OPEN Foundation

R. dos Santos

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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Therapeutic use of serotoninergic hallucinogens: A review of the evidence and of the biological and psychological mechanisms.

Abstract

Serotoninergic hallucinogens include drugs such as lysergic acid diethylamide (LSD), dimethyltryptamine (DMT) and psilocybin. Recent trials with single/few doses of these compounds show that they induce rapid and sustained antidepressive, anxiolytic, and antiaddictive effects. These effects are also observed in religious groups using the DMT-containing brew ayahuasca. The agonist action of these substances on 5-HT2A receptors expressed in frontal and limbic areas increase glutamatergic transmission and neuroplasticity. These neurochemical effects are associated with acute alterations on self-perception and increases in introspection and positive mood, and with subacute and long-term decreases in psychiatric symptoms, increases in some personality traits such as openness, improvements in emotional processing, and increases in empathy. These are preliminary but promising results that should be further explored in controlled trials with larger sample sizes, especially considering that these compounds could be beneficial in the treatment of treatment-resistant psychiatric disorders.
dos Santos, R. G., & Hallak, J. E. C. (2019). Therapeutic use of serotoninergic hallucinogens: a review of the evidence and of the biological and psychological mechanisms. Neuroscience & Biobehavioral Reviews., https://doi.org/10.1016/j.neubiorev.2019.12.001
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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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Possible Interactions Between 5-HT2A Receptors and the Endocannabinoid System in Humans: Preliminary Evidence of Interactive Effects of Ayahuasca and Endocannabinoids in a Healthy Human Subject

Excerpt

To the Editors

Ayahuasca is an ethnobotanical hallucinogenic preparation traditionally used for ritual and therapeutic purposes in the Northwestern Amazon Basin. It is prepared by the decoction of the bark of the vine Banisteriopsis caapi with the leaves of the shrub Psychotria viridisBanisteriopsis caapi contains the β-carbolines harmine, tetrahydroharmine, and harmaline, which are reversible inhibitors of monoamine oxidase type A (MAO-A), whereas P. viridis contains N,N-dimethyltryptamine (DMT), an agonist at 5-HT1A/2A/2C receptors. Pure DMT is not active orally because it is metabolized by MAO-A, but the β-carbolines in ayahuasca inhibit peripheral MAO-A and allow DMT to reach the brain. The β-carbolines also reach the systemic circulation in humans, but their effects are poorly characterized.

A recent randomized controlled trial (RCT) with 29 patients with treatment-resistant depression showed that, compared with placebo, a single ayahuasca dose induced significant antidepressant effects 7 days after drug intake. The mechanisms behind these effects are not clear but seem to involve agonism at cortical 5-HT2A receptors in brain areas related to emotional processing. 5-HT2A receptor activation also leads to the formation and release of endocannabinoids (ECs), and both the production and release of the EC 2-arachidonoylglycerol (2-AG) are induced by 5-HT2A agonists. Considering that the 5-HT2Areceptor and the EC system (ECS) are coexpressed in brain regions related to emotional processing, they could be involved in the antidepressive effect of ayahuasca. To test the possible interaction between both systems, we administered in an open-label design a single oral ayahuasca dose (1 mL/kg) to a healthy 34-year-old man and assessed subjective effects (Visual Analog Mood Scale [VAMS], Bodily Symptoms Scale, Beck Anxiety Inventory [BAI]), tolerability (blood pressure and heart rate, self-report), and EC plasma levels (anandamide [AEA], 2-AG) at several time points: VAMS, Bodily Symptoms Scale, blood pressure, and heart rate at baseline and 40, 90, 120, 150, and 240 minutes after drug intake; BAI–baseline, 240 minutes after drug intake; AEA, 2-AG (blood samples) at baseline and 90 and 240 minutes after drug intake. Analysis of the ayahuasca sample using gas chromatography with nitrogen-phosphorus detection showed the following alkaloid content (in mg/mL): 0.702 DMT, 1.748 harmine, 0.780 tetrahydroharmine, and 0.039 harmaline. Analysis of plasma ECs was performed using ultrahigh-performance liquid chromatography–tandem mass spectrometry. Detailed information on subjective measures and ayahuasca and EC analyses is described in the Supplemental Digital Content, http://links.lww.com/JCP/A532

The volunteer was not taking any medication and was requested to abstain from alcohol, tobacco, and caffeinated drinks 12 hours before ayahuasca intake. He arrived in the laboratory at 7:00 AM under fasting conditions, and urinalysis for illicit drug use was performed before ayahuasca intake (the test measured cannabis and cocaine and was negative for both drugs). Afterward, a cannula was introduced in his arm for collecting blood samples. Ayahuasca was administered at approximately 8:00 AM, and the experimental session lasted 5 hours. The experimental session consisted in the administration of the drug followed by application of the scales and assessment of tolerability measures at the aforementioned time points. During measurements, the volunteer remained seated in a comfortable reclining chair in a quiet dimly lit room. There was no psychological intervention before, during, or after the session.The volunteer remained in the laboratory under observation to see if the effects had subsided and was discharged around 6 hours after drug intake, which is the approximate duration of the psychoactive effects of ayahuasca.

dos Santos, R. G., Crippa, J. A., de Lima Osório, F., Rocha, J. M., Rossi, G. N., Marchioni, C., … & Hallak, J. E. C. (2018). Possible Interactions Between 5-HT2A Receptors and the Endocannabinoid System in Humans: Preliminary Evidence of Interactive Effects of Ayahuasca and Endocannabinoids in a Healthy Human Subject. Journal of clinical psychopharmacology38(6), 644-646., 10.1097/JCP.0000000000000973
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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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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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Detoxification from methadone using low, repeated, and increasing doses of ibogaine: A case report

Abstract

Background and aims

Ibogaine is a natural alkaloid that has been used in the last decades as an adjuvant for the treatment of opiate withdrawal. Despite the beneficial results suggested by animal studies and case series, there is a lack of clinical trials to assess the safety and efficacy of ibogaine. Moreover, the majority of reports described cases of heroin-dependent individuals, with and without concomitant use of methadone, using high doses of ibogaine. Therefore, it is not clear if ibogaine at low doses could be used therapeutically in people on methadone maintenance treatments (MMT).

Methods

Case report of a female on MMT for 17 years who performed a self-treatment with several low and cumulative doses of ibogaine over a 6-week period.

Results

The patient successfully eliminated her withdrawals from methadone with ibogaine. Each administration of ibogaine attenuated the withdrawal symptoms for several hours, and reduced the tolerance to methadone until all signs of withdrawal symptoms disappeared at the end of the treatment. No serious adverse effects were observed, and at no point did the QTc measures reach clinically significant scores. Twelve months after the treatment, she was no longer on MMT.

Conclusions

To our knowledge, this is the first case report describing an ibogaine treatment using low and cumulative doses in a person on MMT. Although preliminary, this case suggests that low and cumulative doses of ibogaine may reduce withdrawal symptoms in patients undergoing MMT.

Wilkins, C., dos Santos, R. G., Solá, J., Aixalá, M., Cura, P., Moreno, E., … & Bouso, J. C. (2017). Detoxification from methadone using low, repeated, and increasing doses of ibogaine: A case report. Journal of Psychedelic Studies1(1), 29-34. 10.1556/2054.01.2017.005
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