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Acute subjective effects in LSD- and MDMA-assisted psychotherapy

March 16, 2022 / LSD, MDMA, Papers, Phenomenology, Psychotherapy / Leave a Comment / By / , , ,

Abstract

Background: Lysergic acid diethylamide (LSD) and 3,4-methylenedioxymethamphetamine (MDMA) were used in psychotherapy in the 1960s-1980s, and are currently being re-investigated as treatments for several psychiatric disorders. In Switzerland, limited medical use of these substances is possible in patients not responding to other treatments (compassionate use).

Methods: This study aimed to describe patient characteristics, treatment indications and acute alterations of mind in patients receiving LSD (100-200 µg) and/or MDMA (100-175 mg) within the Swiss compassionate use programme from 2014-2018. Acute effects were assessed using the 5 Dimensions of Altered States of Consciousness scale and the Mystical Experience Questionnaire, and compared with those in healthy volunteers administered with LSD or MDMA and patients treated alone with LSD in clinical trials.

Results: Eighteen patients (including 12 women and six men, aged 29-77 years) were treated in group settings. Indications mostly included posttraumatic stress disorder and major depression. Generally, a drug-assisted session was conducted every 3.5 months after 3-10 psychotherapy sessions. LSD induced pronounced alterations of consciousness on the 5 Dimensions of Altered States of Consciousness scale, and mystical-type experiences with increases in all scales on the Mystical Experience Questionnaire. Effects were largely comparable between patients in the compassionate use programme and patients or healthy subjects treated alone in a research setting.

Conclusion: LSD and MDMA are currently used medically in Switzerland mainly in patients with posttraumatic stress disorder and depression in group settings, producing similar acute responses as in research subjects. The data may serve as a basis for further controlled studies of substance-assisted psychotherapy.

Schmid, Y., Gasser, P., Oehen, P., & Liechti, M. E. (2021). Acute subjective effects in LSD- and MDMA-assisted psychotherapy. Journal of psychopharmacology (Oxford, England), 35(4), 362–374. https://doi.org/10.1177/0269881120959604

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Microdosing psychedelics: Subjective benefits and challenges, substance testing behavior, and the relevance of intention

February 6, 2022 / Microdosing, Papers, Psychopharmacology / Leave a Comment / By / , , , , ,

Abstract

Background: Microdosing psychedelics is the practice of taking small, sub-hallucinogenic doses of lysergic acid diethylamide or psilocybin-containing mushrooms. Despite its surging popularity, little is known about the specific intentions to start microdosing and the effects of this practice.

Aims: First, we aimed to replicate previous findings regarding the subjective benefits and challenges reported for microdosing. Second, we assessed whether people who microdose test their substances before consumption. Third, we examined whether having an approach-intention to microdosing was predictive of more reported benefits.

Methods: The Global Drug Survey runs the world’s largest online drug survey. Participants who reported last year use of lysergic acid diethylamide or psilocybin in the Global Drug Survey 2019 were offered the opportunity to answer a sub-section on microdosing.

Results: Data from 6753 people who reported microdosing at least once in the last 12 months were used for analyses. Our results suggest a partial replication of previously reported benefits and challenges among the present sample often reporting enhanced mood, creativity, focus and sociability. Counter to our prediction, the most common challenge participants associated with microdosing was ‘None’. As predicted, most participants reported not testing their substances. Counter to our hypothesis, approach-intention – microdosing to approach a desired goal – predicted less rather than more benefits. We discuss alternate frameworks that may better capture the reasons people microdose.

Conclusion: Our results suggest the perceived benefits associated with microdosing greatly outweigh the challenges. Microdosing may have utility for a variety of uses while having minimal side effects. Double-blind, placebo-controlled experiments are required to substantiate these reports.

Petranker, R., Anderson, T., Maier, L. J., Barratt, M. J., Ferris, J. A., & Winstock, A. R. (2022). Microdosing psychedelics: Subjective benefits and challenges, substance testing behavior, and the relevance of intention. Journal of psychopharmacology (Oxford, England), 36(1), 85–96. https://doi.org/10.1177/0269881120953994

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Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans

February 6, 2022 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychopharmacology, Spirituality / Leave a Comment / By / , , , , , , ,

Abstract

Background: Psilocybin is a serotonergic psychedelic with psychoactive effects mediated by serotonin 2A receptor (5-HT2AR) activation. It produces an acute psychedelic altered state of consciousness with a unique phenomenology that can be temporally characterized by three intensity phases: onset of psychoactive effect, a peak plateau and return to normal consciousness.

Aims: We evaluated whether pre-drug brain 5-HT2AR binding predicted the three phases of psilocybin subjective drug intensity (SDI) and retrospective self-report of mystical type experiences in healthy individuals.

Method: Sixteen participants completed a pre-drug [11C]Cimbi-36 positron emission tomography scan to assess 5-HT2AR binding. On a separate day, participants completed a single psilocybin session (oral dose range 0.2-0.3 mg/kg), during which SDI was assessed every 20 min. The Mystical Experience Questionnaire (MEQ) was completed at the end of the session. The three SDI phases were modelled using segmented linear regressions. We evaluated the associations between neocortex 5-HT2AR binding and SDI/MEQ outcomes using linear regression models.

Results: Neocortex 5-HT2AR was statistically significantly negatively associated with peak plateau duration and positively with time to return to normal waking consciousness. It was also statistically significantly negatively associated with MEQ total score.

Conclusion: This is the first study to investigate how individual brain 5-HT2AR binding predicts subjective effects of a single dose of psilocybin. Our findings reinforce the role of cerebral 5-HT2AR in shaping the temporal and mystical features of the psychedelic experience. Future studies should examine whether individual brain levels of 5-HT2AR have an impact on therapeutic outcomes in clinical studies.

Stenbæk, D. S., Madsen, M. K., Ozenne, B., Kristiansen, S., Burmester, D., Erritzoe, D., Knudsen, G. M., & Fisher, P. M. (2021). Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans. Journal of psychopharmacology (Oxford, England), 35(4), 459–468. https://doi.org/10.1177/0269881120959609

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Polypharmacology or “Pharmacological Promiscuity” In Psychedelic Research: What Are We Missing?

November 26, 2021 / Ayahuasca, Mushrooms / Psilocybin, Papers, Psychopharmacology / Leave a Comment / By / , , ,

Abstract

Research with psychedelic drugs has mainly focused on isolated compounds. However, this approach is challenged by the “polypharmacology” paradigm. In this Viewpoint, we suggest that we may be missing something if we do not use the whole product in the case of ayahuasca or Psilocybe mushrooms. After describing how research on psychedelic drugs can be effectively combined with the polypharmacology paradigm, ethical issues are also briefly discussed.

Ona, G. S., Dos Santos, R. G., Hallak, J., & Bouso, J. C. (2020). Polypharmacology or “Pharmacological Promiscuity” In Psychedelic Research: What Are We Missing?. ACS chemical neuroscience, 11(20), 3191–3193. https://doi.org/10.1021/acschemneuro.0c00614

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Potential safety, benefits, and influence of the placebo effect in microdosing psychedelic drugs: A systematic review

November 26, 2021 / LSD, Microdosing, Mushrooms / Psilocybin, Papers, Psychology / Leave a Comment / By / ,

Abstract

Microdosing psychedelic drugs-that is, taking sub-behavioral doses of lysergic acid diethylamide (LSD) or psilocybin-is a growing practice in Western societies. Taken mainly for creative or mood-enhancing purposes, thousands of users are increasingly being exposed to (micro)doses of psychedelic drugs. In this systematic review, we searched the available evidence from human studies, focusing our results in terms of three main axes: efficacy, safety, and the influence of the placebo effect in microdosing practices. While the available evidence has some strengths (e.g. large sample sizes, robust methodologies) there are also remarkable limitations (e.g. gender bias, heterogeneity of dosing schedules and drugs used). Highly contradictory results have been found, showing both the benefits and detriments of microdosing in terms of mood, creative processes, and energy, among other regards. This review provides a general overview of the methods and approaches used, which could be useful for improving future studies.

Ona, G., & Bouso, J. C. (2020). Potential safety, benefits, and influence of the placebo effect in microdosing psychedelic drugs: A systematic review. Neuroscience and biobehavioral reviews, 119, 194–203. https://doi.org/10.1016/j.neubiorev.2020.09.035

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The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain

November 26, 2021 / Neuroscience, Papers, Psychopharmacology, Salvia / Salvinorin A / Leave a Comment / By / , , , , , , ,

Abstract

Salvinorin A (SA) is a κ-opioid receptor agonist and atypical dissociative hallucinogen found in Salvia divinorum. Despite the resurgence of hallucinogen studies, the effects of κ-opioid agonists on human brain function are not well-understood. This placebo-controlled, within-subject study used functional magnetic resonance imaging for the first time to explore the effects of inhaled SA on strength, variability, and entropy of functional connectivity (static, dynamic, and entropic functional connectivity, respectively, or sFC, dFC, and eFC). SA tended to decrease within-network sFC but increase between-network sFC, with the most prominent effect being attenuation of the default mode network (DMN) during the first half of a 20-min scan (i.e., during peak effects). SA reduced brainwide dFC but increased brainwide eFC, though only the former effect survived multiple comparison corrections. Finally, using connectome-based classification, most models trained on dFC network interactions could accurately classify the first half of SA scans. In contrast, few models trained on within- or between-network sFC and eFC performed above chance. Notably, models trained on within-DMN sFC and eFC performed better than models trained on other network interactions. This pattern of SA effects on human brain function is strikingly similar to that of other hallucinogens, necessitating studies of direct comparisons.

Doss, M. K., May, D. G., Johnson, M. W., Clifton, J. M., Hedrick, S. L., Prisinzano, T. E., Griffiths, R. R., & Barrett, F. S. (2020). The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain. Scientific reports, 10(1), 16392. https://doi.org/10.1038/s41598-020-73216-8

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The emerging role of psilocybin and MDMA in the treatment of mental illness

November 26, 2021 / MDMA, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychotherapy / Leave a Comment / By / , , , , , , , , , , , , ,

Abstract

Introduction: Mental illness has a chronic course of illness with a number of clinical manifestations. Affected individuals experience significant functional, emotional, cognitive, and/or behavioral impairments. The growing prevalence of mental illness has been associated with significant social and economic costs. Indeed, the economic burden of mental illness is estimated to exceed $1.8 trillion USD over the next 30 years. A significant number of individuals affected by mental illness fail to respond to first-line treatment options. Therefore, there remains an unmet need for rapidly attenuating therapeutic options for mental health disorders with minimal social and economic burden.

Areas covered: The paucity of novel treatment options warrants a renewed investigation of psychedelic-based psychotherapy. Herein, the authors will evaluate the therapeutic potential of traditional psychedelics, psilocybin, and MDMA, in the treatment of mental illness with a narrative review of available literature.

Expert opinion: Psychedelics, such as psilocybin and MDMA, offer an alternative avenue of therapy for many mental health disorders. Available evidence indicates that psychedelics may offer a single-dose, rapid effect model that have robust effects with treatment-resistant mental disorders and a unique advantage as a possible monotherapy for mental illness. Novel clinical trials that evaluate the safety, tolerability, and efficacy in clinically representative populations are warranted.

Gill, H., Gill, B., Chen-Li, D., El-Halabi, S., Rodrigues, N. B., Cha, D. S., Lipsitz, O., Lee, Y., Rosenblat, J. D., Majeed, A., Mansur, R. B., Nasri, F., Ho, R., & McIntyre, R. S. (2020). The emerging role of psilocybin and MDMA in the treatment of mental illness. Expert review of neurotherapeutics, 20(12), 1263–1273. https://doi.org/10.1080/14737175.2020.1826931

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Biosynthesis, total synthesis, and biological profiles of Ergot alkaloids

February 21, 2022 / LSD, Papers / Leave a Comment / By / ,

Abstract

While the use of ergot alkaloids in folk medicine has been practiced for millennia, systematic investigations on their therapeutic potential began about 100 years ago. Subsequently, Albert Hofmann’s discovery of lysergic acid diethylamide (LSD) and its intense psychedelic properties garnered worldwide attention and prompted further studies of this compound class. As a result, several natural ergot alkaloids were discovered and unnatural analogs were synthesized, and some were used to treat an array of maladies, including Alzheimer’s and Parkinson’s disease. While LSD was never commercially approved, recent clinical studies have found it can be an innovative and effective treatment option for several psychiatric disorders. Ongoing biosynthetic and total synthetic investigations aim to understand the natural origins of ergot alkaloids, help develop facile means to produce these natural products and enable their continued use as medicinal chemistry lead structures. This review recounts major developments over the past 20 years in biosynthetic, total synthetic, and pharmaceutical studies. Many ergot alkaloid biosynthetic pathways have been elucidated, with some of them subsequently applied toward “green” syntheses. New chemical methodologies have fostered a fast and efficient access to the ergoline scaffold, prompting some groups to investigate biological properties of natural product-like ergot alkaloids. Limited pharmaceutical applications have yet to completely bypass the undesirable side effects of ergotism, suggesting further studies of this drug class are likely needed and will potentially harness major therapeutic significance.

Tasker, N. R., & Wipf, P. (2021). Biosynthesis, total synthesis, and biological profiles of Ergot alkaloids. The Alkaloids. Chemistry and biology, 85, 1–112. https://doi.org/10.1016/bs.alkal.2020.08.001

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N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo

November 26, 2021 / Ayahuasca, DMT, Neuroscience, Papers, Psychopharmacology / Leave a Comment / By / , , , , , ,

Abstract

N,N-dimethyltryptamine (DMT) is a component of the ayahuasca brew traditionally used for ritual and therapeutic purposes across several South American countries. Here, we have examined, in vitro and vivo, the potential neurogenic effect of DMT. Our results demonstrate that DMT administration activates the main adult neurogenic niche, the subgranular zone of the dentate gyrus of the hippocampus, promoting newly generated neurons in the granular zone. Moreover, these mice performed better, compared to control non-treated animals, in memory tests, which suggest a functional relevance for the DMT-induced new production of neurons in the hippocampus. Interestingly, the neurogenic effect of DMT appears to involve signaling via sigma-1 receptor (S1R) activation since S1R antagonist blocked the neurogenic effect. Taken together, our results demonstrate that DMT treatment activates the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks.

Morales-Garcia, J. A., Calleja-Conde, J., Lopez-Moreno, J. A., Alonso-Gil, S., Sanz-SanCristobal, M., Riba, J., & Perez-Castillo, A. (2020). N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo. Translational psychiatry, 10(1), 331. https://doi.org/10.1038/s41398-020-01011-0

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Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study

December 2, 2021 / Mushrooms / Psilocybin, Papers, Psychology, Psychotherapy, Safety / Leave a Comment / By / , , , , , , , , , ,

Abstract

Background: Psilocybin therapy has shown promise as a rapid-acting treatment for depression, anxiety, and demoralization in patients with serious medical illness (e.g., cancer) when paired with individual psychotherapy. This study assessed the safety and feasibility of psilocybin-assisted group therapy for demoralization in older long-term AIDS survivor (OLTAS) men, a population with a high degree of demoralization and traumatic loss.

Methods: Self-identified gay men OLTAS with moderate-to-severe demoralization (Demoralization Scale-II ≥8) were recruited from the community of a major US city for a single-site open-label study of psilocybin-assisted group therapy comprising 8-10 group therapy visits and one psilocybin administration visit (0·3-0·36 mg/kg po). Primary outcomes were rate and severity of adverse events, and participant recruitment and retention. The primary clinical outcome was change in mean demoralization from baseline to end-of-treatment and to 3-month follow-up assessed with a two-way repeated measures ANOVA. Trial registration: Clinicaltrials.gov (NCT02950467).

Findings: From 17 July 2017 to 16 January 2019, 18 participants (mean age 59·2 years (SD 4·4)) were enrolled, administered group therapy and psilocybin, and included in intent-to-treat analyses. We detected zero serious adverse reactions and two unexpected adverse reactions to psilocybin; seven participants experienced self-limited, severe expected adverse reactions. We detected a clinically meaningful change in demoralization from baseline to 3-month follow-up (mean difference -5·78 [SD 6·01], ηp 2 = 0·47, 90% CI 0·21-0·60).

Interpretation: We demonstrated the feasibility, relative safety, and potential efficacy of psilocybin-assisted group therapy for demoralization in OLTAS. Groups may be an effective and efficient means of delivering psychotherapy pre- and post-psilocybin to patients with complex medical and psychiatric needs.

Anderson, B. T., Danforth, A., Daroff, P. R., Stauffer, C., Ekman, E., Agin-Liebes, G., Trope, A., Boden, M. T., Dilley, P. J., Mitchell, J., & Woolley, J. (2020). Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study. EClinicalMedicine, 27, 100538. https://doi.org/10.1016/j.eclinm.2020.100538

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