OPEN Foundation

J. Bouso

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

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

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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Serotonergic hallucinogens/psychedelics could be promising treatments for depressive and anxiety disorders in end-stage cancer.

Abstract

In a recent issue of the BMC Psychiatry, the evidence of effectiveness of treatments for psychiatric conditions in end-stage cancer patients was reviewed (Johnson, 2018). The review was comprehensive, and included traditional and non-traditional/alternative treatments, including herbal medicines and spirituality. However, evidence showing that classic or serotonergic hallucinogens/psychedelics such as psilocybin and lysergic acid diethylamide (LSD) could be effective treatments for depressive and anxiety disorders in end-stage cancer was not included. In this commentary, we expand the information available on the original article by briefly reviewing data from recent placebo-controlled, double-blind, cross-over clinical trials showing evidence that administration of single (or few) doses of LSD and psilocybin was associated with rapid and sustained reductions in depressive and anxiety symptoms in patients with end-stage cancer and other life-threatening diseases (e.g., Bechterew’s disease, Parkinson’s disease, Celiac disease). Since these substances seem to produce rapid and sustained therapeutic effects with single (or few) doses and well tolerated, large-scale, prospective, multi-site studies of end-stage cancer and classical/serotonergic hallucinogens/psychedelics should be performed to improve our understanding of the therapeutic potentials of these drugs and their use on clinical practice.
dos Santos, R. G., Bouso, J. C., & Hallak, J. E. (2019). Serotonergic hallucinogens/psychedelics could be promising treatments for depressive and anxiety disorders in end-stage cancer. BMC psychiatry19(1), 321., https://doi.org/10.1186/s12888-019-2288-z
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Serotonergic hallucinogens and recognition of facial emotion expressions: a systematic review of the literature.

Abstract

BACKGROUND:
Recognition of emotions in facial expressions (REFE) is a key aspect of social cognition. Anxiety and mood disorders are associated with deficits in REFE, and anxiolytics and antidepressants reverse these deficits. Recent studies have shown that serotonergic hallucinogens (i.e. ayahuasca, dimethyltryptamine, psilocybin, lysergic acid diethylamide [LSD], and mescaline) have anxiolytic and antidepressant properties, but their effects on REFE are not well understood. The purpose of the study was to conduct a systematic review analyzing the effects of serotonergic hallucinogens on REFE in humans.
METHODS:
Studies published in the PubMed, PsycINFO, and Web of Science databases until 19 October 2018 which analyzed the effects of serotonergic hallucinogens on REFE in humans were included.
RESULTS:
Of the 62 studies identified, 8 studies were included. Included studies involved the administration of a single or a few doses of LSD or psilocybin, and most trials were randomized and controlled with placebo. LSD and psilocybin reduced the recognition of negative emotions in most studies and modulated amygdala activity to these stimuli, which was correlated with antidepressive effects in patients. Both drugs were well tolerated.
CONCLUSIONS:
Serotonergic hallucinogens reduced the recognition of negative emotions by modulating amygdala activity. Despite the small sample sizes, results suggest that serotonergic hallucinogens show promising beneficial effects on deficits in REFE.
Rocha, J. M., Osório, F. L., Crippa, J. A. S., Bouso, J. C., Rossi, G. N., Hallak, J. E., & dos Santos, R. G. (2019). Serotonergic hallucinogens and recognition of facial emotion expressions: a systematic review of the literature. Therapeutic advances in psychopharmacology9, 2045125319845774., https://doi.org/10.1177/2045125319845774
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Ayahuasca and Public Health: Health Status, Psychosocial Well-Being, Lifestyle, and Coping Strategies in a Large Sample of Ritual Ayahuasca Users

Assessing the health status of ayahuasca users has been challenging due to the limitations involved in randomized clinical trials and psychometric approaches. The main objective of this study is the implementation of an approach based on public health indicators. We developed a self-administered questionnaire that was administered to long-term ayahuasca users around Spain. The questionnaire was administrated face-to-face to participants (n = 380) in places where ayahuasca ceremonies were occurring. Public health indicators were compared with Spanish normative data, and intergroup analyses were conducted. Long-term ayahuasca use was associated with higher positive perception of health or with a healthy lifestyle, among other outcomes. Fifty-six percent of the sample reported reducing their use of prescription drugs due to ayahuasca use. Participants who used ayahuasca more than 100 times scored higher in personal values measures. The main conclusion of this study is that a respectful and controlled use of hallucinogenic/psychedelic drugs taken in communitarian settings can be incorporated into modern society with benefits for public health. This new approach, based on the use of health indicators that were not used in previous ayahuasca studies, offers relevant information about the impact of long-term exposure to ayahuasca on public health.

Ona, G., Kohek, M., Massaguer, T., Gomariz, A., Jiménez, D. F., Dos Santos, R. G., … & Bouso, J. C. (2019). Ayahuasca and Public Health: Health Status, Psychosocial Well-Being, Lifestyle, and Coping Strategies in a Large Sample of Ritual Ayahuasca Users. Journal of psychoactive drugs, 1-11., 10.1080/02791072.2019.1567961
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Psychedelics and Personality.

Abstract

In the past decade, an increasing number of clinical trials are reporting evidence that psychedelics or serotonergic hallucinogens (such as lysergic acid diethylamide, psilocybin, and ayahuasca/dimethyltryptamine) could be effective in the treatment of mood, anxiety, and substance use disorders. The mechanisms responsible for these effects are not fully understood but seem to involve changes in bran dynamics in areas rich in serotonergic 5-HT2A receptors and in personality. In the present text, we present a brief and critical overview of the current research in this field, pointing out both promises and limitations of these studies.
Aixalà, M., dos Santos, R. G., Hallak, J. E., & Bouso, J. C. (2018). Psychedelics and Personality., https://doi.org/10.1021/acschemneuro.8b00237
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Efficacy, tolerability, and safety of serotonergic psychedelics for the management of mood, anxiety, and substance-use disorders: a systematic review of systematic reviews

Abstract

Mood, anxiety, and substance-use disorders are among the most prevalent psychiatric disorders in the population. Although several pharmacological treatments are available, they are not effective for a significant proportion of patients and are associated with several adverse reactions. Therefore, new treatments should be explored. Recent studies suggest that serotonergic hallucinogens/psychedelics including ayahuasca, psilocybin, and lysergic acid diethylamide (LSD) have anxiolytic, antidepressive, and antiaddictive effects. Areas Covered: A systematic review of systematic reviews assessing the efficacy, safety, and tolerability of serotonergic hallucinogens/psychedelic was performed using the PubMed data base until 11 April 2018. Systematic reviews with or without meta-analysis were analyzed, but only reviews that described at least one randomized controlled trial (RCT) were included. Expert Commentary: Psilocybin and LSD reduced anxiety and depression in cancer patients and symptoms of alcohol and tobacco dependence, and ayahuasca reduced depression symptoms in treatment-resistant depression. Although the results are promising, several studies were open label, and only few were RCTs, and most had small sample sizes and a short duration. Single or few doses of these drugs seem to be well tolerated, but long-term studies are lacking. New RCTs with bigger samples and longer duration are needed to replicate these findings.

dos Santos, R. G., Bouso, J. C., Alcázar-Córcoles, M. Á., & Hallak, J. E. (2018). Efficacy, tolerability, and safety of serotonergic psychedelics for the management of mood, anxiety, and substance-use disorders: A systematic review of systematic reviews. Expert review of clinical pharmacology11(9), 889-902., 10.1080/17512433.2018.1511424
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Psychological variables implied in the therapeutic effect of ayahuasca: A contextual approach

Abstract

Ayahuasca is a psychedelic decoction originating from Amazonia. The ayahuasca-induced introspective experience has been shown to have potential benefits in the treatment of several pathologies, to protect mental health and to improve neuropsychological functions and creativity, and boost mindfulness. The underlying psychological processes related to the use of ayahuasca in a psychotherapeutic context are not yet well described in the scientific literature, but there is some evidence to suggest that psychological variables described in psychotherapies could be useful in explaining the therapeutic effects of the brew. In this study we explore the link between ayahuasca use and Decentering, Values and Self, comparing subjects without experience of ayahuasca (n = 41) with subjects with experience (n = 81). Results confirm that ayahuasca users scored higher than non-users in Decentering and Positive self, but not in Valued living, Life fulfillment, Self in social relations, Self in close relations and General self. Scores in Decentering were higher in the more experienced subjects (more than 15 occasions) than in those with less experience (less than 15 occasions). Our results show that psychological process variables may explain the outcomes in ayahuasca psychotherapy. The introduction of these variables is warranted in future ayahuasca therapeutic studies.
Franquesa, A., Sainz-Cort, A., Gandy, S., Soler, J., Alcázar-Córcoles, M. Á., & Bouso, J. C. (2018). Psychological variables implied in the therapeutic effect of ayahuasca: A contextual approach. Psychiatry research264, 334-339. 10.1016/j.psychres.2018.04.012
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Serotonergic psychedelics and personality: A systematic review of contemporary research

Abstract

Serotonergic psychedelics act as agonists at cortical 5-HT2A receptors and seem to induce personality changes. We conducted a systematic review of studies assessing the effects of these drugs on personality. Papers published from 1985–2016 were included from PubMed, LILACS, and SciELO databases. Three hundred and sixty-nine studies were identified, and 18 were included. Specific personality traits, such as Absorption and Self-Transcendence, seem to influence the effects of psychedelics, and psychedelic drug users and nonusers appear to differ in some personality traits. Psychedelics administered in controlled settings may induce personality changes, such as increased Openness and Self-Transcendence. Increases in global brain entropy induced by acute psychedelic administration predicted changes in Openness, and Self-Transcendence was negatively correlated with cortical thinning of the posterior cingulate cortex in long-term religious ayahuasca users. Acute and long-term use of psychedelics is associated with personality changes that appear to be modulated by 5-HT2A receptors. These changes seem to induce therapeutic effects that should be further explored in randomized controlled studies.

Bouso, J. C., dos Santos, R. G., Alcázar-Córcoles, M. Á., & Hallak, J. E. (2018). Serotonergic psychedelics and personality: a systematic review of contemporary research. Neuroscience & Biobehavioral Reviews. 10.1016/j.neubiorev.2018.02.004
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Ayahuasca: what mental health professionals need to know

Abstract

Background

Ayahuasca is a psychoactive ethnobotanical concoction that has been used for decades by indigenous groups of the Northwestern Amazon and by syncretic religious organizations for ritual and therapeutic purposes. In the last two decades, it is being used worldwide in evolving practices. Ayahuasca seem to therapeutic effects, but controlled studies are lacking. Moreover, its safety and toxicity are not completely understood.

Objectives

To present an overview of the effects of ayahuasca based on the most recent human studies.

Methods

Narrative review.

Results

Ayahuasca administration in controlled settings appears to be safe from a subjective and physiological perspective, with few adverse reactions being reported. More frequent adverse reactions occur in non-controlled settings. Prolonged psychotic reactions are rare and seem to occur especially in susceptible individuals. Ayahuasca showed antidepressive, anxiolytic, and antiaddictive effects in animal models, observational studies, and in open-label and controlled studies.

Discussion

Ayahuasca administration in controlled settings appear to be safe. Moreover, ayahuasca seem to have therapeutic effects for treatment-resistant psychiatric disorders that should be further investigated in randomized controlled clinical trials. However, medical complications and cases of prolonged psychotic reactions have been reported, and people with personal or family history of psychotic disorders should avoid ayahuasca intake.

Santos, R. G. D., Bouso, J. C., & Hallak, J. E. C. (2017). Ayahuasca: what mental health professionals need to know. Archives of Clinical Psychiatry (São Paulo)44(4), 103-109. 10.1590/0101-60830000000130
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