Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. There is now exciting evidence that the psychedelic compound psilocybin produces not only powerful alterations of consciousness, but also rapid and persistent antidepressant effects. How psilocybin exerts its therapeutic actions is not known, but it is widely presumed that these actions require altered consciousness, which is known to be dependent on serotonin 2A receptor (5-HT2AR) activation. This hypothesis has never been tested, however. We therefore asked whether psilocybin would exert antidepressant-like responses in mice and, if so, whether these responses required 5-HT2AR activation. Using chronically stressed male mice, we observed that a single injection of psilocybin reversed anhedonic responses assessed with the sucrose preference and female urine preference tests. The antianhedonic response to psilocybin was accompanied by a strengthening of excitatory synapses in the hippocampus-a characteristic of traditional and fast-acting antidepressants. Neither behavioral nor electrophysiological responses to psilocybin were prevented by pretreatment with the 5-HT2A/2C antagonist ketanserin, despite positive evidence of ketanserin’s efficacy. We conclude that psilocybin’s mechanism of antidepressant action can be studied in animal models and suggest that altered perception may not be required for its antidepressant effects. We further suggest that a 5-HT2AR-independent restoration of synaptic strength in cortico-mesolimbic reward circuits may contribute to its antidepressant action. The possibility of combining psychedelic compounds and a 5-HT2AR antagonist offers a potential means to increase their acceptance and clinical utility and should be studied in human depression.
Hesselgrave, N., Troppoli, T. A., Wulff, A. B., Cole, A. B., & Thompson, S. M. (2021). Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proceedings of the National Academy of Sciences of the United States of America, 118(17), e2022489118. https://doi.org/10.1073/pnas.2022489118
Background: Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking.
Methods: In a phase 2, double-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6.
Results: A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were -8.0±1.0 points in the psilocybin group and -6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], -5.0 to 0.9) (P = 0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, -3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups.
Conclusions: On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants.
Carhart-Harris, R., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., Martell, J., Blemings, A., Erritzoe, D., & Nutt, D. J. (2021). Trial of Psilocybin versus Escitalopram for Depression. The New England journal of medicine, 384(15), 1402–1411. https://doi.org/10.1056/NEJMoa2032994
Background: With support from the Radcliffe Institute for Advanced Study at Harvard University, we convened researchers representing palliative care, psychosocial oncology, spiritual care, oncology, and psychedelic-assisted therapies. We aimed to define priorities and envision an agenda for future research on psychedelic-assisted therapies in patients with serious illness. Over two days in January 2020, participants engaged in an iterative series of reflective exercises that elicited their attitude and perspectives on scientific opportunities for this research. Objectives: The aim of the study is to identify themes that shape priorities and an agenda for research on psychedelic-assisted therapy for those affected by serious illness. Methods: We collected data through preconference interviews, audio recordings, flip charts, and sticky notes. We applied thematic qualitative analysis to elucidate key themes. Results: We identified seven key opportunities to advance the field of psychedelic-assisted therapies in serious illness care. Four opportunities were related to the science and design of psychedelic-assisted therapies: clarifying indications; developing and refining therapeutic protocols; investigating the impact of set and setting on therapeutic outcomes; and understanding the mechanisms of action. The other three pertained to institutional and societal drivers to support optimal and responsible research: education and certification for therapists; regulations and funding; and diversity and inclusion. Additionally, participants suggested epistemological limitations of the medical model to understand the potential value and therapeutic use of psychedelics. Conclusions: Medicine and society are witnessing a resurgence of interest in the effects and applications of psychedelic-assisted therapies in a wide range of settings. This article suggests key opportunities for research in psychedelic-assisted therapies for those affected by serious illness.
Beaussant, Y., Tulsky, J., Guérin, B., Schwarz-Plaschg, C., Sanders, J. J., & Radcliffe Institute for Advanced Study Working Group on Psychedelic Research in Serious Illness (2021). Mapping an Agenda for Psychedelic-Assisted Therapy Research in Patients with Serious Illness. Journal of palliative medicine, 24(11), 1657–1666. https://doi.org/10.1089/jpm.2020.0764
Creativity is an essential cognitive ability linked to all areas of our everyday functioning. Thus, finding a way to enhance it is of broad interest. A large number of anecdotal reports suggest that the consumption of psychedelic drugs can enhance creative thinking; however, scientific evidence is lacking. Following a double-blind, placebo-controlled, parallel-group design, we demonstrated that psilocybin (0.17 mg/kg) induced a time- and construct-related differentiation of effects on creative thinking. Acutely, psilocybin increased ratings of (spontaneous) creative insights, while decreasing (deliberate) task-based creativity. Seven days after psilocybin, number of novel ideas increased. Furthermore, we utilized an ultrahigh field multimodal brain imaging approach, and found that acute and persisting effects were predicted by within- and between-network connectivity of the default mode network. Findings add some support to historical claims that psychedelics can influence aspects of the creative process, potentially indicating them as a tool to investigate creativity and subsequent underlying neural mechanisms. Trial NL6007; psilocybin as a tool for enhanced cognitive flexibility; https://www.trialregister.nl/trial/6007 .
Mason, N. L., Kuypers, K., Reckweg, J. T., Müller, F., Tse, D., Da Rios, B., Toennes, S. W., Stiers, P., Feilding, A., & Ramaekers, J. G. (2021). Spontaneous and deliberate creative cognition during and after psilocybin exposure. Translational psychiatry, 11(1), 209. https://doi.org/10.1038/s41398-021-01335-5
“I am proud to have ‘killed’ government-authorized research on psychedelics.” Timothy Leary, 1992
Most stories about the early psychedelic research in the 1960s tend to converge towards a common narrative: Timothy Leary, a rogue researcher turned LSD prophet, triggered the social backlash that would ultimately condemn psychedelics to decades of prohibition. In her book “Acid Revival”, sociologist Danielle Giffort explores the history of psychedelic science and how the controversial figure of Leary has shaped the path towards legitimacy for contemporary researchers. In this interview, we discussed Leary’s responsibility for the demise of the first wave, as well as the history of self-experimentation, controlled methodologies and spirituality in psychedelic science.
Dr Danielle Giffort – Assistant professor of Sociology at St. Louis College of Pharmacy
How did you become interested in the history of psychedelic science? I have always been very interested in Science & Technology Studies (STS) work on non-knowledge or what’s sometimes called “scientific ignorance”, not in the sense of studying public ignorance of science but in the sense of studying what kind of knowledge is not produced in science and why is that the case. Psychedelic science offered a really good case to study how a group of scientists rallies to bring their field back to life. I wanted to trace the trajectory of psychedelic science to understand its ebbs and flows from knowledge to nonknowledge and back again. When I started this project, as a sociologist, I thought I would be writing a broad institutional story about how governments, science, and the media shaped this field. But as I interviewed the researchers doing this work, listened to their presentations at conferences, and read their published commentaries and research, I found that their explanation for what happened to their field was very different. They told me that Timothy Leary, the infamous Harvard psychologist turned countercultural guru, caused the demise of this field. The consistency with which he came up in my data was such that I ended up organizing my whole book around the story. In your book, you argue that Leary represents the figure of the “Impure Scientist” for contemporary researchers. Can you elaborate on what you mean with this concept? I argue that the researchers are not necessarily just talking about Leary in their stories but that he comes to symbolize a larger figure in the field. The impure scientist is a person who defies the norms and the boundaries of science. In each chapter, I show how Leary crossed different boundaries in ways that caused all sorts of problems for the field of psychedelic science. First, there’s the boundary between science and pseudoscience. In other words, I’m talking about the legitimacy of the methods researchers are using. Second, there’s the boundary between objectivity and subjectivity in science; in the case of psychedelic science, this boundary has to do with whether a researcher has personal experience with these substances and whether that spoils, so to speak, their objectivity. Third, I discuss the seemingly irreconcilable gap between spirituality and science, which comes up again and again in psychedelic therapy with its recurrent focus on mystical experiences. Finally, I cover the boundary between “mainstream” society and the counterculture. But I also found evidence of other researchers that did quite similar things during the first wave of psychedelic science. That’s why I say Leary, as the impure scientist, is a figure. Even though many other researchers could be accused of the same behaviors, Leary becomes the fall guy because he is this easily identifiable person that they can all point to and say: “He did it, he crossed these boundaries and polluted the whole field”. Leary represents a bad expert that current researchers are really trying to push away from. Ostensibly, they do that by being the opposite of what the impure scientist was, what some have even dubbed the “Anti-Leary.” You stress that the goal of the book is far from reassessing the historical responsibility of Leary in the failure of the first wave of psychedelic research. At the same time, after reading your book, readers may wonder what criticism he rightly deserves for his behavior. I am explicit, as you said, about how the point of the book is not to ask whether this story is true. That is, whether Leary is really to blame or not. In the book, I am more interested in studying how people use these subjective narratives and their accompanying performances to make sense of their situation and take action. So I asked myself, if psychedelic researchers are using this idea of the impure scientist to make sense of the situation, regardless of its truth, how does that interpretation influence what they do? Ultimately, I am not blaming Leary nor exonerating him because the reasons why psychedelic science became forbidden knowledge are multifaceted. If Leary had been a bit more reserved, would it have caused such a media spectacle and subsequent public backlash against psychedelic drugs? The stories suggest that might be the case, but the fact that there were other researchers at the time who were doing similar things, even before Leary came on to the psychedelic scene in 1960, also suggests that what happened to this field is not all about him. He was a part of it, for sure. But Leary, the government regulations, the media coverage, the scientific expectations, the cultural panic; they all contributed to what happened with psychedelic science. In the end, the focus on Leary does serve a strategic purpose. Instead of blaming institutions like the FDA or DEA (in the US), which are necessary for this research to happen, the story blames an individual. While the narrative avoids making a more direct critique of institutional systems of power, at the same time it still allows researchers to get work done within the system, potentially making change from within, for example, getting psychedelic drugs rescheduled. You dedicate one chapter to the topic of objectivity and scientists’ self-experience with the drugs they study. This is still a contentious issue today when it comes to whether therapists should have personal experience with psychedelics to guide patients. Can you elaborate on this method of drug self-experimentation and how it has played out in the history of psychedelic science? One of the first recommended uses for LSD was self-experimentation. The idea was that psychiatrists who took the drug themselves could understand what their schizophrenic patients were feeling because, at the time, LSD was thought to mimic endogenous psychosis. As such, it offered a tool for healthcare professionals to develop empathy towards their patients and a shared understanding of their mental health problems. As many LSD researchers moved away from this “model psychosis” framework towards studying potential therapeutic uses, some investigators said that it was also important for therapists to take the substances themselves. The thinking was that if you have had a psychedelic experience, you can develop a kind of tacit, embodied knowledge that can help you as a healthcare provider know when to step in and offer support for your patient or when to back off and let them be. Here, self-experience was once again about empathy but also about patient safety. Not everyone self-experimented because it raised questions about objectivity. Some argued that if the researcher has had a psychedelic experience, it will influence how they interpret their data or how they guide their participants through a psychedelic therapy session, potentially in a way that leads to a particular outcome. Personal experience with psychedelic drugs continues to create dilemmas for researchers because objectivity is synonymous with legitimate science. The public wants you, the researcher, and all your values and opinions, to be detached from what you are studying so that I, as the consumer of knowledge, know that the knowledge produced from your research is credible. That is the public imaginary around science. So there is a desire among many psychedelic researchers to keep hush-hush about any personal experiences with these drugs to avoid accusations of being biased or being like Leary, but at the same time, these experiences are very meaningful for those who have had them. Like their predecessors, the researchers I spoke with agree that, although not strictly necessary, self-experimentation is important for patient safety and empathetic interactions.
Should psychedelic guides keep spirituality out of the therapy room? – Interview with Daan Keiman
Spirituality has featured prominently in psychedelic research throughout its history. How would you evaluate the relation between spirituality and science in the field of psychedelic research?
Since the early days, spirituality has also been controversial in psychedelic therapy. Some people believed that spirituality wasn’t compatible with scientific inquiry. It would bring up questions, such as, “How do you objectively quantify a psychedelic-induced spiritual experience?” which then brings up larger scientific issues surrounding conceptualization and operationalization. In other words, how are we defining what we are studying and how are we measuring it? Answering these questions has been key to demonstrating scientific objectivity.
Despite such obstacles, we see this mystical discourse popping up again in the revival. Some research teams, like the group at Johns Hopkins, have embraced this approach, and they have worked to validate mystical experience questionnaires that they use to assess people’s experiences and outcomes. Neuroscientists are also using brain scans to study the spiritual experiences induced by psychedelics, although some groups, such as the team at Imperial College in London, prefer the language of “ego dissolution” to describe them. If scientists can actually uncover these processes happening in the brain, then they can make the case that what happens when people take psychedelics is not simply a subjective experience. They can back up patient accounts with quantified questionnaires and brain scans. That kind of evidence could help legitimate psychedelic treatments further, as numbers and neuroscience hold a lot of weight in today’s scientific environment. So far, it doesn’t seem like people are totally against the idea of mystical experiences in psychedelic science. Research on this exact topic is getting published in mainstream scientific journals, getting approval from advisory boards, and getting a lot of positive attention in the media. So, although it continues to create dilemmas for researchers on their road to legitimacy, I see this intertwining of spirituality and science unfolding a bit differently than it did in the first wave. Findings from LSD research in the 60s are often dismissed because of the lack of rigorous methodologies. In the book you say that questions about aligning psychedelic therapy with the method of randomized controlled trials (RCT) remain in the renaissance. What methodological lessons do you think contemporary researchers have learnt from the first wave? They learned that to be seen as legitimate researchers, they need to use controlled methodologies.The US-based researchers I spoke with regularly shared with me the arduous process of getting FDA approval, and how they need to submit proposals that include an experimental group, a placebo, and so on. So RCT methods have been legitimated institutionally, not just within scientific cultures. Looking at the past, researchers learned that they need to play that game for their studies to get approval, get funding, and get published. But I think that today’s researchers are also careful to avoid past mistakes that happened when researchers who didn’t have a lot of experience doing LSD therapy focused too closely on sticking to the RCT model. The poor treatment outcomes observed in some of the studies of LSD therapy for alcoholism in the 1960s were not necessarily because the treatment didn’t work, but because researchers failed to optimize set and setting. One group of researchers, for example, gave LSD to patients, strapped them to a hospital bed and left them alone for hours. Based on what we know about the interactive effects between drugs, the mind, and the physical and social environment, it is not surprising that these patients consistently reported terrible LSD trips and that the drug was deemed not therapeutic by some researchers. So I think that today’s researchers learned that controlled methodologies are legitimate and they need to use them, but at the same time, they recognize that an excessive focus on that step-by-step process isn’t a good fit for psychedelic therapy. That is why you see this merging of set and setting, such as preparing the treatment room and the patients to optimize the experience, while also having placebos and control groups, in much of today’s psychedelic research protocols.
The influence of society on the psychedelic experience – Interview with Ido Hartogsohn
At the OPEN Foundation, we try to foster interdisciplinary dialogue between the social and the medical sciences. How do you think that psychedelic researchers may benefit from reading your book? I still can’t decide if I want to be a historian or a sociologist. But here is where my historian side comes out. Delving into the past can be very important for helping us understand how people act in the present. Regarding psychedelic research in particular, this means understanding not just cultural narratives about Leary or figures like him, but understanding, for instance, the institutional regulations in the first wave regarding scientific methods that changed how clinical research gets approved, conducted, and hence, legitimated. Knowing these contextual influences can change what researchers do in the present in ways that can help them make this work happen. From a sociological perspective, I hope that the book helps researchers and readers think about science not as insular but very much as a social endeavor. The production of scientific knowledge does not exist in a vacuum, and psychedelic science is a great example of this. As Ido Hartogsohn shows in his book “American Trip”, for example, in developing protocols for psychedelic therapy, researchers not only have to take into consideration the setting of the therapy room itself, but the broader environmental factors that are shaping this research in the first place. They must navigate different social obstacles and opportunities, such as government regulations for clinical drug trials or public preconceptions about psychedelic drugs. Thinking sociologically about science and psychedelic drugs helps us take into consideration larger social factors that potentially affect this work, both in ways that can help and in ways that can hinder psychedelic research.
Background: 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) is used both recreationally and therapeutically. Little is known about the factors influencing inter- and intra-individual differences in the acute response to MDMA. Effects of other psychoactive substances have been shown to be critically influenced by personality traits and mood state before intake.
Methods: We pooled data from 10 randomized, double-blind, placebo-controlled, cross-over studies performed in the same laboratory in 194 healthy subjects receiving doses of 75 or 125mg of MDMA. We investigated the influence of drug dose, body weight, sex, age, drug pre-experience, genetics, personality and mental state before drug intake on the acute physiological and psychological response to MDMA.
Results: In univariable analyses, the MDMA plasma concentration was the strongest predictor for most outcome variables. When adjusting for dose per body weight, we found that (a) a higher activity of the enzyme CYP2D6 predicted lower MDMA plasma concentration, (b) a higher score in the personality trait “openness to experience” predicted more perceived “closeness”, a stronger decrease in “general inactivation”, and higher scores in the 5D-ASC (5 Dimensions of Altered States of Consciousness Questionnaire) scales “oceanic boundlessness” and “visionary restructuralization”, and (c) subjects with high “neuroticism” or trait anxiety were more likely to have unpleasant and/or anxious reactions.
Conclusions: Although MDMA plasma concentration was the strongest predictor, several personality traits and mood state variables additionally explained variance in the response to MDMA. The results confirm that both pharmacological and non-pharmacological variables influence the response to MDMA. These findings may be relevant for the therapeutic use of MDMA.
Studerus, E., Vizeli, P., Harder, S., Ley, L., & Liechti, M. E. (2021). Prediction of MDMA response in healthy humans: a pooled analysis of placebo-controlled studies. Journal of psychopharmacology (Oxford, England), 35(5), 556–565. https://doi.org/10.1177/0269881121998322
Objectives: Accumulating evidence has implicated that brain derived neurotrophic factor (BDNF) is thought to be involved in the pathophysiology of depression, but its correlation with ketamine’s antidepressant efficacy focusing on Chinese individuals with depression is not known. This study was aim to determine the correlation of plasma BDNF (pBDNF) concentrations and ketamine’s antidepressant efficacy.
Methods: Ninety-four individuals with depression received six intravenous infusions ketamine (0.5 mg/kg). Remission and response were defined as Montgomery-Asberg Depression Rating Scale (MADRS) scores less than 10 and a reduction of 50% or more in MADRS scores, respectively. Plasma was collected at baseline and at 24 h and 2 weeks after completing six ketamine infusions (baseline, 13 d and 26 d).
Results: A significant improvement in MADRS scores and pBDNF concentrations was found after completing six ketamine infusions compared to baseline (all ps < 0.05). Higher baseline pBDNF concentrations were found in ketamine responders/remitters (11.0 ± 6.2/10.1 ± 5.8 ng/ml) than nonresponders/nonremitters (8.0 ± 5.5/9.2 ± 6.4 ng/ml) (all ps < 0.05). Baseline pBDNF concentrations were correlated with MADRS scores at 13 d (t = – 2.011, p = 0.047) or 26 d (t = – 2.398, p = 0.019) in depressed patients (all ps < 0.05). Subgroup analyses found similar results in individuals suffering from treatment refractory depression.
Conclusion: This preliminary study suggests that baseline pBDNF concentrations appeared to be correlated with ketamine’s antidepressant efficacy in Chinese patients with depression.
Zheng, W., Zhou, Y. L., Wang, C. Y., Lan, X. F., Zhang, B., Zhou, S. M., Yan, S., & Ning, Y. P. (2021). Plasma BDNF concentrations and the antidepressant effects of six ketamine infusions in unipolar and bipolar depression. PeerJ, 9, e10989. https://doi.org/10.7717/peerj.10989
The interest in lysergic acid diethylamide (LSD) has sparked again due to its supposed positive effects on psychopathological conditions. Yet, most research focuses on the actions of LSD on the central nervous system. The interaction with the autonomic nervous system (ANS) has been neglected so far. Therefore, the aim was to assess the effects of LSD and the serotonin 2A receptor antagonist ketanserin on the ANS as assessed by heart rate variability (HRV) measures and their correlation with subjective drug-induced effects in a randomized, placebo-controlled crossover trial. Thus, ANS activity was derived from electrocardiogram recordings after intake of placebo, LSD or ketanserin, and LSD by calculating R-peak-based measures of sympathetic and parasympathetic activity. Repeated measure ANOVA and partial correlation for HRV measures and subjective experience questionnaires were performed. LSD predominantly increased sympathetic activity, while ketanserin counteracted this effect on the ANS via an increase of parasympathetic tone. Sympathetic activity was positively and parasympathetic activity negatively associated with psychedelic effects of LSD. Furthermore, Placebo HRV measures predicted subjective experiences after LSD intake. The association between trait ANS activity and LSD-induced subjective experiences may serve as a candidate biomarker set for the effectiveness of LSD in the treatment of psychopathological conditions.
Olbrich, S., Preller, K. H., & Vollenweider, F. X. (2021). LSD and ketanserin and their impact on the human autonomic nervous system. Psychophysiology, 58(6), e13822. https://doi.org/10.1111/psyp.13822
While the use of psychedelics has been closely entwined with spiritual practice, prominent voices in psychedelic research have called for the demystification of these substances and the adoption of more secular approaches to psychedelic therapy. I sat down with OPEN Foundation collaborator and psychedelic chaplain, Daan Keiman, to discuss the ethical issues that have been raised around the introduction of spiritual frameworks in psychedelic therapy sessions. From his experience facilitating psilocybin truffle ceremonies at one of the many legal psychedelic retreats in the Netherlands, he thinks that rather than secularize psychedelic guidance and integration, we should tackle these concerns through an interfaith approach. If therapists acknowledge that they are not “existentially neutral” about the nature of the psychedelic experience and its meaning, they should therefore reflect honestly with patients on their therapeutic relation and their respective existential views.
The risk of imposing religious beliefs In a recent viewpoint article about the pitfalls of psychedelic medicine, researcher Matthew Johnson has raised concerns around the possibility of imposing religious beliefs on patients undergoing psychedelic therapy. Johnson warns therapists about the risks of using concepts from Eastern or indigenous spiritualities in integration sessions or even displaying particular religious icons in the therapy room. In his own words, “in addition to other concerns about conflating religious beliefs with empirically based clinical practice, the introduction of such religious icons into clinical practice unnecessarily alienates some people from psychedelic medicine, e.g., atheists, Christians, and Muslims. It will ultimately interfere with the mainstream adoption of these treatments.” Daan shares some of these concerns given that psychedelics may put patients in particularly vulnerable states that must be handled with care and responsibility. “Under the effects of psychedelics, the suggestibility goes up significantly and we know that people often have noetic experiences: a feeling that something is being revealed to them that is incredibly true.” Although we know that these experiences are deeply mediated by the context in which they are used, their noetic quality feels as unmediated, as completely independent from the set and setting. Therapeutic work with this kind of deeply felt experiences of truth is proving challenging for psychedelic researchers concerned about the ethics of inducing or validating profound metaphysical beliefs in patients. They worry that such revelations facilitated by the combination of drug and setting may turn psychedelic therapy into a form of non-consented spiritual conversion. Therefore, as Johnson argues, researchers and clinicians should adhere to a secular approach and refrain from introducing any “non-empirically verified beliefs” into their therapeutic protocols. Daan agrees with the difficulties of introducing elements from particular spiritual traditions in pluralistic settings such as the truffle retreats that he facilitates. In fact, the Buddhist teachings and stories that he used to share with participants in preparation for their ceremonies did not always resonate with everyone’s worldviews. In one of these stories, the Buddha is seduced by the demon god Mara during meditation and, instead of ignoring his calls, he accepts them and invites the demon to tea. With this story, Daan would encourage psychedelic journeyers to confront challenging experiences: “invite your demons to tea, and see what you can learn from them”. However, he recounts an occasion on which a couple of Christian retreaters felt incredibly uncomfortable with the idea of inviting their demons to tea. “Although I had been trained as an interfaith spiritual caregiver, I had wrongfully assumed that the prevailing clinical and therapeutic best practices, those underlying the Buddhist story, were universally applicable. The incident made me realize that they can come with ontological or theological assumptions”.
Daan Keiman, MA
Empirically verified frameworks of meaning While discarding religious iconography and language appears as an easy solution, the distinction between belief and empirically based clinical practice is not always so straightforward. As Daan shows, the main psychotherapeutic frameworks used nowadays in psychedelic research are shaped by spiritual beliefs and practice. “If we look at ACT and other third-generation behavioral-cognitive therapies, we see that they are based on mindfulness. A lot of Buddhist insights deeply inform the ways people are encouraged to go into psychedelic experiences”. Transpersonal psychology and existential psychotherapy are other examples of how psychedelic therapy draws from traditions that have their own ontological assumptions. Some in the psychedelic community have expressed their criticisms to Johnson’s article. “Something that a lot of people take issue with,” explains Dann, “is what comes across as yet another white man pretending that his secular psychotherapeutic perspective is the position of no-position; as if it is neutral, as if it doesn’t come with its own baggage and its own set of assumptions which are not empirically verified.” Daan acknowledges that Johnson is actually much more nuanced than how he is depicted by critics. However, he also thinks that secularizing psychedelic therapy might not be the best solution.
There are good reasons to be careful when introducing spiritual frameworks as meaning-making tools in integration sessions. Yet ruling them out completely due to the lack of evidence to support them seems premature. Daan adds: “Let’s not pretend that psychotherapeutic approaches are neutral. They are deeply informed by certain assumptions. The interesting thing is that currently accepted approaches, like mindfulness-based cognitive therapy or Internal Family Systems, were not empirically verified before they were put into practice and researched. They were met with scepticism, and it took effort to research them and show their validity.” Excluding all spiritually oriented elements from therapeutic and research protocols would only perpetuate their non-empirical status. Instead, perhaps more research should be dedicated to questions about the ideal therapeutic setting and the necessary competencies to accompany the meaning-making process of patients of diverse existential orientations. In regards to such questions, Dann believes that “spiritual traditions, alongside with the richness of shamanic approaches and their accompanying ontologies, might provide fruitful and wholesome insights, and could inform contemporary psychedelic-assisted psychotherapy; as long as they are presented as exactly that: spiritual narrative or practice, not ultimate truth.”
The influence of society on the psychedelic experience (Interview with Ido Hartogsohn)
In contrast to this proposal, Johnson’s article seems to “naively suggest that if we just wear a white coat and strip our protocols of anything that remotely smells like meaning, we will be fine”. However, meaning pervades every element of the therapeutic protocols, from psychometric tests to music playlists, driving the psychedelic experience in subtle ways. This is something that researchers are still struggling to deal with. Current research about the psychological mechanisms of action of psychedelics is running into the problems of shaping people’s expectations as they prepare for a trip. Along these lines, Daan wonders “to what extent the flight instructions are not some sort of descriptive tool but actually a primer for the experience”. Yet, rather than a mere source of confusion, these feedback loops may help us better understand the interplay of drug, set and setting that determines psychedelic effects. “We need a deeper understanding of how everything we do is endowed with meaning. Therefore, it is more useful to be transparent, reflect on the meaning of what we do and work towards a more patient-centered approach based on informed consent.”
From secular neutrality to interfaith positionality Psychedelic researchers agree that therapists should empower patients to make sense of the metaphysical aspects of their experiences by themselves. “I am not against that idea,” says Daan, “but as a spiritual caregiver trained to talk about existential questions, I think you need particular competencies to discuss these issues with patients.” Daan advocates the figure of the psychedelic chaplain, a guide who is fully equipped to help patients with the ontological shock that may be triggered by intense psychedelic experiences. In his view, “to have a psychotherapist helping you interpret those experiences from a purely secular standpoint might become very difficult and could actually harm the existential or spiritual integrity of the client.” Instead of secularizing psychedelic therapy, Daan suggests working within an interfaith approach that emphasizes the positionality of both therapist and patient. Deep awareness about the spiritual integrity of the patient and a clear agreement about the framework within which the therapist will guide the patient, therefore, become central in establishing trust in the therapeutic alliance. “Before you start to work with me, I am going to be honest about the fact that I am a Buddhist psychedelic chaplain. Even though I work with a client-centered interfaith approach, there are things that I am bringing into the psychedelic context which I cannot erase and which will influence your journey. If you are uncomfortable with this situation that we call “Daan”, then I might not be the right person to guide you.” This notion of positionality that Daan borrows from anthropology is aimed at promoting self-reflection and ensuring transparency in face of the potential ethical issues that may arise in situations where being neutral appears as a naive ideal. To Daan, this self-reflection is very much needed in psychedelic therapy given the position of power and authority that therapists and guides often hold in relation to their patients. “It is very important that psychedelic psychotherapists are honest about the baggage that they carry in a much deeper way than just in terms of spirituality and ontology. Race, sex and gender play crucial roles in the power disparities between the guide and the person being guided. In the same way that Mathew Johnson identifies the risks of the spiritual orientations of therapists, we also need to become aware of the risks inherent to these power relations, by elucidating them, by articulating them and by reflecting on them with peers and supervisors.” Should psychedelic therapists then keep their spiritual beliefs away from patients? Perhaps, a self-reflecting interfaith approach is better attuned to cultivate meaningful therapeutic encounters. Patients should have the last word about this. Written by Alberto Cantizani López Art by Anna Temczuk
Mescaline is a naturally occurring psychoactive alkaloid that has been used as a sacrament by Indigenous populations in spiritual ritual and healing ceremonies for millennia. Despite promising early preliminary research and favorable anecdotal reports, there is limited research investigating mescaline’s psychotherapeutic potential. We administered an anonymous online questionnaire to adults (N = 452) reporting use of mescaline in naturalistic settings about mental health benefits attributed to mescaline. We assessed respondents’ self-reported improvements in depression, anxiety, post-traumatic stress disorder (PTSD), and alcohol and drug use disorders (AUD and DUD). Of the respondents reporting histories of these clinical conditions, most (68-86%) reported subjective improvement following their most memorable mescaline experience. Respondents who reported an improvement in their psychiatric conditions reported significantly higher ratings of acute psychological factors including mystical-type, psychological insight, and ego dissolution effects compared to those who did not report improvements (Cohen’s d range 0.7 – 1.5). Many respondents (35-50%) rated the mescaline experience as the single or top five most spiritually significant or meaningful experience(s) of their lives. Acute experiences of psychological insight during their mescaline experience were associated with increased odds of reporting improvement in depression, anxiety, AUD and DUD. Additional research is needed to corroborate these preliminary findings and to rigorously examine the efficacy of mescaline for psychiatric treatment in controlled, longitudinal clinical trials.
Agin-Liebes, G., Haas, T. F., Lancelotta, R., Uthaug, M. V., Ramaekers, J. G., & Davis, A. K. (2021). Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes. ACS pharmacology & translational science, 4(2), 543–552. https://doi.org/10.1021/acsptsci.1c00018
