OPEN Foundation

R. dos Santos

Risk assessment of ayahuasca use in a religious context: self-reported risk factors and adverse effects

Abstract

Objective: Whether for spiritual, recreational, or potential therapeutic use, interest in ayahuasca has grown remarkably. Ayahuasca’s main active substances are N,N-dimethyltryptamine and certain monoamine oxidase inhibitor β-carbolines. Possible drug interactions are a major concern, and research is lacking in this area. The objective of this study was to evaluate the safety of ritual ayahuasca use regarding adverse effects and risk factors.

Methods: In this cross-sectional study, ayahuasca users from a religious institution answered an online questionnaire about its safety. Adverse effects, safety measures, and possible risk factors (psychiatric diagnosis and medications) were investigated.

Results: The most frequent adverse effects among the 614 participants were transient gastrointestinal effects (nausea and vomiting). Fifty participants self-reported a psychiatric diagnosis (depression and anxiety were the most prevalent), and these participants experienced adverse effects more frequently. Psychiatric medication use was reported by 31 participants. No indication of increased adverse effects due to drug-drug interactions was found.

Conclusion: A minority of participants reported being very negatively affected by persistent adverse effects. Psychiatric medication use while participating in ayahuasca rituals was not associated with increased adverse effects. For the most part, the institution’s practices seem sufficient to prevent exacerbated reactions. Future studies may focus on negatively affected users.

Durante, Í., Dos Santos, R. G., Bouso, J. C., & Hallak, J. E. (2021). Risk assessment of ayahuasca use in a religious context: self-reported risk factors and adverse effects. Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999), 43(4), 362–369. https://doi.org/10.1590/1516-4446-2020-0913

Link to full text

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

Link to full text

Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action

Abstract

Major depressive disorder (MDD) is among the most prevalent mental health disorders worldwide, and it is associated with a reduced quality of life and enormous costs to health care systems. Available drug treatments show low-to-moderate response in most patients, with almost a third of patients being non-responders (treatment-resistant). Furthermore, most currently available medications need several weeks to achieve therapeutic effects, and the long-term use of these drugs is often associated with significant unwanted side effects and resultant reductions in treatment compliance. Therefore, more effective, safer, and faster-acting antidepressants with enduring effects are needed. Together with ketamine, psychedelics (or classic or serotoninergic hallucinogens) such as lysergic acid diethylamide (LSD), psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Several studies in the 1950s to 1970s reported antidepressive and anxiolytic effects of these drugs, which are being confirmed by modern trials (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). The effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5-HT2A receptor. Considering the overall burden of MDD and the necessity of new therapeutic options, the promising (but currently limited) evidence of safety and efficacy of psychedelics has encouraged the scientific community to explore more fully their beneficial effects in MDD.

Dos Santos, R. G., Hallak, J. E., Baker, G., & Dursun, S. (2021). Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action. Journal of psychopharmacology (Oxford, England), 35(4), 453–458. https://doi.org/10.1177/0269881120986422

Link to full text

The Use of Classic Hallucinogens/Psychedelics in a Therapeutic Context: Healthcare Policy Opportunities and Challenges

Abstract

Psychedelics or serotonergic hallucinogens are a group of substances that share the agonism of serotonergic 5-HT2A receptors as their main mechanism of action. Its main effects include changes in perception, cognitive process, and mood. Despite being used for centuries by different cultures in ritual contexts, these substances have currently aroused the interest of science and industry for their promising antidepressant, anxiolytic, and anti-addictive effects. Considering this evidence, this article aims to explore some of the possible health policy challenges to integrate these therapeutic tools into broad and heterogeneous health systems. As a main benefit, these substances produce rapid and enduring effects with the administration of single or few doses, which could lead to new treatment possibilities for patients with severe mental disorders resistant to the usual medications. The main challenge is associated with the fact that these substances remain scheduled in most countries and are associated with social stigma related to their recreational use (especially LSD and psilocybin). This situation makes it exceedingly difficult to conduct clinical trials, although international conventions allow such research. Ethically, this could be interpreted as a violation of human rights since thousands of people are prevented from having access to possible benefits. Interestingly, ritual ayahuasca use is more acceptable to the public than the use of psilocybin-containing mushrooms or LSD. The controlled, clinical use of LSD and psilocybin seems to be less criticized and is being explored by the industry. Rigorous scientific evidence coupled with industrial interests (LSD and psilocybin), together with respect for traditional uses (ayahuasca) and international conventions, seems to be the best way for these drugs to be integrated into health systems in the next years. Which highlights the need for an urgent dialogue between science, health system, society, and politics.

Dos Santos, R. G., Bouso, J. C., Rocha, J. M., Rossi, G. N., & Hallak, J. E. (2021). The Use of Classic Hallucinogens/Psychedelics in a Therapeutic Context: Healthcare Policy Opportunities and Challenges. Risk management and healthcare policy, 14, 901–910. https://doi.org/10.2147/RMHP.S300656

Link to full text

Psychedelic Medicines in Major Depression: Progress and Future Challenges

Abstract

The volume of research on the therapeutic use of psychedelic drugs has been increasing during the last decades. Partly because of the need of innovative treatments in psychiatry, several studies have assessed the safety and efficacy of drugs like psilocybin or ayahuasca for a wide range of mental disorders, including major depression. The first section of this chapter will offer an introduction to psychedelic research, including a brief historical overview and discussions about appropriate terminology. In the second section, the recently published clinical trials in which psychedelic drugs were administered to patients will be analysed in detail. Then, in the third section, the main neurobiological mechanisms of these drugs will be described, noting that while some of these mechanisms could be potentially associated with their therapeutic properties, they are commonly used as adjuvants in psychotherapeutic processes. The last section suggests future challenges for this groundbreaking field of research and therapy.

Bouso, J. C., Ona, G., Dos Santos, R. G., & Hallak, J. (2021). Psychedelic Medicines in Major Depression: Progress and Future Challenges. Advances in experimental medicine and biology, 1305, 515–533. https://doi.org/10.1007/978-981-33-6044-0_26

Link to full text

Rapid and sustained decreases in suicidality following a single dose of ayahuasca among individuals with recurrent major depressive disorder: results from an open-label trial

Abstract

Rationale: Suicidality is a major public health concern with limited treatment options. Accordingly, there is a need for innovative interventions for suicidality. Preliminary evidence indicates that treatment with the psychedelic ayahuasca may lead to decreases in depressive symptoms among individuals with major depressive disorder (MDD). However, there remains limited understanding of whether ayahuasca also leads to reductions in suicidality.

Objective: To examine the acute and post-acute effect of ayahuasca on suicidality among individuals with MDD.

Methods: We conducted a secondary analysis of an open-label trial in which individuals with recurrent MDD received a single dose of ayahuasca (N = 17). Suicidality was assessed at baseline; during the intervention; and 1, 7, 14, and 21 days after the intervention.

Results: Among individuals with suicidality at baseline (n = 15), there were significant acute (i.e., 40, 80, 140, and 180 min after administration) and post-acute (1, 7, 14, and 21 days after administration) decreases in suicidality following administration of ayahuasca. Post-acute effect sizes for decreases in suicidality were large (Hedges’ g = 1.31-1.75), with the largest effect size 21 days after the intervention (g = 1.75).

Conclusions: When administered in the appropriate context, ayahuasca may lead to rapid and sustained reductions in suicidality among individuals with MDD. Randomized, double-blind studies with larger sample sizes are needed to confirm this early finding.

Zeifman, R. J., Singhal, N., Dos Santos, R. G., Sanches, R. F., de Lima Osório, F., Hallak, J., & Weissman, C. R. (2021). Rapid and sustained decreases in suicidality following a single dose of ayahuasca among individuals with recurrent major depressive disorder: results from an open-label trial. Psychopharmacology, 238(2), 453–459. https://doi.org/10.1007/s00213-020-05692-9

Link to full text

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

Link to full text

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
Link to full text
 

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
Link to full text

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
Link to full text