OPEN Foundation

Psychology

psychedelic clinical trial participants share their stories

Story by Vardit Kohn
Illustration by Anna Temczuk

Until recently, there was no advocacy or central voice for the participants in clinical trials involving psychedelics. Now, there is PsyPAN, a non-profit organisation set up to connect and empower psychedelic participants. Founders Ian Roullier and Leonie Schneider both participated in such trials. Ian took part in the psilocybin for depression trials at Imperial College (2015) and Compass Pathways (2019). Leonie took part in the second phase of the psilocybin for depression study at Imperial College (2019) and the DMT for depression trial at Small Pharma (2022). They were later invited to take part in Dr. Rosalind Watts’ one-year integration programme, where they met.

Towards the end of the programme, Leonie and Ian discovered they had a shared interest – both in advocating for the spread of psychedelic treatment for mental health as well as having the patients’ perspective duly represented. No organisation representing the patient’s viewpoints existed, while the number of participants in psychedelic trials is increasing by the day. And as the standards for these novel treatments are now being developed, both felt that the voice of the patient needed to be heard louder.

So, in 2021, Leonie and Ian founded the Psychedelic Participant Advocacy Network: PsyPAN. It’s a non-profit organisation set up to connect and empower all psychedelic participants. PsyPAN aims to give a collective voice to all participants and help improve participant safety and wellbeing, by working on developing best practices across all levels of the global psychedelic sector – clinical and non-clinical alike. 

As the psychedelic sector is expanding at a breathtaking pace, companies, clinicians and modern-day curanderos alike have a lot to learn from the persons seeking their help. We talked to Leonie and Ian for this interview.

Leonie and Ian will also be speaking at ICPR 2022, the psychedelic conference organised by the OPEN Foundation, which has been promoting psychedelic research and therapy since 2007.

What motivated you to set up PsyPAN?
Ian: We both participated in clinical trials designed to test the effects of psilocybin and DMT on depression.  Our wildly varied, but generally positive personal experiences triggered a wish to bring these treatments to more people and at the same time ensure the treatments are delivered safely and responsibly. 

Leonie: We want to ensure the ‘participant’s voice’ is taken into account when clinical trials are designed, so that the trials can be tailored to meet the wide range of experiences. Despite some unifying themes across the psychedelic experience,, it is such a personal process, and deep trauma and psychological issues can present in so many different ways.  We want to provide a feedback loop: taking what participants say, giving that to industry, and having industry respond to what participants require in this process. So that we can ensure these treatments are tailored and take nuances and details into account.

Ian: Next to the ‘participants’ voice’ we keenly engage in advocacy work, destigmatizing the image of psychedelics, dispelling misunderstandings and fear. We are keen to ensure that more people can benefit from these treatments in a safe and appropriate way. 

Ian Roullier and Leonie Schneider recently launched the Psychedelic Participant Advocacy Network – PsyPAN. With their new organisation, they want to represent the voice of the participants of psychedelic trials. In this video, we go over some of the highlights of our conversation.

Is psychedelic therapy especially prone to safety risks?
Ian: Yes, psychedelic therapy is more risky than, for example, giving someone an SSRI. Psychedelic substances lay you bare and much more vulnerable, you can’t just get up and go back to work as if nothing happened. It is also their strength; but therein also lies the potential for healing. 

Leonie: Safety is therefore key, so developing psychedelic safeguarding guidelines is where we can help organisations.

Where do you see your contribution to the rapidly developing market of psychedelic therapy?
Ian: We work with organisations to ensure that they have the finer details in place, and we hope to develop a model of best practice that organisations could follow. 

Leonie: Sometimes there are issues organisations simply haven’t thought of because those involved haven’t suffered from the issues that people with a clinical diagnosis have gone through, nor have they taken part in clinical trials, so our feedback is valuable. We aim to help ensure that trials or treatments are delivered safely and appropriately, because the more corners cut, the less effective the treatment will be. 

What have you learned so far in the process that you were not expecting?
Ian: We found out that simply connecting people who have been through similar experiences is in itself of vital importance.

Leonie: Yeah. There is no community, or a place where you can go, to land after your experience. So it can be incredibly isolating. If you’ve been through a profound experience but can’t speak to anyone about it, you may still feel as isolated as you did pre-treatment, only in a different way. The circle of family and friends you go back to can’t necessarily understand what you have been through. We learned that there is a lot of value in simply creating a peer community for support.

Ian Rouillier and Leonie Schneider, featured in this article, will share their full stories at ICPR 2022, organised by the OPEN Foundation and held in Haarlem from 22-24 September 2022. Get €100 off on all tickets by using the code OPENBLOG100

If there was one thing you as participants in clinical trials would like to draw attention to, what would it be?
Ian : Open-label trials, in other words making sure that all participants who go through the process have access to a treatment dose. Contributing to science is wonderful, but if you’re so desperate as to be willing to participate in a clinical trial of a new substance, you really are in need of relief. To go through the process and only have a placebo is quite heartbreaking and potentially re-traumatising. To have access to the full treatment dose could therefore be life-saving for some. 

Leonie: Integration. Both of us participated in Rosalind Watts’ “Connectedness” program at Synthesis Institute which was the precursor to Dr Watts’ ACER Integration Programme, which was hugely beneficial. It connected us in monthly group meetings and group work (two groups of 10 participants each) for one full year. The psychedelics are catalysts, they likely allow more progress to be made during the integration. But this kind of deep, long-term integration and connection work has been hugely beneficial. 

Tell me more about Integration
Leonie: Having a space in which to integrate these experiences brought about by psychedelics is incredibly important, whether one-on-one or in a group, especially if the person has had long-term mental health issues. There is a need for longer-term and deeper level integration, not just a courtesy call of ‘how are you’. It’s about witnessing and supporting people every step of the journey.

As mentioned, we both participated in Rosalind Watts’ 1-year long “Connectedness” program. Due to Covid-19, the whole program was delivered online, which wasn’t the plan at all! And still it was so valuable. It kept many of us afloat, especially considering the pandemic. As long as there is a safe container, an online program can genuinely work.

The sweet spot could be to have online content enhanced with in-person meetings, hopefully in smaller, local groups (as treatments become more common) and outdoors, which allows for engagement with Nature. 

What part did the connection with Nature play in your healing process?
Leonie: Reconnecting with Nature and with every living thing is very powerful. For example, watching the same tree go through its year-long cycle, especially during the dark, deathly-looking winter months, realising this period is part of a longer cycle, realizing there is still a lot happening under the surface even if above ground the tree looks barren – this was all very meaningful. 

Most of mental illness is exacerbated by trying to avoid feelings as opposed to accepting them. When you learn to see low moods as “this is my Wintering, and Spring will come”, it creates a meaningful marker, a reference point. 

What should organisations emphasise as the most important factors for a patient to consider before deciding to join a clinical psychedelic study?
Leonie: Organisations running clinical trials must make potential participants aware that the ‘trip day’ is just a catalyst. You’re in the process for the long run and there will be plenty of long-term, steady work that only starts after the day at the clinic. The importance of long-term integration and connection after the ‘trip day’ cannot and should not be underestimated.

Ian: Expectations should also be carefully managed regarding the chances of getting into the trial. Many people aren’t accepted. Furthermore, organisations would do well to question the kind of support networks potential candidates have in place, because a lot of support is needed right from the recruitment and screening stages. What further support is available during and after the treatment? Is there a community and family in place that can hold your experience, so you do not end up in crushing isolation, which might negate any benefit you could get from the treatment?

Organisations engaging in double-blind trials should also make it very clear that participants have a 50-50 chance of getting a placebo, which may result in disappointment. In the case of depression, you need to come off the anti-depressant medication, which makes you more vulnerable. You hope for an improvement but may end up with a placebo, with all the disappointment and anxiety this may cause. You may potentially end up in a worse position than you were before entering the trial. 

To what extent if any does treatment with different psychedelic substances require different guidelines?
Leonie: It is certainly important to bear in mind what medicine you’re working with and then tailor the guidelines appropriately since the experiences vary in intensity, the type of in-session interaction and the kind of post-treatment support required depending on the medicine used. Furthermore, the theme of the session matters, too. As an example, if sexual issues are likely to arise, two therapists present and a recording of the sessions may provide more accountability.

How could the current positive hype around psychedelics impact patients and therapists?
Ian: There’s a risk in the current media hype for psychedelic therapy to be seen as a ‘one dose and you’re fixed forever’ treatment. It sets expectations too high, and, in the absence of legal treatments, people may opt to try the psychedelics themselves without appropriate support. 

Psychedelics are catalysts, not cures. In reality, when it comes to mental health a lot of the healing work happens afterwards.  It’s a long process that involves a lot of integration and support going forward. The focus should be more on the psychotherapy, not completely on the psychedelic aspect of the process. If this point isn’t made clear, the risk is that the treatments will be seen as ineffective, which would be a shame as there is huge potential in psychedelics.

How do participants’ opinions get heard through you?
Leonie: Participants who have been through the clinical trial setting are the ones most interested in our work, We raise awareness within organisations who run such trials and invite participants informally to join our efforts. Going forward, we want references to PsyPAN to be built into the treatment protocol so that participants can be seamly signposted to us and welcomes to participate if they choose to. 

Speaking at ICPR and other events where participants are present is another way of creating awareness of our work. We also help organisations put together a working or focus group, so participants can share their experiences and have a say in the way trial protocols are designed. 

Ian: As far as we know, there’s nobody doing exactly what we’re doing. If there are other such groups or networks, we will be delighted to connect with them and support each other. We’re all doing it for the greater good of people who are struggling with mental health conditions.

How do you view depression, as you were both treated for it.
Leonie: Depression is a disease of disconnection. In society we are disconnected in so many ways. Depression alerts us to a deep need to slow down, take deep rest and to reconnect: to Nature, to ourselves, to our feelings – all of them, including the painful ones. 

Ian: We live in a world where we’re atomized and isolated, and the pandemic only exacerbated that. We are raised to dismiss a large part of our emotional range as human beings. We try to deny the more challenging parts of ourselves and our histories. 

Leonie: Antidepressants are a powerful intervention when you are in an acute, overwhelming crisis. But they should be seen as a short-term, symptom management intervention. They should not be viewed as something that is taken indefinitely, as if depression was a terminal disease that you had to learn to live with, as they don’t just numb you to the negative emotions; they limit and numb you in many other ways, too. If you don’t deal with the underlying causes of your depression, the issues come up in a different way at a different time. 

Ian: Psychedelics work in the completely opposite way: they enable you to connect with your full range of emotions and learn to be comfortable with your fuller self. Psychedelics help you dig down to the roots of your depression and work out new ways to deal with difficult feelings within a natural container that is larger than just yourself. 

You mentioned several spiritual themes: connection to Nature, connection to something that is larger than us, the Cycle of Life. How does that sit with the current clinical, medical training?
Leonie: No participant or clinician starts the trial thinking clinically-diagnosed patients need more trees in their life… We must be careful not to be too reductionist – depression is not solely a function of neurochemistry. There needs to be some space for mystery, too. 

Ian: Psychedelics can engender deeply profound spiritual experiences, which can manifest in different ways; we must not be prescriptive as to the nature of the spiritual experience to be expected. Yet organisations who run the studies must be aware that these experiences do happen. 

Leonie: The concept of connectedness is a good place to start. Everyone can understand how being better connected to ourselves, each other and Nature is beneficial to all. It is definitely a point to bring to the discussion, otherwise we will be selling the psychedelic treatment short.

In loving memory of ann shulgin

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.

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. 

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. 

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.

We are forever grateful for their contribution to the development and therapeutic use of (novel) psychedelic compounds and aim to continue their legacy. 

Hope or hype? Head of OPEN Foundation calls for caution in psychedelic renaissancE

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. 

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.”

Professional field

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.”

Get €100 off on all tickets by using the code OPENBLOG100

The Way of the Psychonaut Vol. 1: Encyclopedia for Inner Journeys

The Way of the Psychonaut Vol. 1: Encyclopedia for Inner Journeys. Stanislav Grof. MAPS. ISBN: 9780998276595

Written in an easy, understandable tone, this comprehensive work is a tour de force works its way through the worlds of psychology and psychotherapy, Holotropic Breathwork, maps of the psyche, birth, sex, and death, psychospiritual rebirth, the roots of trauma, spiritual emergency and transpersonal experiences, karma and reincarnation, higher creativity, great art, and archetypes.

Buy this book through bookdepository.com and support the OPEN Foundation

Effects of Ayahuasca on the Recognition of Facial Expressions of Emotions in Naive Healthy Volunteers: A Pilot, Proof-of-Concept, Randomized Controlled Trial

Abstract

Background: The recognition of emotions in facial expressions (REFE) is a core aspect of social cognition. Previous studies with the serotonergic hallucinogens lysergic acid diethylamide and psilocybin showed that these drugs reduced the recognition of negative (fear) faces in healthy volunteers. This trial assessed the acute and prolonged effects of a single dose of ayahuasca on the REFE.

Methods: Twenty-two healthy volunteers participated in a pilot, proof-of-concept, randomized trial. Study variables included a REFE task performed before and 4 hours after drug intake, subjective effects (self-reports/observer impressions), tolerability measures (cardiovascular measures, self-reports), and brain-derived neurotrophic factor plasma levels. The REFE task was applied again 1, 7, 14, and 21 days and 3 months after drug intake. Stability of ayahuasca alkaloids during the study was also assessed (room temperature, 18 months).

Findings: Compared with placebo, ayahuasca did not modify the REFE. No significant effects were observed on cardiovascular measures and brain-derived neurotrophic factor levels. Volunteers reported visual effects, tranquility/relaxation, and well-being, with few reports of transient anxiety/confusion. Ayahuasca was well tolerated, producing mainly nausea, gastrointestinal discomfort, and vomiting. A significant time-dependent deterioration of alkaloids was observed, especially for dimethyltryptamine.

Conclusions: Absence of significant effects on the REFE task could be due to lack of effects of ayahuasca (at the doses used), alkaloid degradation, learning effects, and the high educational level of the sample. Further trials with different samples are needed to better understand the effects of ayahuasca and other serotonergic hallucinogens on the REFE. Future trials should improve methods to guarantee the stability of ayahuasca alkaloids.

Rocha, J. M., Rossi, G. N., de Lima Osório, F., Bouso, J. C., de Oliveira Silveira, G., Yonamine, M., Campos, A. C., Bertozi, G., Cecílio Hallak, J. E., & Dos Santos, R. G. (2021). Effects of Ayahuasca on the Recognition of Facial Expressions of Emotions in Naive Healthy Volunteers: A Pilot, Proof-of-Concept, Randomized Controlled Trial. Journal of clinical psychopharmacology, 41(3), 267–274. https://doi.org/10.1097/JCP.0000000000001396

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Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial

Abstract

Importance: Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression.

Objective: To investigate the effect of psilocybin therapy in patients with MDD.

Design, setting, and participants: This randomized, waiting list-controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population).

Interventions: Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay.

Main outcomes and measures: The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR).

Results: Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.5; 95% CI, 1.4-3.5; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.5-3.7; P < .001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d = 2.6; 95% CI, 1.8-3.5; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 2.3; 95% CI, 1.5-3.0; P < .001). In the overall sample, 17 participants (71%) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score).

Conclusions and relevance: Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression.

Trial registration: ClinicalTrials.gov Identifier: NCT03181529.

Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., Finan, P. H., & Griffiths, R. R. (2021). Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA psychiatry, 78(5), 481–489. https://doi.org/10.1001/jamapsychiatry.2020.3285

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Examining changes in personality following shamanic ceremonial use of ayahuasca

Abstract

The present study examines the association between the ceremonial use of ayahuasca-a decoction combining the Banistereopsis caapi vine and N,N-Dimethyltryptamine-containing plants-and changes in personality traits as conceived by the Five-Factor model (FFM). We also examine the degree to which demographic characteristics, baseline personality, and acute post-ayahuasca experiences affect personality change. Participants recruited from three ayahuasca healing and spiritual centers in South and Central America (N = 256) completed self-report measures of personality at three timepoints (Baseline, Post, 3-month Follow-up). Informant-report measures of the FFM were also obtained (N = 110). Linear mixed models were used to examine changes in personality and the moderation of those changes by covariates. The most pronounced change was a reduction in Neuroticism dzself-reportT1-T2 = – 1.00; dzself-reportT1-T3 = – .85; dzinformant-reportT1-T3 = – .62), reflected in self- and informant-report data. Moderation of personality change by baseline personality, acute experiences, and purgative experiences was also observed.

Weiss, B., Miller, J. D., Carter, N. T., & Keith Campbell, W. (2021). Examining changes in personality following shamanic ceremonial use of ayahuasca. Scientific reports, 11(1), 6653. https://doi.org/10.1038/s41598-021-84746-0

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A placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats

Abstract

Ayahuasca is a plant concoction containing N,N-dimethyltryptamine (DMT) and certain β-carboline alkaloids from South America. Previous research in naturalistic settings has suggested that ingestion of ayahuasca can improve mental health and well-being; however, these studies were not placebo controlled and did not control for the possibility of expectation bias. This naturalistic observational study was designed to assess whether mental health changes were produced by ayahuasca or by set and setting. Assessments were made pre- and post-ayahuasca sessions in 30 experienced participants of ayahuasca retreats hosted in the Netherlands, Spain, and Germany. Participants consumed ayahuasca (N = 14) or placebo (N = 16). Analysis revealed a main effect of time on symptoms of depression, anxiety, and stress. Compared to baseline, symptoms reduced in both groups after the ceremony, independent of treatment. There was a main treatment × time interaction on implicit emotional empathy, indicating that ayahuasca increased emotional empathy to negative stimuli. The current findings suggest that improvements in mental health of participants of ayahuasca ceremonies can be driven by non-pharmacological factors that constitute a placebo response but also by pharmacological factors that are related to the use of ayahuasca. These findings stress the importance of placebo-controlled designs in psychedelic research and the need to further explore the contribution of non-pharmacological factors to the psychedelic experience.

Uthaug, M. V., Mason, N. L., Toennes, S. W., Reckweg, J. T., de Sousa Fernandes Perna, E. B., Kuypers, K., van Oorsouw, K., Riba, J., & Ramaekers, J. G. (2021). A placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats. Psychopharmacology, 238(7), 1899–1910. https://doi.org/10.1007/s00213-021-05817-8

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Self-blinding citizen science to explore psychedelic microdosing

Abstract

Microdosing is the practice of regularly using low doses of psychedelic drugs. Anecdotal reports suggest that microdosing enhances well-being and cognition; however, such accounts are potentially biased by the placebo effect. This study used a ‘self-blinding’ citizen science initiative, where participants were given online instructions on how to incorporate placebo control into their microdosing routine without clinical supervision. The study was completed by 191 participants, making it the largest placebo-controlled trial on psychedelics to-date. All psychological outcomes improved significantly from baseline to after the 4 weeks long dose period for the microdose group; however, the placebo group also improved and no significant between-groups differences were observed. Acute (emotional state, drug intensity, mood, energy, and creativity) and post-acute (anxiety) scales showed small, but significant microdose vs. placebo differences; however, these results can be explained by participants breaking blind. The findings suggest that anecdotal benefits of microdosing can be explained by the placebo effect.

Szigeti, B., Kartner, L., Blemings, A., Rosas, F., Feilding, A., Nutt, D. J., Carhart-Harris, R. L., & Erritzoe, D. (2021). Self-blinding citizen science to explore psychedelic microdosing. eLife, 10, e62878. https://doi.org/10.7554/eLife.62878

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Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission

Abstract

Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT2A, but not N-methyl-D-aspartate (NMDA) and 5-HT1A, synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons (Raptor f/f :Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT2A/AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC (Raptor f/f :Gad2-Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.

De Gregorio, D., Popic, J., Enns, J. P., Inserra, A., Skalecka, A., Markopoulos, A., Posa, L., Lopez-Canul, M., Qianzi, H., Lafferty, C. K., Britt, J. P., Comai, S., Aguilar-Valles, A., Sonenberg, N., & Gobbi, G. (2021). Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission. Proceedings of the National Academy of Sciences of the United States of America, 118(5), e2020705118. https://doi.org/10.1073/pnas.2020705118

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