about concepts as the mystical experience and entropy. As a result, we risk losing our ideas in translation because we might have diametrically opposed views of what these concepts actually entail. This is in part because, as Aidan has written in his Mystical Entropy Manifesto prior to the event, the mystical experience and entropy “are notoriously difficult to define” and that even entropy itself “is a mystical notion.”

As it turns out, there are numerous types of entropy in physics that has left me with various questions for future study. What are all the kinds of entropy? Which one of these could conceptualize the mystical experience in the most parsimonious way possible? The same holds true for the mystical experience, not only after attending Josjan’s workshop session, but also following other sessions where the phenomenology (subjective experience) of the mystical experience was widely discussed and met with considerable debate. Indeed, what kind of characteristics or features are essential to the so-called mystical experience? Is there only one (perennial) mystical experience? Or is there a Buddhist-like mystical experience and a more Sufi-like mystical experience?

Some of the attendees were jokingly telling me over lunch that they even got more confused after some of the workshop sessions. And to show some epistemic humility, I can certainly say the same for myself and was lost in some of the discussions. But then again, maybe this state of uncertainty and of not knowing might just be the experience that some of us need as it potentially helps bring us back to the so-called beginner’s mind of shoshin. And maybe this could eventually lead to a better understanding of the mystical experience and entropy.

In a sense, the workshop as a whole felt like going back to the drawing board and attaining shoshin. This can be particularly important for us academics. All of us can get stuck in a rut every once in a while. We become rigid in our way of thinking. We only stay in our field of interest. Shaking up our belief systems with more entropy – uncertainty, disorder, and information – certainly changes our way of looking at things and potentially put more ‘balance’ to this belief system.

^{Lunch with all attendees of the Mystical Entropy Workshop in the IJ-kantine Amsterdam}

Memento Mori

The workshop sessions were interspersed with various experiential sessions to get us out of our heads that varied from yoga, meditation, to biofeedback. One session that stayed with me for days after the Mystical Entropy workshop took place on the first day of the workshop and was created and led by Dr. Mark Miller, a philosopher, cognitive scientist, and happiness aficionado, who is affiliated with several universities across the world, including the Centre for Consciousness and Contemplative Studies at Monash University,  the Psychology department at the University of Toronto, and the Centre for Human Nature, Artificial Intelligence and Neuroscience at Hokkaido University. From the very beginning of the Mystical Entropy workshop, Mark already caught my attention because of his highly energetic persona marked by his turbulent stride through the IJ-kantine. As soon as he proposed a session to reflect on death, a practice that intrigued me ever since reading the Stoics, I knew I had to be there.

We sat around in a circle in the main room (Sophia) with approximately twenty individuals. Mark instructed us to sit comfortably in our chairs and to close our eyes. He then posed the question: “Will I die?” This question essentially became a mantra and was repeated several times for about two minutes and followed by his answer: “Yes, you will die.” Other questions and reflections on death continued for the next ten minutes, including “When will I die?”, “How do I want people to remember me when I die?”, and “Where do I want to be if this were my last day?”

Mark instructed us to slowly open our eyes after ten minutes and silently reflect on the thoughts that came up during the meditation. He then went around the circle and asked every participant to give one word, or describe in one sentence, the most important thing to him or her. Across the board, people announced words as love, meaning, relationships, authenticity, and family. Mark has conducted these sessions all over the world and never in his life has he heard someone say: “I want to be remembered because of my kick-ass Ferrari.” Indeed, across cultures he has found that human beings are ultimately longing and striving for the same: love, meaning, a sense of purpose, family, and relationships. And I think this experience brought us closer as a group and further facilitated the sessions in the days to come.

^{Experiential sessions at the Mystical Entropy Workshop (left: biofeedback, right: meditation guided by music)}

In closing

On the final day, I talked to Aidan in the main room when everyone was rounding things off and preparing their presentation of the respective workshop session. Seeing how things came to fruition these past few days, I was eager to ask him the question of how he thought the workshop turned out, to which he responded: “I cannot believe how perfect it is!”. I can imagine the anticipation must have been very stressful and to see it turn out with such engagement from all participants must have been extremely satisfying and fulfilling.  

After an hour of presentations and further discussion, it was time to finish the Mystical Entropy workshop with drinks and good food. This was also the time for us to show our creative side and I was astounded by the talent of some participants. In just one evening, I have seen a professor of religion play the blues on piano, a cognitive neuroscientist performing four dances of ballet, a physicist reciting a self-written poem, and I got to perform in a jam session with other attendees from the event.

A second Mystical Entropy workshop has already been scheduled for next year that will have a primary focus on neuroscience. By then we will probably have tackled the current challenges at hand and come to a better understanding and definition of mystical experiences and entropy. Hopefully, the second edition will be as successful as the first and we can explore various neuroscientific frameworks to conceptualize these key concepts.

^{Jam session after dinner at the final day of the Mystical Entropy workshop}

When you enter the landscape of psychedelic-assisted therapy, there are two colloquial terms, or so-called extra-pharmacological (contextual) factors, that are deemed essential in preparation and facilitating therapeutic outcome. These are of course the ‘set’ and ‘setting’ that, respectively, broadly refer to how current-moment mindsets (expectations and intentions) and the environment are able to shape the psychedelic experience. But what about potential environmental influences from the past, a phenomenon also referred to as ‘imprinting’?

The phenomenon of imprinting is not entirely new and was recently brought to my attention during OPEN’s online panel discussion ‘Reality Check: Psychedelic Industrial Complex, Hype, Funding, and Research’ with Jane Hu, David Yaden, Josh Hardman, and Shayla Love. Somewhere halfway through the discussion, Shayla Love mentioned how the so-called ‘Brain-Reset’ mechanism of psychedelics was instantiated by the media, as one journalist picked this up by a participants’ report of how psychedelic-assisted therapy felt. It has since reverberated into the culture with many articles purporting this as an established mechanism of action of psychedelics and that in turn, according to Shayla, could influence (‘imprint’) expectations of participants in future clinical trials.

A recent study sought out to investigate whether imprinting has any kind of effects on therapeutic outcome. Accordingly, the study assessed a total of 26 previously recorded treatments sessions and phenomenological follow-up interviews from participants receiving ketamine for their treatment-resistant depression (TRD). In short, the acute experience of ketamine was significantly altered by digital media use prior to treatment and that higher levels of media exposure actually reduced the mystical/emotional qualities of subsequent psychedelic ketamine experiences. Below are summarized two typical examples of imprinting.

The first example consisted of a 28-year-old woman with TRD who reported that her ketamine experience was “hijacked” by Disney iconography. The study reports that this was influenced in particular by the observation that the participant spent up to six hours a day trading Disney pins on a social media forum prior to her treatment with ketamine. This diminished the amount of emotional and mystical content and greatly disappointed the individual. Yet, the participant did change her behavior because of this and ended up spending only one hour a day on social media and Disney pin trading. Notably, the participant posited that her insight in this kind of behavior was actually profound and lasting.

The second example concerns a 34-year-old man with TRD who summed up his ketamine experiences as “a pixelated consciousness” with videogame-like hallucinations, potentially due to the study’s observation that he played videogames for up to 16 hours a day. This was rather enjoyable for the participant, but he was also somewhat disappointed because it lacked any mystical or emotional content. The therapist and participant decided to cut down on videogame hours for the subsequent ketamine sessions and instead spent time with friends and family. Notably, this resulted in significantly different ketamine experiences that were more emotionally intense with marked feelings of grief related to past relationships. Most notably, the participant reported no more “pixelated consciousness.”

These findings corroborate and expand the extra-pharmacological model of psychedelic-assisted therapy, as imprinting seems to significantly influence the phenomenology and therapeutic outcome. The paper ends with a discussion on how imprinting is not the same as priming and suggestion, whether it is underrecognized or unimportant, if it is unique to ketamine or also applies to other psychedelics, various factors that could influence imprinting, dreams as a mechanistic model for imprinting, and how imprinting seems to be consistent with the relaxed beliefs under psychedelics (REBUS) model, and further clinical and scientific implications.

Read the full publication here!

_{Image credit: ART IS AN EXPLOSION – stock.adobe.com}

Human beings of all cultures have been seeking altered states of consciousness (ASCs) since time immemorial. As a matter of fact, it has been posited by Ronal Siegel in his magnum opus Intoxication that our need to use mind-alter substances to induce ASCs has so much force and persistence that it functions almost like our drive for food, sleep, and sex.

In recent years, the therapeutic use of ASCs has become increasingly relevant in the treatment of various psychiatric disorders, thanks in part to the psychedelic renaissance. The phenomenology of psychedelics has often been compared to other ASC methods that do not require the ingestion of mind-altering substances, such as meditation, but also hypnosis. Yet, no study to date has made a direct comparison of these when it comes to their so-called ‘neural correlates’, which generally refers to the neural representation of a subjective experience. A recent study sought to address this knowledge gap in the literature by comparing resting state functional connectivity of psilocybin, LSD, meditation, and hypnosis in order to establish the neural correlates of each ASC method.

One of the most striking results of the study is that there was no common network in all four ASC methods, despite their significant phenomenological overlap. Perhaps this is due to the prominence of ineffability that is an inextricable part of ASCs, something that ultimately hints towards the fallibility of human self-report. Furthermore, the study shows that the direct comparison between hypnosis and meditation is associated with significant differences in functional connectivity and also differ when both of them are directly compared to either psilocybin or LSD. A final finding of the study, which might come as no surprise to some of you readers, is that psilocybin and LSD show no differences in functional connectivity when directly compared to each other. However, some results also suggest that they do show distinct relationships between their respective behavioral and neural correlates. In other words, this indicates that there are some discrepancies between the neural representation and what someone experiences subjectively when comparing psilocybin and LSD.

Overall, the authors conclude that the current results extend our understanding of the underlying mechanisms of ASCs. Most importantly, it highlights the clinical importance of investigating how ASCs can be utilized most effectively in the treatment of psychiatric disorders. Even though the current study looked at the acute effects of ASCs, there is increasing evidence that these are necessary for their enduring therapeutic effects. Although some researchers like Dr. David Olson argue to the contrary, a recent study caught my eye that further corroborates this view. Specifically, it demonstrated significant antidepressant effects two weeks following psilocybin that were correlated with increases in theta power,  an effect that is similarly observed following the practice of meditation and is accompanied by feelings of peace or blissfulness and low thought content.

But I digress… Ultimately, if we want to increase the efficacy of psychedelic-assisted therapy, the authors argue that it is of vital importance to understand the relationship between the acute effects of ASCs and the enduring therapeutic response given the observation that there is substantial variability in the acute response in psychedelics and that this acute experience can be shaped according to an individual’s set, setting, and dose. Accordingly, it is important to establish the acute neural correlates of various ASC methods in healthy controls, as it could contribute to the development of clinical biomarkers and map specific mechanisms of action to either a disease area or individual patient. Finally, given the observation that psilocybin, LSD, meditation, and hypnosis engage in distinct brain circuits, they could have potential synergistic properties that further facilitate the therapeutic response.

Read the full publication here!

_{Image via Dall-E}

The chronicles of the psychedelic renaissance continue as Ernst Kuipers responds to a recent report regarding psychedelics’ potential therapeutic use. The following article provides a brief recap of the past year and summarises Kuipers’ response that could provide a glimpse of what the future of psychedelic-assisted therapy and research in the Netherlands is going to look like.

Approximately one year ago, I wrote a piece about our Dutch Health Minister Ernst Kuipers and how he stated that the Netherlands should be at the forefront of psychedelic research. This response was exciting to me, to put it mildly, and something I did not expect because of the stigma surrounding psychedelics. In short, Kuipers seemed very thrilled and up to date regarding psychedelic-assisted therapy (PAT). Specifically, Kuipers was aware of the potential of PAT for treating various treatment-resistant psychiatric disorders, while simultaneously maintaining a measured stance and acknowledging the various barriers that still persist today (e.g., lack of financial resources and therapy training).

Later that year on October 13^th, 2022, the therapeutic use of psychedelics was introduced to other members of the Dutch parliament. This happened during a roundtable discussion that was divided into four blocks and consisted of patient perspectives with PAT, the most recent scientific findings, stories from several therapists, and future perspectives for this novel treatment. At that time, I believed this was going to be a pivotal and historic moment for psychedelics and tried to watch most of the livestream whilst being in the midst of my own research that day. When tuning in, I was both relieved and elated when I heard one of the politicians saying: “I don’t know about the rest of you, but I find this extremely interesting!” Across the political spectrum, the Dutch parliament was excited about recent developments regarding PAT.

This brings us to the aforementioned report written by OPEN executive director Joost Breeksema, professor of psychiatry Robert Schoevers, and neuroscientist Rutger Boesjes. This report was presented to Kuipers on March 6^th, 2023, during a mini symposium at the University Medical Centre of Groningen (UMCG). In an earlier blog post, I wrote about how the report was aimed at further informing the Dutch Health minister regarding the current state of affairs of PAT.

And now, on June 26^th, 2023, Kuipers has written his official response towards the Dutch parliament in which he first and foremost “would like to thank ZonMw and the authors for the report that explores the opportunities, challenges, and health care innovation of psychedelic-assisted therapy for treatment-resistant psychiatric disorders.” In particular, these include the use of various psychedelics as psilocybin or ketamine for chronic depression or addiction, the use of MDMA for post-traumatic stress disorder, but also the use of LSD for cluster headache. Kuipers: “This report entails the first overview of the current state of affairs of PAT in the Netherlands and provides a significant contribution to the conversation about PAT and decisions about future steps.”

After proving a summary of the earlier report, Kuipers agrees with the authors and remains “positive about the development of PAT and its use in the treatment of severe or treatment-resistant psychiatric disorders.” He further states that “the development of psychedelics as treatment needs to be considered as the development of a medicine and should thus adhere to applicable guidelines.” Put simply, this means conducting the necessary clinical trials that are required to get a market registration for psychedelics. To pull this off requires a tremendous amount of effort and teamwork, which is why Kuipers “encourages various university medical centres and special health care facilities to engage in a national collaboration that allows for the coordination of the necessary research and gathering of information regarding quality, efficacy, and safety of PAT. I am exploring possibilities for financing a multiple year research program, potentially with a collaboration between the public and private sector.” 

Yet, this team effort also requires attenuating the various barriers associated with conducting psychedelic research. This includes the fact that psychedelics are illegal according to the so-called Dutch ‘Opiumwet’ that follows similar classifications of psychoactive substances as the United States Drug Enforcement Agency. For example, MDMA is listed as having no currently accepted medical use, despite its huge promise in the treatment of post-traumatic stress disorder when given with psychotherapeutic support. Furthermore, Kuipers states from the UMCG report that “researchers are concerned about political and societal acceptance when considering psychedelics as a potential medicine”, but also about “the increase in media attention towards PAT that can lead to non-medical use in society.” Indeed, it is important to remember that psychedelics are able to cause harm, particularly when given in an uncontrolled setting without any support. I highly recommend Jules Evans’ Challenging Psychedelic Experiences Project that focuses on psychedelic risk and harm reduction. Evans recently joined us for a live online event ‘Extended Difficulties After Trips, and What Helps People Deal with Them’ talk more about this and can be rewatched on our Circle community platform.

Another topic that is addressed in Kuipers’ letter is the compassionate use of psychedelics. This is a situation in which patients with a terminal illness or chronic disease have exhausted all current proven and available treatment options. Because these people are in dire straits, they are able to ask for early access to investigational drugs, including psychedelic substances as psilocybin or LSD. This could outweigh the expected value of routine care, palliative care, or no care at all, with the addition of assessing the expected value of PAT. Kuipers mentions that “compassionate use can be requested through the CBG (College ter Beoordeling van Geneesmiddelen)” – a Dutch independent authority that assesses the quality, effects, and safety of various medications in order to adequately inform the patient.

Although Kuipers mentions that “compassionate use is on the horizon”, he also says that “it might be untenable in the current phase, considering there is no clarity regarding market registration.” This is consistent with the UMCG report, where Breeksema and his colleagues stated that compassionate use is dependent on how PAT is going to be implemented within a therapeutic context.

Other questions according to Kuipers remain. Who is going to pay for psychedelics? Who is going to produce psychedelics? And what about paying therapists and clinicians for their treatment hours before, during, and after the dosing session? For scheduled substances, such as psychedelics, Kuipers emphasises that “there needs to be a location for the industry in the Netherlands, and this is currently not the case.”

Currently, the Dutch ministry of Health, Welfare, and Sport is frequently in contact with researchers and mental health care institutions to provide an advisory and faciliatory role. In addition, organisations as CBG can advise parties about the necessary steps towards market registration and provide advice about possibilities for compassionate use. Kuipers further mentions how other organisations, such as the Dutch ‘Care Institute’ (Zorginstituut), expertise centre FAST, and patient organisations, could further assist in conducting research and the ultimate implementation of PAT (e.g., insurance reimbursements and patient perspectives).

Kuipers mentions that this also includes the European Medicine Agency (EMA) – a decentralised agency of the European Union that is aimed at fostering scientific excellence in the evaluation and supervision of medicines, for the benefit of public and animal health. In particular, Kuipers statest that “the EMA is actively involved in the subject and encourage researchers to ask for support when facing current challenges regarding recent development of PAT.” These challenges were recently published in The Lancetand the OPEN foundation hosted an online event with some of the paper’s authors, including Gitte Moos Knudsen, Marion Haberkamp, and Lionel Thelen. A recording of this event can be rewatched on our Circle platform.

Another notable recent development is the Platform for Psychedelics that has been launched within the Dutch Society for Psychiatry (NVvP). According to Kuipers, the “NVvP is an important party as it concerns itself with the advocacy of scientific and professional interests of psychiatrists and the advancement and stimulus of education and training in psychiatry.” Indeed, this is significant for PAT because the field still lacks an infrastructure for education. It is necessary for members of the NVvP and psychedelic researchers to come together to determine the next steps in developing education for PAT.

I think it is safe to say that psychedelics have now truly hit the mainstream. At the beginning of 2023, I watched an educational video about psychedelics from NOS – one of the biggest news and media outlets in the Netherlands – and only one month later I saw John Oliver do a sketch on his HBO show Last Week Tonight talk about the potential of PAT and mentioning documentaries as Fantastic Fungi and How to Change Your Mind. I highly recommend watching all of these videos and documentaries, because they are tremendously informative, funny, and very well produced.

In closing, however, I would want to emphasise here the following in accordance with the final words of Kuipers’ letter to the Dutch parliament: “the attention for psychedelics in the media has increased in recent years”, which has “created a hype with too high expectations regarding PAT.” Most notably, Kuipers refers to the UMCG report that illustrates how this hype has created the risk of self-experimentation in individuals with a severe psychiatric disorder that do not want, or cannot afford, to wait on market registration. This is why Kuipers favours the monitoring of potential increases in self-experimentation and incidences, and to explore possibilities of providing prevention, education, and harm reduction for the people that are, unfortunately, in dire straits.

List of ongoing studies in the Netherlands

Phase I:

N,N-dimethyltryptamine (DMT)

• Smoking addiction – Center for Human Drug Research

Phase II:

5-MeO-DMT (DMT)

• Treatment-resistant depression – UMCG

MDMA

• Post-traumatic stress disorder – ARQ Nationaal Psychotrauma Centrum and Maastricht University

LSD

• Low dose LSD for ADHD – Maastricht University
• Low dose LSD for chronic cluster headaches – Radboud UMC and Leiden UMC

Ketamine

• Demoralisation in cancer – UMCG
• Acute suicidality – UMCG
• S-ketamine for pain sensitivity in patients with fibromyalgia – LUMC

Psilocybine

• Low doses of psilocybin and ketamine for cognitive and emotional dysfunction in Parkinson – Maastricht University
• Pain in fybromyalgia – Maastricht University
• Neuropathic pain – Amsterdam UMC, LUMC en Antoni van Leeuwenhoek

Phase III

Ketamine

• Assessing S-ketamine compared to electroconvulsive therapy for severe depression – UMCG, ProPersona Nijmegen, Parnassia/PsyQ Den Haag and LUMC.

NOTE. Phase I concerns the safety and determining the dosage of a compound, phase II focuses on a small group of patients that are administered one dose to determine preliminary therapeutic efficacy, and phase III consists of a large group in which patients receive both a psychedelic substance and a placebo.

On March 19 and 20, 2023, the European College of Neuropsychopharmacology (ECNP) organised the New Frontiers Meeting on Psychedelics in Nice, France. Various researchers and clinicians joined this event to talk about the current state of psychedelic-assisted psychotherapy (PAT). Here are some of the most interesting developments in the field of psychedelic research.

The ECNP New Frontiers Meeting: Psychedelics 2023 was kicked off by Gitte Moos Knudsen, the current Chair and president of the ENCP and professor of the neurology department at the Rigshospitalet and University of Copenhagen, Denmark. She laid out the program of the conference that consisted of three sub-topics, including pharmacology, clinical aspects, and clinical trials. Furthermore, Knudsen presented the Gartner Hype Cycle to the audience and asked whether there is a current hype in psychedelic research and where we might be in this Hype Cycle. Virtually everyone raised their hands which made it clear there is indeed a hype in the psychedelic field.

Knudsen’s introduction was followed up by Professor David Nutt from Imperial College London who gave an overview of the current state of psychedelics. In brief, he mentioned how psychedelics seem to show efficacy in depression and addiction and shared some of the therapeutic mechanisms of action in the brain, such as alterations in brain connectivity, reduced modularity, and increased neuroplasticity.

Most notably, Nutt shared one of the most recent brain imaging findings of N,N-Dimethyltryptamine (DMT) that were yet to be published. According to Nutt, this work is probably the “most impressive study ever done at our department” as it contains the most comprehensive view of the acute brain action of psychedelics to date. This was made possible through the use of both electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) to record brain activity before, during, and after the ingestion of intravenous DMT and comparing it to placebo in twenty healthy individuals. In general, the results of the now published study demonstrate that DMT is able to induce network disintegration and desegregation, decreases in alpha power, increases in entropy, altered traveling waves, and global functional connectivity. In other words, a lot is happening during the DMT-experience, and this naturally reflects the peculiar and extraordinary experiences that individuals generally report.

In the evening of March 20^th, directly after the ECNP conference, the results of the study were published in The Guardian reporting how the recordings of DMT reveal a “profound impact across the brain.” One can safely say that this is a clear testament of the hype of psychedelic research and how the media wants to pick up on this latest news.

Nutt further showed yet to be published results from another neuroimaging study that is based on the well-known psilocybin versus escitalopram trial. The team already demonstrated psilocybin-specific effects in the brain last year, such as increases in global integration and decreases in modularity. And now they found more differences between the two substances, namely that escitalopram resulted in a blunted response towards emotional faces. This finding was not demonstrated in the psilocybin condition of the study and further adds to the view that antidepressants seem to blunt people’s emotions.

Finally, Nutt notified the audience of some future policy decisions. This included the statement that US president Biden will make psilocybin and MDMA legal in the next two years and that Australia will reschedule both substances by July 2023.

Animal research: psychoplastogens and affective bias tests

Another prominent subject that has recently entered the field of psychedelic research is the therapeutic use of so-called psychoplastogens. Psychoplastogens refer to a class of substances that are able to rapidly promote neuroplasticity without any hallucinogenic effects. This presentation was given by David Olsen, an associate professor of chemistry, biochemistry and molecular medicine at the University of California, Davis. Olsen is also the co-founder and Chief Innovation Officer of Delix Therapeutics, a company that focuses on the development of psychoplastogens.

As mentioned briefly, psychoplastogens are aimed rapidly promoting neuroplasticity. Olsen mentioned during his presentation that this happens through “transforming the structure of the neuron.” Psychoplastogens establish this transformation in particular through “targeting dendritic spine density and increasing both their growth and complexity.” According to Olsen, a lot of neuropsychiatric disorders are due to a lack of dendritic spine density, hence the recent development of psychoplastogens.

One of the primary psychoplastogen candidates under development is tabernanthalog. This is a novel compound that is structurally similar to the psychedelic drug ibogaine. One study published in Nature in 2020 demonstrated that tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects in rodents. What seems to be very promising is that all this was accomplished without any of the hallucinogenic effects generally observed following the use of ibogaine. Another more recent study found that only a single dose of tabernanthalog was able to promote the regrowth of neuronal connections and restoring functional neural circuits in the brain disrupted by unpredictable stress. This increase in neuroplasticity was accompanied by a correction in behavioural deficits, including anxiety and inflexibility.

But how did the researchers know that the rodents were actually not hallucinating? This was established by using the so-called head-twitch response, which is suggested to be a rodent behavioural proxy for hallucinations induced by 5-HT_2A agonists. But I always wondered: How do we really know? Is the head-twitch response truly representative of hallucinogenic effects? Not surprisingly, one of the audience members asked during a discussion session what actually occurs in rodents during the head-twitch response. As it turns out, when you compare rodents who received 5-MeO-DMT to those who receive tabernanthalog, the former will show a robust head-twitch response, whereas the latter will not.

The discussion continued during dinner on day one with some other attendees and someone hypothesized that rodents not only see through their eyes, but through their whiskers. This sounded very fascinating and, as it turns out, the whiskers of rodents consist of sensory nerves that connect to well-defined structures in the cortex. Indeed, much like humans that use their fingers to navigate the world around, rodents use their whiskers to map out their surroundings and in turn build a 3D picture of the world.

Nevertheless, there are still many difficulties in translating subjective measures from humans to animals, particularly when doing research on depression-like behaviour. This was particularly signified by speaker Emma Robinson, professor of psychopharmacology at the University of Bristol. Nex to the head-twitch response, Robinson presented many other animal testing paradigms, particularly the sucrose preference test, forced swim test, and the novelty seeking test, which are used to assess depression-like behaviour in rodents. She stated that the use of any of these paradigms is suspect to lots of false-positives or false-negatives.

Because of the problems with current animal assays, Robinson and her team used the affective bias test (ABT) as it is suggested to have a better translational validity to humans. Within this assay, animals are trained for a week and have to learn to choose between two options (one positive, one negative) that will in turn reflect a positive or negative bias. It was developed to investigate the hypothesis that the cognitive processes associated with reward-related learning and memory may be modified by affective states. Robinson further explained that this is based on Aaron Beck’s cognitive triad model of depression, a cognitive framework that is often used to account for the negative views and dysfunctional thoughts observed in depression. The research that she presented is not yet published but revealed that one dose of psilocybin or ketamine is able to “completely attenuate the negative bias in rodents.” Translated to humans, this indicates that either psilocybin or ketamine might be able to help individuals with depression mitigate their dysfunctional and negative thoughts. But most importantly, it provides a therapeutic window and opportunity to develop a more realistic view about oneself, the world, and the future.

Drug-Drug Interactions to Increase Therapeutic Efficacy and Improve Harm Reduction

Robinson was followed up by professor of clinical pharmacology and internal medicine, Matthias Liechti, from the University of Basel in Switzerland. Liechti’s presentation was particularly mind-opening to me as he discussed some of the drug-drug interaction effects between psychedelics and other substances. For instance, when individuals with depression receive pre-treatment with the antidepressant escitalopram and then take psilocybin, there were less signs of anxiety and adverse cardiovascular effects. The most striking finding was that this interaction did not alter the psychedelic effects following the ingestion of psilocybin at all. Although this study was quite small with 27 participants and the daily pre-treatment of escitalopram only consisted of 7 days, this finding can be a huge implication for harm reduction in the field of psychedelic research.

Something else that Liechti presented came from an older study that was published in 2015. This study demonstrated that the co-administration of bupropion significantly increased plasma MDMA concentrations and, as a result, prolonged the positive mood effects of MDMA. But maybe even more important, this is another drug-drug interaction that can be used to improve harm reduction during a dosing session due to bupropion’s ability to significantly reduce the heart rate response to MDMA. Together, this indicates that using MDMA with bupropion can enhance mood effects while also lower cardiac stimulation.

Another drug that was mentioned during Liechti’ presentation was ketanserin. Ketanserin has been used in the past to demonstrate that psychedelics primarily target the 5-HT_2A receptor. Indeed, when this drug is taken prior to LSD, ketanserin is able to completely attenuate the subjective effects. But a recent study has now also demonstrated its use for the reversal of the acute response to LSD. Specifically, ketanserin was able to significantly reduce the duration of LSD’s subjective effects from 8.5 hours to 3.5 hours and was able to reduce adverse cardiovascular effects. As such, ketanserin can be “effectively used as a planned or rescue option to shorten and attenuate the LSD experience in humans in research and LSD-assisted therapy.” 

The Neurobiology of Psychedelics and Inter-Individual Heterogeneity

The second day was opened by Katrin Preller, a junior Group Leader at the University of Zurich, and a visiting Assistant Professor at Yale University. She talked about numerous subjects, including the neurobiology of psychedelics, the acute modulation of brain connectivity through psychedelics, and the four current network-level models of psychedelic action (for a full explanation of these models, please continue reading here).

Preller pointed out during her talk that virtually everything we know so far about psychedelics and their effects on the brain is based on averages of a group. This is why she asked the audience “what about inter-individual heterogeneity?” In other words, what about the differences between individuals when we compare them before, during, or after the psychedelic experience? Indeed, not everyone’s brain is exactly the same at the start of a clinical trial and it is something we should consider when evaluating the therapeutic effects of psychedelics. This conundrum led Preller to hypothesize the following, namely that “baseline connectivity is predictive of the acute effects and determines how someone responds to a psychedelic.” This hypothesis is explored further in upcoming papers that are yet to be published.

As a clinical neuropsychologist and someone who conducts neuroimaging research myself, I became very interested in this hypothesis and approached Preller during one of the coffee breaks to ask her how this brain connectivity would look like. She was not able to answer this question in detail because as the research stands, it has not been explored in full yet. I continued to ask whether such connectivity could be used as a marker to determine the dosage of a psychedelic or maybe even the type of therapeutic framework. We know, for example, that high connectivity in the Default Mode Network is associated with a high degree of rumination – one of the salient and important features of in major depressive disorder. Maybe this could in turn indicate the dosage amount and possibly even determine the choice of a specific therapeutic framework, such as Acceptance and Commitment Therapy targeted at increasing psychological flexibility. She partly agreed and reflected that it is particularly important to get a better understanding of the synergistic effects of both psychedelics and therapy that in turn optimize therapeutic outcome. But how brain connectivity can be used for this remains to be explored because we simply need more studies. Similar to how she concluded her presentation, we need to learn more about the brain so we can optimize PAT and prevent cost and frustration with patients.

The Design of Clinical Trials: a European Regulatory Perspective and Music

Nearing the end of the conference we were informed about the challenges regarding the design of clinical trials by Gerhard Gründer, Professor of Psychiatry and Chair of Department of Molecular Neuroimaging at Central Institute of Mental Health, Mannheim. As the research stands today, we have small sample sizes to fails to account for sufficient statistical power, there is a lack of control and difficulty with blinding, and an expectation bias with nocebo effects. These challenges are troublesome, but can be overcome when we conduct more research. Gründer also shared some e-mail messages from participants in order to show that the therapeutic alliance is the most important factor for efficacy and that we should take this into account when conducting trials. 

To help establish the rigorousness of clinical trials with psychedelics, ECNP invited speaker Marion Haberkamp, a current core member of the CNS Working Party (CNSWP) at the European Medicines Agency (EMA), Amsterdam, and a long-time member and now expert of the Scientific Advice Working Party (SAWP). When it comes to psychedelic research, Haberkamp told the audience that “the findings are both intriguing and sobering” but that “we need longer and more trials.”  Accordingly, Haberkamp talked about European regulatory guidelines and challenges that were recently published in the Lancet. As the age-old adage goes in academia, the authors of this paper posit that more rigorous research is needed, but not without giving any specific recommendations. For instance, they added that it is important to reconsider double blinding in clinical trials and the roles of both positive and negative expectancy created during preparatory sessions. Other points include the need to compare psychedelics with psychotherapy, further establish the safety profile of psychedelics, and continue to assess potential drug-drug interactions.

To realise all this, Haberkamp told the audience that there is direct help from the European regulatory office. For instance, researchers are able to come to the SAWP for qualification procedures. Moreover, there are already EMA guidelines for setting up clinical trials for major depressive disorder, substance use disorder, and anxiety. Haberkamp also announced that such guidelines will be available for psychedelics by the summer of 2023.

Patient Perspectives

I want to finale bring attention to Tadeusz Hawrot from PAREA (Psychedelics Access and Research European Alliance). Hawrot is doing a tremendous job in bringing attention to patients’ perspectives, because according to him it is “the patients who are the experts and the most we can learn from.” And this message particularly hit home through the testimony of Dave Pounds, a 59-year-old patient who has been suffering from post-traumatic stress disorder (PTSD) for almost his entire life. A short summary of his story is described down below.

Dave explained to the audience that when he was just a young little boy, he witnessed his mother being raped and murdered at their home. This horrific experience led to the development of recurrent panic attacks in his teenage years and Dave was ultimately diagnosed with PTSD. He tried several types of treatment and an exorbitant amount of different drugs in order to get better, but nothing seemed to work. Even worse, the drugs only seemed to blunt his feelings. A few years ago, he discovered the work of Ben Sessa while Googling on the internet and read about the benefits of MDMA-assisted psychotherapy. He decided to try it out and told the audience about his 1^st experience with MDMA. Dave mentioned first of all how this was all very lucid and completely sober. While on MDMA, he returned to his own bedroom at 12 years old, frozen with fear, knowing what had just happened downstairs. The perpetrator came to his room upstairs, but whilst under the influence of MDMA he was not frightened anymore. His mom was also present in the bedroom, while Dave talked to the perpetrator about how he is going to be punished for what he has done. The most striking part of this story is how his mom turned to the perpetrator, hugged him, and wished him well. This left Dave completely astonished, but it gave him the feeling and conviction that he was able to continue with his life, possibly through the act of forgiveness. Dave further stated that he had a long afterglow while in the hospital and never felt unsafe during his experience. What is more, Dave has developed a so-called MDMA mindset that he can access at will at any time during the day. This has finally brought him warmth and calmness after decades. Dave stated that “it is the best treatment I have had in almost 40 years.” But he is also “frustrated by the lack of governmental acceptance and approval”, as both he, and many others suffering from PTSD, have improved so dramatically after MDMA-assisted psychotherapy. Dave concluded his testimony by saying that stating that “this could be the most profound transformation in healthcare.” There are many profound stories out there like Dave’s that almost seem too good to be true. Right after this testimony, the audience was confronted with the dark side of psychedelics. 

Jules Evans, an academic philosopher and director of Challenging Psychedelic Experiences Project, is aware of the ongoing psychedelic renaissance and many benefits associated with it, but he also acknowledges the various difficulties and challenges associated with psychedelics. This is based on his own personal experience and research with psychedelics. For instance, Evans had his own bad trip at 18 years and developed PTSD and social anxiety after taking LSD with some of his friends. Fortunately, Evans got better after receiving cognitive-behavioural therapy. Evans further gave notice of a bigger survey (n = 10,836) conducted by ICEERS that collected data from more than 50 countries to assess the adverse events following the use of ayahuasca. This survey showed that there is a high rate of adverse physical effects, primarily vomiting (69.9%), and adverse mental health effects (55.9%) in the weeks or months following consumption. Yet, the authors of this paper also concluded that these experiences “are not generally severe, and most ayahuasca ceremony attendees continue to attend ceremonies, suggesting they perceive the benefits as outweighing any adverse effects.” More recently, Evans has conducted an interview study with 30 individuals after a psilocybin truffle retreat in the Netherlands and was able to show that 30% of individuals experienced challenging experiences.

Our very own Joost Breeksema also acknowledges in a recent review of 44 articles that psychedelics are associated with adverse events and that they are probably underreported due to a lack of systematic assessment and sample selection. Yet, this review also stated that challenging experiences can sometimes be therapeutically meaningful and that we should focus on “disentangling truly adverse events from potentially beneficial effects in order to improve our understanding of psychedelic treatments.”

Moving Forward

The amount of knowledge gaps discussed during the conference are manyfold. One message seemed to reverberate through the two days of the ENCP conference – and that is we simply need more research. We need larger studies with more participants and longer follow-ups. Besides this, I went over and compared all my notes from the conference and was able to distil the most prominent knowledge gaps consistent among both speakers and attendees. Here are the three key knowledge that can help move the psychedelic research forward in the upcoming years.

First and foremost, there is the question whether subjective effects are truly responsible for the therapeutic efficacy of psychedelics. Novel psychoplastogens as tabernanthalog developed by David Olsen seem to negate this view. However, the work that has been done so far is based entirely on animal research paradigms, which Emma Robinson pointed out lacks translational validity in humans. It would be interesting to see Olsen and Robinson pair up in order to assess whether the findings still hold up when rodents receive the non-hallucinogenic compound tabernanthalog and are put to the ‘affective bias test’.

Second, our understanding of the neurobiology of psychedelics remains somewhat underdeveloped. Katrin Preller signified this during her talk by pointing out the degree of inter-individual heterogeneity. To reconcile this, we simply need to conduct more studies that are longer and more complex. The multimodal brain imaging study conducted by Imperial College London that assessed the effects of psychedelics before, during, and after a DMT experience using both EEG and fMRI serves as a perfect example of such a study. And we need lots of it.

Third, the investigation of drug-drug interactions, be it the antidepressant escitalopram, bupropion, or ketanserin, show their utility for potential harm reduction and how through pharmacological interaction we could improve psychedelic therapy and outcome. This could have huge implications for how we conduct psychedelic therapy 

The Hype is Real

After the ECNP conference, I can confidently say that “the hype is real” in the field of psychedelic research. Even though the legendary hip-hop group Public Enemy stated that we should not believe the hype, I have garnered only more hype in the form of inspiration, enthusiasm, and realistic optimism. The future for psychedelic research looks promising with lots of different topics to explore and it is truly great that European regulatory committees as the SAWP are involved to help establish rigorous and robust scientific research that will only affirm the validity and credibility of psychedelic-assisted psychotherapy. And we are very fortunate that all this is accompanied by a healthy dose of scepticism by the likes of individuals as Jules Evans. Ultimately, there is enough balance of both yin and yang that can help move the field forward and I am proud to be a part of it.

There were other speakers that I did not mention as this was beyond the scope of this blog post. Despite this, I wanted to clarify here that their talks were greatly appreciated during the conference and have listed their names and credentials down below.

• David E. Nichols, Adjunct Professor at the University of North Carolina, Chapel Hill, NC, is a Distinguished Professor Emeritus at the Purdue University College of Pharmacy. Nichols talked about the basic pharmacology of psychedelics.
• Tomas Palenicek, head of the Psychedelic Research Centre at National Institute of Mental Health, Czech Republic. Palenicek talked about how music genres like psytrance and classic music seem to show the most benefit during psychedelic therapy.
• Jan Raemakers, Professor of Psychopharmacology and Behavioral Toxicology at Maastricht University. Raemakers talked about the feasibility of 5-MeO-DMT in healthy volunteers and individuals with treatment-resistant depression.
• David Erritzoe, Clinical Senior Lecturer and Consultant Psychiatrist at Imperial College London and in CNWL Mental Health NHS Foundation Trust. Erritzoe talked about psilocybin therapy for depression.
• Drummond McCulloch is a PhD who studies the effects of psychedelic drugs on the brain using PET and MR imaging at the Neurobiology Research Unit in Copenhagen. His talk included qualitative data analyses of a clinical trial showing how individuals come more connected to their self, others, and the environment.
• Jaskaran B. Singh, Psychiatry Franchise head at Neurocrine Biosciences. His talk consisted of Industry aspects, precompetitive questions, experience from a related area (esketamine).
• Tiffany Farchione, Director of the Division of Psychiatry in the Office of Neuroscience at FDA. Tiffany’s talk includes regulatory perspectives of the Food and Drug Administration.