OPEN Foundation

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Is MDMA a psychedelic?

In conversation with Rick Doblin and Torsten Passie

Is MDMA a psychedelic or not? And what makes it so well suited for therapy? In this conversation between Rick Doblin, Torsten Passie and Joost Breeksema, the use of MDMA in a therapeutic setting is discussed in-depth.

According to Doblin, MDMA’s potential for healing PTSD-patients differs from the ‘classic’ psychedelics, which usually need a mystical experience or something similar to ego-dissolution in order to show similar results as MDMA. With MDMA, patients feel a sense of safety approaching their trauma ‘with their ego intact’, as Doblin puts it.
Then again, Doblin prefers to use the term broadly, and includes breath-working techniques and dreaming as psychedelic. In this conversation, both guests dive into the intricacies of MDMA therapy. According to both experts, MDMA can be seen as part of psychedelics if the term is used broadly.
Rick Doblin has dedicated his life to making therapeutic MDMA a reality. Ever since 1986, his non-profit association called MAPS has been instrumental in advancing the science of psychedelics and MDMA in particular. Their research into the application of MDMA in therapy received Breakthrough Status from the FDA and he is now in phase 2 and 3 of clinical studies with MDMA-assisted psychotherapy in both Europe and the United States.
Torsten Passie is a Visiting Professor at Harvard Medical School (Boston, USA). His extensive research at Hannover Medical School covers the psycho-physiology of altered states of consciousness and their healing potential, including clinical research with hallucinogenic drugs (cannabis, ketamin, nitrous oxide, MDMA, psilocybin). He is an internationally known expert on altered states of consciousness and the pharmacology of hallucinogenic drugs. He talks about the intricacies of psychedelic therapy, medicalization and how to integrate psychedelics into mainstream health care.
Both Torsten and Rick will present at ICPR 2020, and we’ll have panels on all these topics. A preview of what is to come in this conversation.

The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats

Abstract

Rationale: The nonmedical use of new psychoactive substances (NPS) is a worldwide public health concern. The so-called “benzofury” compounds, 5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (6-APB), are NPS with stimulant-like properties in human users. These substances are known to interact with monoamine transporters and 5-HT receptors in transfected cells, but less is known about their effects in animal models.

Methods: Here, we used in vitro monoamine transporter assays in rat brain synaptosomes to characterize the effects of 5-APB and 6-APB, together with their N-methyl derivatives 5-MAPB and 6-MAPB, in comparison with 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA). In vivo neurochemical and behavioral effects of 5-APB (0.3 and 1.0 mg/kg, i.v.) and 6-APB (0.3 and 1.0 mg/kg, i.v.) were assessed in comparison with MDA (1.0 and 3.0 mg/kg, i.v.) using microdialysis sampling in the nucleus accumbens of conscious male rats.

Results: All four benzofuran derivatives were substrate-type releasers at dopamine transporters (DAT), norepinephrine transporters (NET), and serotonin transporters (SERT) with nanomolar potencies, similar to the profile of effects produced by MDA and MDMA. However, the benzofurans were at least threefold more potent than MDA and MDMA at evoking transporter-mediated release. Like MDA, both benzofurans induced dose-related elevations in extracellular dopamine and serotonin in the brain, but benzofurans were more potent than MDA. The benzofuran derivatives also induced profound behavioral activation characterized by forward locomotion which lasted for at least 2 h post-injection.

Conclusions: Overall, benzofurans are more potent than MDA in vitro and in vivo, producing sustained stimulant-like effects in rats. These data suggest that benzofuran-type compounds may have abuse liability and could pose risks for adverse effects, especially if used in conjunction with abused drugs or medications which enhance monoamine transmission in the brain.

Brandt, S. D., Walters, H. M., Partilla, J. S., Blough, B. E., Kavanagh, P. V., & Baumann, M. H. (2020). The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3, 4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats. Psychopharmacology237(12), 3703-3714; 10.1007/s00213-020-05648-z

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Remembering Jordi Riba – Pioneering ayahuasca researcher


We are deeply saddened by the loss of pharmacologist dr. Jordi Riba, probably the most prominent psychedelic researcher in Catalunya and Spain, and a true pioneer in the biomedical study of ayahuasca.
Jordi was a true explorer who conducted his scientific quest for discovery and information in the same way 15th-century discoverers explored territories on unknown continents: without navigation, but with great dedication and perseverance. He became intrigued by the effects of ayahuasca at a time when research into psychedelics was ignored by most of the scientific community, and actively opposed by governments in many countries. Despite these obstacles, he managed to bring ayahuasca to his Barcelona research clinic and published an unprecedented controlled, dose-ranging study on freeze-dried ayahuasca almost 20 years ago. Since then he has published close to 40 scientific research papers on ayahuasca, greatly advancing psychedelic research and significantly contributing to the re-emerging interest in therapeutic applications of psychedelics.
Jordi Riba was a prominent speaker at all previous editions of ICPR. The first time OPEN met with Jordi was in 2010, right before the Mind Altering Science conference. It was the first conference OPEN had ever organized. As novices in this field, we invited several experts, and to our own amazement, many of them, including Jordi, accepted our invitation. We even managed to find a hotel that would accommodate our speakers for free. Jordi Riba and his colleague José Carlos Bouso were the first to arrive in Amsterdam, and they headed directly to the hotel. Before long, they called us and stated politely but in no uncertain terms that thank you very much, we will not be staying here. Flabbergasted, we apologized and tried frantically to find an alternative hotel. Inexperienced as we were, we had not visited the hotel before accepting their offer, but sure enough, the “Hemp Hotel” was aimed at cannabis tourists; the shabby couches in the lobby were full of stoned tourists, the hemp smoke thick enough to cut with a knife, and the receptionist absolutely clueless that the hotel was reserved for our speakers. Luckily, we found them a decent hotel and by all accounts, the conference was a success. This anecdote was typical for Jordi – a polite and serious gentleman researcher from Spain who would not abide crappy hotels. He would go on to speak at all of our conferences throughout the years, and would have been present at ICPR 2020, had circumstances been different.
Looking back on fifteen years of ayahuasca research in an interview with OPEN, he shared many of the complexities – technically, culturally, and pharmacologically – of studying such a culturally embedded and variable plant mixture. To address some of these, he managed to create standardized, freeze-dried and encapsulated ayahuasca, which he administered to volunteers in various doses in his Barcelona lab. In addition to the pharmacodynamics and pharmacokinetics of ayahuasca, he used neuroimaging techniques to study the brew’s effects on humans, and used in vitro techniques to investigate the effects on a cellular level. At his last lecture at ICPR 2016, he presented ground-breaking findings, showing that the harmala alkaloids, harmine and tetrahydroharmine, induce neurogenesis, which not only provided further evidence that ayahuasca’s effects were due to more than just DMT, made available orally, but that the beta-carbolines present in the brew had important, therapeutically relevant effects of their own. It is unfortunate that throughout most of his career he conducted his research without much scientific support or resources while overall recognition of his work only emerged towards the end of his career. But Jordi accepted irony easily and embraced satire, as he was a man full of wit and humour. It’s quite telling that Don Quixote was among his favourite novels.
During the final years of his career Jordi resigned from Sant Pau Hospital while facing an existential crisis. He felt very lucky to be surrounded by warm-hearted family, friends and colleagues and had every intention to find his way back to academia. He loved the free haven of questioning and exploring minds, driven by curiosity, without prejudice, bias or agenda. Jordi Riba’s passing was sudden and tragic, and we can only remember his curiosity, scientific diligence and wry sense of humor with fondness. He will be sorely missed.

Phytochemical, Cytotoxicity, Antioxidant and Anti-Inflammatory Effects of Psilocybe Natalensis Magic Mushroom

Abstract

Psilocybin-containing mushrooms, commonly known as magic mushrooms, have been used since ancient and recent times for depression and to improve quality of life. However, their anti-inflammatory properties are not known. The study aims at investing cytotoxicity; antioxidant; and, for the first time, anti-inflammatory effects of Psilocybe natalensis, a psilocybin-containing mushroom that grows in South Africa, on lipopolysaccharide-induced RAW 264.7 macrophages. Macrophage cells were stimulated with lipopolysaccharide and treated with different concentrations of Psilocybe natalensis mushroom extracted with boiling hot water, cold water and ethanol over 24 h. Quercetin and N-nitro-L-arginine methyl ester were used as positive controls. Effects of extracts on the lipopolysaccharide-induced nitric oxide, prostaglandin E2, and cytokine activities were investigated. Phytochemical analysis, and the antioxidant and cytotoxicity of extracts, were determined. Results showed that the three extracts inhibited the lipopolysaccharide-induced nitric oxide, prostaglandin E2, and interleukin 1β cytokine production significantly in a dose-dependent manner close to that of the positive controls. A study proposed that ethanol and water extracts of Psilocybe natalensis mushroom were safe at concentrations used, and have antioxidant and anti-inflammatory effects. Phytochemical analysis confirmed the presence of natural antioxidant and anti-inflammatory compounds in the mushroom extracts.

Nkadimeng, S. M., Nabatanzi, A., Steinmann, C. M., & Eloff, J. N. (2020). Phytochemical, Cytotoxicity, Antioxidant and Anti-Inflammatory Effects of Psilocybe Natalensis Magic Mushroom. Plants9(9), 1127; https://doi.org/10.3390/plants9091127

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Plasma psilocin critically determines behavioral and neurobiological effects of psilocybin

Madsen, M. K., & Knudsen, G. M. (2021). Plasma psilocin critically determines behavioral and neurobiological effects of psilocybin. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology46(1), 257-258; 10.1038/s41386-020-00823-4
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A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers

Abstract

Background: Lysergic acid diethylamide (LSD) is an ergot alkaloid derivative with psychedelic properties that has been implicated in the management of persistent pain. Clinical studies in the 1960s and 1970s have demonstrated profound analgesic effects of full doses of LSD in terminally ill patients, but this line of research evaporated after LSD was scheduled worldwide.

Aim: The present clinical study is the first to revisit the potential of LSD as an analgesic, and at dose levels which are not expected to produce profound mind-altering effects.

Methods: Twenty-four healthy volunteers received single doses of 5, 10 and 20 µg LSD as well as placebo on separate occasions. A Cold Pressor Test was administered at 1.5 and 5 h after treatment administration to assess pain tolerance to experimentally evoked pain. Ratings of dissociation and psychiatric symptoms as well as assessments of vital signs were included to monitor mental status as well as safety during treatments.

Results: LSD 20 µg significantly increased the time that participants were able to tolerate exposure to cold (3°C) water and decreased their subjective levels of experienced pain and unpleasantness. LSD elevated mean blood pressure within the normal range and slightly increased ratings of dissociation, anxiety and somatization.

Conclusion: The present study provides evidence of a protracted analgesic effect of LSD at a dose that is low enough to avoid a psychedelic experience. The present data warrant further research into the analgesic effects of low doses of LSD in patient populations.

Ramaekers, J. G., Hutten, N., Mason, N. L., Dolder, P., Theunissen, E. L., Holze, F., … & Kuypers, K. P. (2020). A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers. Journal of Psychopharmacology, 0269881120940937; 10.1177/0269881120940937
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P300-mediated modulations in self-other processing under psychedelic psilocybin are related to connectedness and changed meaning: A window into the self-other overlap

Abstract

The concept of self and self-referential processing has a growing explanatory value in psychiatry and neuroscience, referring to the cognitive organization and perceptual differentiation of self-stimuli in health and disease. Conditions in which selfhood loses its natural coherence offer a unique opportunity for elucidating the mechanisms underlying self-disturbances. We assessed the psychoactive effects of psilocybin (230 μg/kg p.o.), a preferential 5-HT1A/2A agonist known to induce shifts in self-perception. Our placebo-controlled, double-blind, within-subject crossover experiment (n = 17) implemented a verbal self-monitoring task involving vocalizations and participant identification of real-time auditory source- (self/other) and pitch-modulating feedback. Subjective experience and task performance were analyzed, with time-point-by-time-point assumption-free multivariate randomization statistics applied to the spatiotemporal dynamics of event-related potentials. Psilocybin-modulated self-experience, interacted with source to affect task accuracy, and altered the late phase of self-stimuli encoding by abolishing the distinctiveness of self- and other-related electric field configurations during the P300 timeframe. This last effect was driven by current source density changes within the supragenual anterior cingulate and right insular cortex. The extent of the P300 effect was associated with the intensity of psilocybin-induced feelings of unity and changed meaning of percepts. Modulations of late encoding and their underlying neural generators in self-referential processing networks via 5-HT signaling may be key for understanding self-disorders. This mechanism may reflect a neural instantiation of altered self-other and relational meaning processing in a stimulus-locked time domain. The study elucidates the neuropharmacological foundation of subjectivity, with implications for therapy, underscoring the concept of connectedness.

Smigielski, L., Kometer, M., Scheidegger, M., Stress, C., Preller, K. H., Koenig, T., & Vollenweider, F. X. (2020). P300‐mediated modulations in self–other processing under psychedelic psilocybin are related to connectedness and changed meaning: A window into the self–other overlap. Human brain mapping41(17), 4982-4996; 10.1002/hbm.25174

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Psychedelic science in post-COVID-19 psychiatry

Abstract

The medium- to long-term consequences of COVID-19 are not yet known, though an increase in mental health problems are predicted. Multidisciplinary strategies across socio-economic and psychological levels may be needed to mitigate the mental health burden of COVID-19. Preliminary evidence from the rapidly progressing field of psychedelic science shows that psilocybin therapy offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and maladaptive habitual patterns of cognition and behaviour, notably depression, addiction and obsessive compulsive disorder. The COMPASS Pathways (COMPASS) phase 2b double-blind trial of psilocybin therapy in antidepressant-free, treatment-resistant depression (TRD) is underway to determine the safety, efficacy and optimal dose of psilocybin. Results from the Imperial College London Psilodep-RCT comparing the efficacy and mechanisms of action of psilocybin therapy to the selective serotonin reuptake inhibitor (SSRI) escitalopram will soon be published. However, the efficacy and safety of psilocybin therapy in conjunction with SSRIs in TRD is not yet known. An additional COMPASS study, with a centre in Dublin, will begin to address this question, with potential implications for the future delivery of psilocybin therapy. While at a relatively early stage of clinical development, and notwithstanding the immense challenges of COVID-19, psilocybin therapy has the potential to play an important therapeutic role for various psychiatric disorders in post-COVID-19 clinical psychiatry.

Kelly, J. R., Crockett, M. T., Alexander, L., Haran, M., Baker, A., Burke, L., … & O’Keane, V. (2020). Psychedelic science in post-COVID-19 psychiatry. Irish journal of psychological medicine, 1-6; 10.1017/ipm.2020.94

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Psychedelic Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of Patient Experiences in Qualitative Studies

Abstract

Introduction: Interest in the use of psychedelic substances for the treatment of mental disorders is increasing. Processes that may affect therapeutic change are not yet fully understood. Qualitative research methods are increasingly used to examine patient accounts; however, currently, no systematic review exists that synthesizes these findings in relation to the use of psychedelics for the treatment of mental disorders.

Objective: To provide an overview of salient themes in patient experiences of psychedelic treatments for mental disorders, presenting both common and diverging elements in patients’ accounts, and elucidating how these affect the treatment process.

Methods: We systematically searched the PubMed, MEDLINE, PsycINFO, and Embase databases for English-language qualitative literature without time limitations. Inclusion criteria were qualitative research design; peer-reviewed studies; based on verbalized patient utterances; and a level of abstraction or analysis of the results. Thematic synthesis was used to analyze and synthesize results across studies. A critical appraisal of study quality and methodological rigor was conducted using the Critical Appraisal Skills Programme (CASP).

Results: Fifteen research articles, comprising 178 patient experiences, were included. Studies exhibited a broad heterogeneity in terms of substance, mental disorder, treatment context, and qualitative methodology. Substances included psilocybin, lysergic acid diethylamide (LSD), ibogaine, ayahuasca, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Disorders included anxiety, depression, eating disorders, post-traumatic stress disorder, and substance use disorders. While the included compounds were heterogeneous in pharmacology and treatment contexts, patients reported largely comparable experiences across disorders, which included phenomenological analogous effects, perspectives on the intervention, therapeutic processes and treatment outcomes. Comparable therapeutic processes included insights, altered self-perception, increased connectedness, transcendental experiences, and an expanded emotional spectrum, which patients reported contributed to clinically and personally relevant responses.

Conclusions: This review demonstrates how qualitative research of psychedelic treatments can contribute to distinguishing specific features of specific substances, and carry otherwise undiscovered implications for the treatment of specific psychiatric disorders.

Breeksema, J. J., Niemeijer, A. R., Krediet, E., Vermetten, E., & Schoevers, R. A. (2020). Psychedelic treatments for psychiatric disorders: a systematic review and thematic synthesis of patient experiences in qualitative studies. CNS drugs, 1-22; 10.1007/s40263-020-00748-y

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