Ann Shulgin, the wife of renowned chemist genius Alexander “Sasha” Shulgin, passed away at age 91 on July 9. Both were extraordinary human beings and pioneers in the field of psychedelic research, particularly due to their significant contribution in the development and therapeutic use of (novel) psychedelic compounds. To honor both, we gladly share some of her history and both their legacy.
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Laura Ann Gotlieb was born in Wellington, New Zealand on March 22, 1931, and shortly thereafter lived an extraordinary life, spending her time in various places around the world, including Italy, Cuba, Canada, and finally the Bay Area in the US when the Beatnik generation was in full swing. She got married, and divorced, three times and then met her fourth husband, Sasha Shulgin, in the Fall of 1978. After three years of spending time together, they got married in Sasha’s backyard during a surprise ceremony by an official of the Drug Enforcement Administration. Yes, the DEA.
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Ann used to work as a medical transcriber in San Francisco and probably became familiar with Jungian psychology through her third husband who was a Jungian psychiatrist. It was only later after marrying Sasha that she got involved in the development of novel psychedelic compounds. During this period, she started practicing psychedelic-assisted therapy in conjunction with MDMA or 2C-B at a time when these substances were still legal. She became a strong adherent of Jungian psychoanalysis and believed that psychedelics have huge potential for self-actualization when used within such a framework.
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The development and various discoveries of other psychedelics together led to the authoring of two books: PIHKAL: A Chemical Love Story and TIHKAL: The Continuation. Respectively, these titles are acronyms for “Phenethylamines/Tryptamines I Have Known and Loved.” Partly fictional autobiography and partly considered “pretty much cookbooks on how to make illegal drugs” by the DEA, both Ann and Sasha were filled with passion and courage to describe no more than over 179 different psychedelic compounds – all with the main goal of releasing information about psychedelic compounds and its therapeutic properties to the public. Psychedelics, they both believed, were there as valuable tools for human beings to explore and self-actualize. Ann briefly appears on a recent episode of Hamilton’s pharmacopeia,where we see that she continued to live in the house that contains the original lab of Sasha.
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We are forever grateful for their contribution to the development and therapeutic use of (novel) psychedelic compounds and aim to continue their legacy.
Joost Breeksema is the director of the OPEN Foundation and one of the main initiators of the Interdisciplinary Conference on Psychedelic Research. ICPR 2022 will be held in Haarlem from 23-27 Sept
As the director of the OPEN Foundation – founded in 2006 to advance the scientific research of psychedelics – Joost Breeksema has usually found himself being one of the main promotors of psychiatric research into psychedelics and therapies. That has changed, he says: “I find myself in a position of being somebody promoting more caution”.
“I think I still think that psychedelics have huge potential,” Breeksema says, “but I think it’s good to counterbalance this message a little bit and to have a proper balance between hype and hope.”
The OPEN director made his statement during the launch of PAREA, the Psychedelic Access And Research European Alliance, an association of European foundations and institutions advancing holistic and professional psychedelic research and therapy.
Breeksema commented in light of the recent psychedelic renaissance, which has brought renewed attention to the psychedelic field. Strong research results have shown the real efficacy of psychedelic therapy, but this has also spawned a world in which investment is luring, and potential risks of psychedelic therapy might be obscured.
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What the right balance is between hope and hype around psychedelic therapy, needs to be discussed, Breeksema says, because the need is dire: “There are many desperate patients out there. Between a quarter and a third of patients with mental disorders do not respond to conventional treatments. So there is a huge need for better and more effective treatments. But it’s also, I think, very important to remember that these are not magic bullets and there are interests.”
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Professional field
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The mix of patients with severe traumas and big expectations, the potential intenseness of the psychedelic experience, and the history of a black market involvement in the supply of many substances, make the need for safe, professional treatment a necessity: “When you ask patients… it’s hard work. People have challenging experiences, and these are vulnerable patients for the most part. These experiences can be powerful but also potentially destabilizing.”
“These are not typical pharmaceutical drugs: It’s the experience that’s central, and that means people guiding patients through those experiences need to be properly trained. You need to be a mental health professional, but you do also need additional training.”
“We told people that it was in the name of the Holy Spirit, the Father and the Son, but in reality it is in the name of the Sun, the Moon and the Tiger…”
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While the potential benefits of psychedelic plant medicines to society still remain largely unrealised, contemporary psychedelic studies risk replicating harmful colonial practices within the territories and communities in which the use of psychedelic plants originate.
After decades of prohibition, the so-called “psychedelic renaissance” is undertaking a state-of-the-art exploration of the psychology, neurology and medical approaches associated with the effects and benefits of psychedelics. The field runs the risk, however, of privileging the voices of mainstream western male researchers over those of the indigenous practitioners whose ancestral knowledge of psychedelics roots back to their origins (George et al, 2020).
A decolonial approach is essential to the success of the current psychedelic renaissance, as failing to recognize indigenous perspectives as equally valuable to the discussion in the appropriate use of these substances only contributes to deepening the colonial wound within which usage of the plants is interwoven. As academia reconsiders previously taboo subjects (such as mind-altering substances), it has the duty to reconsider also the re-enactment of colonial epistemicide (the killing off of existing systems of knowledge), and give indigenous expertise the space it deserves in scientific research.
The very old relationship between humanity and the ritual alteration of consciousness is, in indigenous communities, deeply linked to systems of traditional medicine. Nevertheless, in the West, practices associated with mind-altering substances have faced decades of strong political opposition and, as the renaissance unfolds, there are other, more subtle threats being held at bay, specifically the peril inherent in silencing other voices because of their culturally diverse backgrounds.
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In the upcoming ICPR 2024, leading experts and cutting-edge research around Ayahuasca will be presented.
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Ayahuasca’s history and its critical entanglement with colonization:
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Ayahuasca, or yagé, is a traditional brew from the Amazon rainforest that contains the classic psychedelic compound DMT. It has a long history of use by indigenous peoples in the Amazon basin, where it is mainly used for ritual and healing purposes, usually in ceremonial settings led by a shaman or curandero.
Ayahuasca is a particularly complex substance that relies on two intersecting components to deliver its psychedelic effects. Psychotria viridis, or chacruna, is a shrub, the leaves of which contain the DMT. Banisteriopsis caapi is a vine that contains monoamine oxidase (MAO) inhibitors, which prevent MAO enzymes in the stomach from breaking down the DMT as they’d normally do, thus allowing the body to actively absorb it when it is consumed orally. Taking into account the improbability of discovering the function of this particular combination of a shrub and a vine amongst the the tens of thousands of different plant species in the Amazon, along with the preparatory process needed to coax out its psychoactive properties, ayahuasca can be considered an invention, a piece of technology developed by the Amazonian people.
The indigenous people of the Amazon relate to their surrounding environment in a way that lends itself to developing a great body of ethnobotanical knowledge. Much of the knowledge that has been produced by indigenous people has, however, been the subject of appropriation and biopiracy, as the history of the rainforest cannot be grasped separately from the history of the colonization of the Americas.
One can go back to Western explorers and botanists to trace historically how ayahuasca came to be known outside the jungle, Richard Spruce and Richard Evans Schultes, for instance, were some of the first outsiders to report on indigenous plant medicines. But, by telling and re-telling the story in such a way, a colonial version of history is reinforced where indigenous peoples and their knowledge are passively discovered by Western institutions, their own contribution, skill, and subjectivity neglected, minimized, or reduced to naturalistic fact.
The history of the Amazon has been shaped by the way that the Western European imagination has interacted with this territory: from the mythic quests to find rivers of gold in the 16th century as the Spanish conquistadors mapped the Amazon river in the search for El Dorado, to the rubber barons of the 20th century who exploited and enslaved hundreds of thousands of indigenous people as they strove to realize enormous profits. The Amazon is a territory that has been perceived as a well of treasures to be extracted and appropriated.
Today’s deforestation crisis, related to the extraction of precious timber and the clearing of trees for cattle, are an inheritance of old relationships with this land that still conceives of the Amazon as an uninhabited space full of natural wealth and resources. The rainforest has been historically included in the world’s economy only in terms of exploitation, and indigenous communities as well as their knowledge have been objectified in the same way as their land.
Ayahuasca, curiously, was used during colonial times as a way of resisting and contesting the settler invasion. As the conquistador’s culture demonized indigenous ritual and traditional medicine, ayahuasca was used as a way of exercising and preserving indigenous identity, and was perceived as a repository of cultural memory for the peoples of the Amazon (Leyva, 1991).
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At ICPR 2020, Olivia Marcus, David Dupuis, Bia Labate and Daniela Peluso discussed the globlisation of ayahuasca
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Other versions of history; Ayahuasca/Yagé and its traditional users:
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To trace historically the movement of ayahuasca and other plant medicines one need not rely entirely on the Western explorers and botanists who explored the Amazon and taxonomized its species. Ayahuasca traveled outside of the Amazon via old shamanic networks that for centuries wove an exchange of knowledge and ritual technologies (Pinzón et al., 2004). For instance, the Putumayo department, located in southwest Colombia, is divided into three sub regions: The Upper Putumayo (Andes mountain range), Middle Putumayo (Amazon foothills) and Lower Putumayo (Amazon basin). The Sibundoy Valley which is famous for being home of prominent ayahuasca shamans in Colombia, is located in the Upper Putumayo, a geographical node between the Andes and the Amazon. People who inhabit the area are both settlers and indigenous people who belong to two ethnic groups, the Inga and the Kamentsá.
Relations – including shamanic ones – have existed for centuries between the Upper Putumayo (Andes) and the Lower Putumayo (Amazon). The Cofán, Siona and Coreguajes, who are known to be powerful shamans, live at lower elevations where rainforest vegetation flourishes. As ayahuasca cannot grow outside of the tropical forest, shamans from the Upper Putumayo have long traveled down to acquire the brew and, in doing so, maintained a cross-pollinating network that exchanges plants, ritual and healing technologies, and cosmological knowledge (Pinzón et al., 2004).
In their travels to the Amazon basin, Ingas from the Upper Putumayo learnt the uses and powers of shamanic plants and engaged in shamanic apprenticeships (Pinzón et al., 2004) with the help of shamans from this area. They then transported plants and other ritual devices, including ayahuasca, from the low tropical forest to Sibundoy. The memory of the botanical relationship between shamans was retained in their respective gardens, disseminating and preserving thus the interchange of knowledge between the Amazon and the Andes.
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ICPR 2024 is in less than 2 months, get your tickets now!
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Such movement helped inform the transformation of indigenous practices which came into contact with Catholic missionaries and the general mestizo culture of the rest of the Colombian territory. As we can read in the next excerpt from an interview with a shaman from the Sibundoy Valley:
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When I was born, the first thing they gave me was three drops of yagé (ayahuasca). We told people that it was in the name of the Holy Spirit, the Father and the Son, but in reality it is in the name of the Sun, the Moon and the Tiger. That’s how my blood began to be painted.” (Pinzón et al. 146 )
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As the previous passage shows, the ritual use of ayahuasca in this area was influenced by the dominant Catholic religion, while at the same time acting as a mechanism to contest and resist the colonial apparatus. The previous statement beautifully depicts how indigenous ritual practices were disguised using catholic motifs as a way to preserve silently their identity: Giving three drops of ayahuasca in the name of the Father, the Son and the Holy Spirit, to conceal it was really given in the name of the Sun, the Moon and the Tiger.
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“…Two years later Eliseo was back again, by bus all the way across the country to dip once more into what he saw as the Indian well of magical power” – (Taussig, 1986. p 435)
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With this sentence Michael Taussig begins chapter 27 of his book “Shamanism, Colonialism and the Wild Man” (1986) where, “The Indian well of magical power,” was, of course, the Amazon. Since the very first stages of colonization, the Amazon was a screen upon which European minds could project fantastical mirages of imaginary geographies populated by noble, primitive, and superstitious savages. The picture of an ‘Indian well of magical power’ is a reflection of this. A well of vast and mysterious treasures, gold, rubber, magic, and endless resources, where indigenous communities were perceived through a lens of intellectual inferiority. The Amazon consequently epitomizes and condenses several European fantasies surrounding a mysterious, irrational and exotic Other.
What Taussig was looking for in that ‘Indian well of magical power’ was ayahuasca shamanism, where the otherness of indigenous knowledge is capable of healing the maladies of the West. It is precisely the same phenomenon seen when the renowned writer William Burroughs went on a journey to find ayahuasca in Colombia, thinking that it might be his ‘final fix’ (Fotiou, 2019).
The same trope is seen with contemporary ayahuasca tourism, where huge numbers of people from all over the world (though predominantly European and American) travel to the Amazon in search of healing through the exotic otherness of ayahuasca (Losonczy & Mesturini, 2010) (Caicedo, 2009). The contemporary medical approaches to ayahuasca and other psychedelic plant medicines follow the same lines, wherein ayahuasca is being researched for its potential to treat some of the most pervasive illnesses of our time, such as depression, anxiety, and addiction (Fotiou 18)(Frecska et al.) (Palhano-Fontes et al.)(Richards) (Watts et al.) (Roseman et al.).
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An interdisciplinary future:
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As psychedelic plant medicines re-enter Western culture, researchers in this field must be aware of the colonial history behind these plants and the communities from which they come to avoid perpetuating the same type of intellectual violence that underlies the old notion of the “noble savage” and current practices of biopiracy. As we enter a globalized society, it will be critical to give regard to knowledge that comes from different cultural and ethnic sources, bestowing upon them equal validity in the discussion of the adequate use of these substances. Mainstream psychedelic research will need to encourage and actively include researchers from diverse ethnic backgrounds, as a diversity of voices and perspectives can only contribute to the advancement of science.
Besides giving credit to indigenous knowledge (which kept this technology alive for at least the past millennium) it is necessary to recognize the contribution of people of color, women, and researchers from Latin American in the development of psychedelic research, as well as to create spaces within which their perspectives can be heard and included.
Understanding how to use these substances will, in the end, require an interdisciplinary effort. The cutting-edge research being performed on psychedelics in the fields of neurobiology and psychology will see its most fruitful results by working hand-in-hand with the humanities (anthropology, decolonial studies, religious studies, philosophy, etc.) to avoid the pitfalls inherent in the epistemicide of non-western voices. The task at hand for the humanities is to reflect on the body-politics of knowledge, help give voice to traditional and indigenous ethno-medicine systems, and create the foundation for a renaissance free from harmful colonial appropriation and silencing.
In conclusion, ayahuasca has a lot to offer the world, as current scientific studies continue to prove its therapeutic potential. It, along with other psychedelic plant medicines, have enormous possibilities in the ongoing fight to alleviate psychological and spiritual suffering. The real question, then, is what can we give back, to the Amazon, to the people that inhabit it, to the preservation of their systems of knowledge, to their worldview and culture, to the most diverse ecosystem of the Earth?
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What can we give back?
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References:
1. Caicedo, Alhena. Nuevos chamanismos Nueva Era. 2009, p. 18. 2. Fotiou, Evgenia. ‘The Role of Indigenous Knowledges in Psychedelic Science’. Journal of Psychedelic Studies, vol. 4, no. 1, Dec. 2019, pp. 16–23. DOI.org (Crossref), doi:10.1556/2054.2019.031 3. Frecska, Ede, et al. ‘The Therapeutic Potentials of Ayahuasca: Possible Effects against Various Diseases of Civilization’. Frontiers in Pharmacology, vol. 7, Mar. 2016. DOI.org (Crossref), doi:10.3389/fphar.2016.00035 4. George, Jamilah R., et al. ‘The Psychedelic Renaissance and the Limitations of a White-Dominant Medical Framework: A Call for Indigenous and Ethnic Minority Inclusion’. Journal of Psychedelic Studies, vol. 4, no. 1, Mar. 2020, pp. 4–15. DOI.org (Crossref), doi:10.1556/2054.2019.015 5. Leiva, A., Guerrero, H., Pardo, M., JUNCOSA, J., & AMODIO, E. (1991). Los espíritus aliados: chamanismo y curación en los pueblos indios de Sudamérica. Ediciones Abya Yala, Quito, (31). p. 47 6. Losonczy, Anne-Marie, and Silvia Mesturini. ‘La Selva Viajera: Rutas del chamanismo ayahuasquero entre Europa y América’. Religião & Sociedade, vol. 30, no. 2, 2010, pp. 164–83. Crossref, doi:10.1590/S0100-85872010000200009 7. Mignolo, Walter D. ‘Epistemic Disobedience, Independent Thought and Decolonial Freedom’. Theory, Culture & Society, vol. 26, no. 7–8, Dec. 2009, pp. 159–81. DOI.org (Crossref), doi:10.1177/0263276409349275 8. Miller, M. J., Albarracin-Jordan, J., Moore, C., & Capriles, J. M. (2019). Chemical evidence for the use of multiple psychotropic plants in a 1,000-year-old ritual bundle from South America. Proceedings of the National Academy of Sciences, 116(23), 11207-11212 9. Palhano-Fontes, Fernanda, et al. ‘The Psychedelic State Induced by Ayahuasca Modulates the Activity and Connectivity of the Default Mode Network’. PLOS ONE, edited by Dewen Hu, vol. 10, no. 2, Feb. 2015, p. e0118143. DOI.org (Crossref), doi:10.1371/journal.pone.0118143 10. Pinzón, Carlos, et al. ‘El Jardín de La Ciencia En El Valle de Sibundoy’. Mundos En Red: La Cultura Popular Frente a Los Retos Del Siglo XXI, 2004, pp. 139–99 11. Richards, William A. ‘Psychedelic Psychotherapy: Insights From 25 Years of Research’. Journal of Humanistic Psychology, vol. 57, no. 4, July 2017, pp. 323–37. DOI.org (Crossref), doi:10.1177/0022167816670996 12. Roseman, Leor, et al. ‘Emotional Breakthrough and Psychedelics: Validation of the Emotional Breakthrough Inventory’. Journal of Psychopharmacology, vol. 33, no. 9, Sept. 2019, pp. 1076–87. DOI.org (Crossref), doi:10.1177/0269881119855974 13. Taussig, Michael. Shamanism, Colonialism and the Wild Man. The University of Chicago Press, 1986 14. Watts, Rosalind, et al. ‘Patients’ Accounts of Increased “Connectedness” and “Acceptance” After Psilocybin for Treatment-Resistant Depression’. Journal of Humanistic Psychology, vol. 57, no. 5, Sept. 2017, pp. 520–64. DOI.org (Crossref), doi:10.1177/0022167817709585
Michiel van Elk, an associate professor of cognitive psychology at the University of Leiden, used to be very anti-drugs after growing up in a conservative Christian community. A psychedelic experience later in life put him on a path towards psychedelic research, and today he has an interdisciplinary approach to studying different aspects of the psychedelic experience – from a religious, neuroscientific, spiritual and cognitive to social scientific. An important part of Van Elk’s current work concerns the role of placebo effects in the psychedelic experience.
In previous research, he used a device ominously called the God Helmet. This helmet is essentially a sham brain-stimulation device: participants were made to believe that the helmet would stimulate their brain – potentially resulting in a mystical experience. In reality, it did nothing at all.
Many participants -indeed- reported having such a mystical experience while carrying the God Helmet. This result creates new questions around the role of the placebo effect in mystical experiences in general, and those induced by psychedelics in particular.
This idea is further supported by the ‘Tripping on Nothing’ study in which researchers made a concerted effort to reproduce the experimental context in which psychedelics tend to be administered, including ambient music, psychedelic paintings and color-changing lights. And there also many participants reported experiences usually associated with a medium to high dose of psilocybin (Olson et al., 2022) – even though they were given a placebo.
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Jasper: What is your perspective on the role of placebo effects in the psychedelic experience?
Michiel: I think that is still very much an open question. One perspective is that the effects of psychedelics are at least partially mediated by placebo effects, because people have expectations about these effects. Another is that psychedelics are essentially super placebos, by making people more suggestible – leading to a stronger placebo response.
Placebo research is an extensive, established field, including my own research with the God Helmet. We aim to integrate this field of study with research into the psychedelic experience: How do expectations influence the psychedelic experience? And how can psychedelics increase the placebo response?
Jasper: It seems there is still much to be discovered about the role of placebo effects in the psychedelic experience. Assuming this role is indeed there, do you think the beliefs of the researcher also play a role, in addition to those of the patient?
Michiel: Placebo effects are partially based on the perceived credibility of the experimenter. The experimenter doesn’t need to believe in certain effects himself, in order to be a credible source.
If I wear the placebo God Helmet myself, not much will happen. But if I give it to a participant and tell them about how it will stimulate their brain, something will happen.
This has to do with authority and suggestibility. What is important is that the participant believes the story, not so much the researcher himself. I do think this also underlies many psychiatric treatments: what matters is the meaning patients attribute to the treatment and their trust in the clinician, rather than the knowledge of the effect of neurotransmitters or SSRI’s.
Jasper: How would you research that? Would you provide different information to different participants? Or would you measure existing differences in expectations?
Michiel: That is indeed one option: to measure individual differences in existing beliefs. Simply asking participants what they think will happen before they take a psychedelic.
We plan to make it explicit by manipulating expectations about the dosage. We could keep the dosage constant but tell them it’s 5 grams one day and 10 grams the other.
Another manipulation is through framing, for example telling people the substance has strong visual effects, or that it induces mystical experiences. This is comparable to what smartshops [legal dispensaries of psychedelic sclerotia in the Netherlands] already do today.
Do people indeed have more ‘philosophical’, self-reflective trips if they take Philosopher’s stones compared to Hawaiian High truffles, if the packaging suggests so?
Jasper: One of the challenges, in my view, is that you can’t control what people read or have already heard about psychedelics – and how that affects people’s expectations. Is there a way to measure those beliefs and use them as a variable?
Michiel: In practice this is very difficult, because to include individual differences such as these, you need humongous sample sizes. In studies with placebo brain stimulation like with the God Helmet – where we place something on people’s heads that supposedly stimulates their brain, which in reality it does not – we do measure what these participants’ beliefs are regarding ‘brain stimulation’. Whether they believe it really exists, what they’ve read about it, etc. However, nothing consistent was ever found there!
Recently a paper in Nature argued convincingly that if you are interested in establishing a relationship between brain measure X and an individual difference measure Y – like the relation between personality and cognitive performance – you need thousands of participants to establish such an effect. This basically illustrates that in almost any study that has looked at the brain – behavior correlations are severely underpowered.
Jasper: That highlights the importance of open science practices like data sharing.
Michiel: Absolutely. What I would like to see more of is collaborative science, where many different institutions adhere to the same protocol and collect data together. Recent clinical trials with psychedelics successfully employed this model for the Phase II studies for example. However, when it comes to fMRI studies, we are currently not even close to this being a reality. Fortunately, recent attempts have been made to share data more, like analysis scripts between different institutions. That is an important and exciting step forwards!
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Jasper: Thank you for offering your thoughts on this topic. Lastly, I would like to ask you: What do you think the status of psychedelics will be in your field of cognitive psychology in the year 2032?
Michiel: Interesting question. I hope different psychedelics will be developed with a more clearly defined mechanism. For example a clearer neurotransmitter profile. Lsd and psilocybin stimulate the 5HT2A receptor but also have many different downstream pharmacological effects, making it difficult to attribute their effects to this receptor alone.
Ketanserin helps a lot already but psychedelics with greater specificity would make this much easier. In this context I also understand why experienced psychopharmacologists are a bit skeptical about psychedelics – pharmacologically speaking it is not a very ‘clean’ manipulation. However, that makes these substances so interesting at the same time as well!
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Recently, Jasper Lucas talked to Michiel in a wide-ranging conversation wide ranging discussion about issues surrounding the psychedelic science field. This is part two of their conversation. Van Elk runs the PRiSM lab at Leiden University, which studies psychedelic, religious, spiritual and mystical experiences, and has received a prestigious NWO (government) VIDI grant to study the effects of psychedelics. He is the author of the book ‘A sober look at psychedelics’ – available in Dutch – and is also a speaker at our upcoming conference ICPR 2022 .
If you’re interested in psychedelics, then you might have heard of the work of Robin Carhart-Harris, who conducted much of the most relevant research in the world of psychedelics together with his team at Imperial College in London.
In this look back at ICPR 2016 we will highlight the talk he held about his team’s trials with psychedelics-assisted psychotherapy, where he also showed some beautiful visuals of his team’s brain research, which happened to become some of the most famous psychedelic brain imagery known on the internet.
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Like our upcoming ICPR 2022 near Amsterdam, the edition in 2016 strove to bring together as many relevant studies from psychedelics as possible, and Carhart-Harris’ talk was most certainly a highlight. His research has been cited often and his talk was one of the best-watched from that year’s ICPR on our Youtube channel.
In his talk, Carhart-Harris talks about the results of his research – that psychedelics can cause a rise in cognitive flexibility, neuroplasticity, creative thinking, imaginative suggestibility, emotional lability, positive moods, and optimism.
He also touches on the idea of depressive realism, a trend he has seen in patients suffering from depression. He describes their depression as a “sort of delusion”, where his patients “don’t see the world as it really is. There is this really quite evident pessimism bias, that is normalised post-treatment with psilocybin.”
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A testimony of one of the participants is featured in the talk:
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26:35 — ‘Although it’s early days yet, the results are amazing. I feel more confident and calm than I have in such a long time. My outlook has changed significantly too, I’m more aware that it’s pointless to get wrapped up in endless negativity. I also feel as if I’ve seen a much clearer picture. [Now] I can enjoy things the way I used to, without the cynicism, without the oppression. At its most basic. I feel like I used to before the depression.”
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Brain Scans
One way to go about investigating psychedelics is by making fMRI brain scans. These scans are made of healthy and depressed individuals before, during and after a psychedelic experience. This way, the brain can be observed for changes.
Through these scans, the team got insights into the inner workings of the brain during psychedelic trips, and how they correlate with described experiences of volunteers, like ego-death. This is a type of experience in which people who are under the influence of psychedelics describe a certain loss of self, and a deeper connection with the wider universe or nature.
Carhart’s studies have highlighted that the Default Brain Network may be connected with our sense of self – our ego – and that the lower activity of this network during a psychedelic session may be associated with the occurrence of ego-death.
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Some of the brain scans from the research team at Imperial, from 2012.
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12:40 — “We see quite reliably a relationship between the magnitude of the disintegration and the default brain network. [..] The greater the disintegration of the default mode network, the greater our volunteers’ ratings of ego-dissolution. ”
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During the psychedelic experience induced with psilocybin, the parts of the brain associated with the Default Brain Network show a drastic reduction in activity, often creating the experience of ego-death. The compulsive activity of the Default Brain Network also has been associated with patients that scored higher in depression ratings.
Robin Carhart-Harris’s argument is that the Default Brain Network may be the source of what most adult people call the ‘ego’. This network is known as the Default Mode Network because, during our daily lives, this brain network becomes more active when we are idle.
The Default Mode is actually a really important part of our mental stability. This network is responsible for keeping our routines in check, making sure that our pending matters stay afloat, and that we’re not overlooking anything.
The mental activity generated by the Default Mode Network is usually stable and consistent day after day. This daily consistency in addition to the fact the DMN is the ‘standard’ mental voice, may contribute to the illusion that the Default Mode Network is the self.
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12:58 — [The Default Brain Network is]: “Arguably the best candidate we have for the neural substrates of the self, or the ego, or our identity and personality.” – Robert Carhart-Harris
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By analyzing the brains of participants who consumed psilocybin, Carhart’s team noticed that there was a process of renewal happening within the structure of the brain, almost like a general mind reset. This process of rebirth has been reported many times by psychedelic subjects.
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17:50 — “We can think of the mind or the brain is reset in the same way that you can think of a computer is malfunctioning and throwing up an error message and you are wondering what you can do. And then you press the reset button and it comes back working nice and smooth as it should.”
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In more recent years, Carhart-Harris has worked on building a more unified model of the workings of psychedelics in the brain. He founded the Psychedelic Research Group at Imperial College in London and focuses on the action of psychedelic drugs in the brain, and their clinical utility as aides to psychotherapy, with a particular focus on depression. He still studies the brain effects of LSD, psilocybin (magic mushrooms), and MDMA.
Robin Carhart-Harris will not be speaking at ICPR 2022, but his colleague and the new head of the Psychedelic Research Group at Imperial College will: David Nutt.
Notes about the author: Alexandre Perrella is a writer for Cabbanis!
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.
Interviewee: Cato de Vos
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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.
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.”
The Psychedelic Experience: A Manual Based on The Tibetan Book of the Dead. Timothy Leary, Ralph Metzner, and Richard Alpert. Penguin Books. ISBN: 978-0141189635
The authors process the concepts of death and rebirth presented in Tibetan Book of the Dead as a metaphor for the experience of ego death or depersonalization that is commonly experienced under the influence of psychedelic drugs. The book also describes broadening spiritual consciousness through a combination of Tibetan meditation techniques and psychotropic substances.
The Electric Kool-Aid Acid Test. Tom Wolfe. Transworld Publishers. ISBN: 978-0552993661
Wolfe presents a firsthand account of the experiences of Ken Kesey and his band of Merry Pranksters, who traveled across the US in a colorfully painted school bus became famous for their use of psychedelic drugs such as LSD in order to achieve expansion of their consciousness. This book has long been considered one of the greatest books about the history of the hippie movement.
LSD, My Problem Child. Albert Hofmann. Oxford University Press. ISBN: 978-0198840206
In a highly candid and personal account, the father of LSD details the history of his “problem child” and his long and fruitful career as a research chemist. An essential read for anyone wanting to learn about how LSD originated and Hofmann’s view on its transition to recreational use.
