Risk Management and Healthcare Policy
March 1, 2021
Rafael G. Dos Santos, José Carlos Bouso, Juliana Mendes Rocha et al.
58 citations
Psychedelics such as LSD, psilocybin, and ayahuasca act mainly by stimulating serotonin 5-HT2A receptors, producing changes in perception, cognition, and mood. Although used ritually for centuries, they now show promise for rapid and lasting antidepressant, anxiolytic, and anti-addictive effects after single or few doses, especially in patients resistant to standard treatments. However, their legal status as scheduled substances and social stigma, particularly for LSD and psilocybin, hinder clinical trials and access, potentially violating human rights. Ayahuasca rituals face less public criticism. Integrating these therapies into health systems requires rigorous evidence, respect for traditional use, and dialogue among science, society, and policy.
Epilepsy & Behavior
June 7, 2019
Rafael G. Dos Santos, Jaime E. C. Hallak
58 citations
Ayahuasca, a botanical hallucinogenic preparation traditionally used for ritual and therapeutic purposes by native populations of the Northwestern Amazon, has spread globally in recent decades, increasing interest in its potential therapeutic uses for anxiety, mood disorders, and substance-use disorders. Preclinical, observational, and preliminary clinical studies have corroborated some therapeutic findings. This article provides an overview of these studies and highlights current uses of ayahuasca in neuroscience, including as a tool to investigate the neural basis of introspection and other complex cognitive processes.
Brazilian Journal of Psychiatry
October 30, 2020
Ícaro Durante, Rafael G. Dos Santos, José Carlos Bouso et al.
49 citations
A small fraction of participants experienced lasting negative effects from ayahuasca use. Taking psychiatric medication during ayahuasca ceremonies did not raise the risk of adverse effects. The safety practices of the institution appear adequate to prevent severe reactions. Future research should investigate those who are negatively affected.
Journal of Clinical Psychopharmacology
April 13, 2021
Juliana Mendes Rocha, Giordano Novak Rossi, Flávia de Lima Osório et al.
46 citations
A single dose of ayahuasca did not alter the recognition of emotions in facial expressions compared with placebo in healthy volunteers. The drug was well tolerated, producing nausea, gastrointestinal discomfort, and vomiting, with some reports of visual effects, tranquility, and well-being, and few reports of transient anxiety or confusion. No significant effects appeared on cardiovascular measures or brain-derived neurotrophic factor levels. A significant time-dependent deterioration of alkaloids, especially dimethyltryptamine, was observed. The absence of effects on emotion recognition may stem from the dose used, alkaloid degradation, learning effects, or the sample's high educational level.
Brazilian Journal of Psychiatry
November 21, 2018
Flávia S. Da Silva, Erick Allan Dos Santos Silva, Geovan Menezes de Sousa et al.
46 citations
In a juvenile marmoset model of depression, a single dose of ayahuasca reversed stress-induced hypocortisolemia within 24 hours, reduced stereotypic scratching in males, increased feeding in males, and restored body weight in both sexes, with behavioral effects lasting up to 14 days. Saline vehicle did not produce these effects. The findings suggest ayahuasca may have rapid and sustained antidepressant properties, supporting further research into psychedelics for early-onset depression.
Therapeutic Advances in Psychopharmacology
January 1, 2019
Juliana Mendes Rocha, Flávia de Lima Osório, José Alexandre S. Crippa et al.
44 citations
A systematic review of 8 studies found that serotonergic hallucinogens such as LSD and psilocybin reduce the recognition of negative emotions in facial expressions and modulate amygdala activity in response to these stimuli. These effects correlated with antidepressive benefits in patients. The drugs were well tolerated. Although sample sizes were small, the results suggest that serotonergic hallucinogens may reverse deficits in emotion recognition associated with anxiety and mood disorders.
Frontiers in Psychiatry
June 16, 2021
Dóra Révész, Genís Ona, Giordano Novak Rossi et al.
42 citations
During the first strict COVID-19 lockdown (April–July 2020), people who had used psychedelic drugs regularly (more than once per six months) reported less psychological distress, less peritraumatic stress, and more social support than occasional or non-users. Regular users also scored higher on novelty-seeking and self-transcendence and lower on cooperativeness. The findings suggest that lifetime psychedelic use may be a protective factor for mental health under stressful confinement, or that pre-existing personality traits make some individuals more likely to use psychedelics. The study surveyed 2,974 English, Portuguese, and Spanish speakers online.
Psychopharmacology
June 1, 2022
Genís Ona, Juliana Mendes Rocha, José Carlos Bouso et al.
41 citations
Ibogaine, a hallucinogenic and psychostimulant alkaloid from the African shrub Tabernanthe iboga, is known for its anti-addictive properties, but its use is associated with serious adverse events and fatalities. A systematic review of 18 studies from 2015 to 2020 found highly heterogeneous results regarding the product used and dosages. Adverse events were classified as acute effects (within 24 hours) and persistent cardiac, psychiatric, and neurological alterations. The review highlights the need for phase I clinical trials to establish safety for standardized ibogaine products, and for research to identify vulnerable populations and develop effective screening and clinical procedures.
Brazilian Journal of Psychiatry
February 18, 2021
Mara C. Guimarães, Tiago M. Guimarães, Jaime E. C. Hallak et al.
41 citations
In a small pilot trial, adding nitrous oxide (N2O) to ongoing antidepressant treatment for major depressive disorder produced significantly greater improvement in depressive symptoms than placebo (100% oxygen). After four weeks of twice-weekly 60-minute sessions, depression scores on the Hamilton Depression Rating Scale dropped from an average of 22.58 to 5.92 in the N2O group, compared with a drop from 22.44 to 12.89 in the placebo group. Most participants receiving N2O met criteria for response (91.7%) and remission (75%). Common side effects included nausea, vomiting, and headache. The results suggest N2O may be a useful augmentation strategy for treatment-resistant depression.
BMC Neuroscience
March 5, 2015
Ludmyla Kandratavicius, Priscila Alves Balista, Daniele C. Wolf et al.
40 citations
Nitric oxide donors, especially sodium nitroprusside (SNP), show promise for treating schizophrenia. In a rat model using ketamine to induce schizophrenia-like behaviors, SNP given either before or after ketamine consistently reduced hyperlocomotion. Glyceryl trinitrate and SNP given after ketamine improved long-term memory, while methylene blue given before ketamine also improved long-term memory. The effects depended on whether the drug was administered before or after ketamine, suggesting the timing of treatment matters. These findings indicate that nitric oxide modulation could be a new pharmacological approach for schizophrenia.
Frontiers in Psychiatry
August 6, 2021
Juliana Mendes Rocha, Giordano Novak Rossi, Flávia de Lima Osório et al.
37 citations
In two small randomized placebo-controlled trials, ayahuasca did not consistently change personality traits. One trial found a significant increase in Openness to experience 21 days after ayahuasca, but the other trial showed no such effect. Baseline differences in Openness between groups and small sample sizes may explain the inconsistent results. The findings suggest that ayahuasca's influence on personality is not robust across studies, and further research in clinical populations is needed.
Archives of Clinical Psychiatry (São Paulo)
February 1, 2018
Rafael G. Dos Santos, Rafael Faria Sanches, Flávia de Lima Osório et al.
37 citations
Ayahuasca, a botanical hallucinogenic preparation containing β-carboline alkaloids and DMT, was well tolerated by patients with treatment-resistant major depressive disorder in an open-label trial. Symptom reductions lasted only a few weeks, but most patients considered the experience among the most important of their lives, even 4 to 7 years later. This is the first long-term follow-up of a clinical sample from an ayahuasca trial, suggesting that while acute antidepressant effects are short-lived, the subjective significance endures.
Frontiers in Pharmacology
June 21, 2017
Rafael Naime Ruggiero, Matheus Teixeira Rossignoli, Jana Batista de Ross et al.
37 citations
Research on the endocannabinoid system in schizophrenia has largely relied on rodent behavioral measures such as prepulse inhibition and open-field locomotion, often combined with neurochemical or drug challenge methods. These approaches help map sensorimotor gating, hyperlocomotion, social interaction, and underlying neurotransmitter disturbances. However, greater use of neurophysiological tools like electrophysiology and optogenetics is needed to clarify how exogenous cannabinoids—THC worsening symptoms and CBD ameliorating them—affect hallucinations, delusions, and cognitive deficits. Recent evidence also highlights a complex interplay between the endocannabinoid and endovanilloid systems, particularly anandamide's influence on cognitive variables like aversive memory extinction, with TRPV1 receptors emerging as promising therapeutic targets.
Molecules
April 29, 2020
Gabriela de Oliveira Silveira, Rafael G. Dos Santos, Felipe Rebello Lourenço et al.
36 citations
Ayahuasca tea, a hallucinogenic beverage used in religious and therapeutic contexts, was tested for the stability of its main alkaloids—DMT, harmine, tetrahydroharmine, and harmaline—under three storage conditions: one year in a refrigerator (plastic or glass containers), seven days at 37°C (simulating mail transport), and three freeze-thaw cycles. DMT showed no significant degradation in any condition. However, harmala alkaloids exhibited substantial variation, including degradation and concentration increases, likely due to inter-conversion and leaching from tea precipitate. Thus, quantifying alkaloids before administration in controlled studies is essential.
Journal of Psychedelic Studies
April 1, 2017
Rafael G. Dos Santos, José Carlos Bouso, Jaime E. C. Hallak
36 citations
Ibogaine, a naturally occurring hallucinogenic alkaloid, may reduce drug craving and withdrawal. A systematic review of human studies identified eight relevant papers: seven open-label case series and one randomized, placebo-controlled trial. The case series suggest that one or a few ibogaine treatments can significantly reduce withdrawal, craving, and drug self-administration in dependent individuals, with effects lasting from 24 hours to weeks or months. However, the clinical trial found no significant effects of noribogaine on opiate or opioid withdrawal. Given the need for fast-acting, sustained treatments for opiate and cocaine dependence, further controlled trials of ibogaine and noribogaine are warranted.
Biomolecules
November 2, 2022
Giordano Novak Rossi, Lorena T. L. Guerra, Glen B. Baker et al.
29 citations
Ayahuasca, a psychoactive brew used in South American rituals, contains DMT from Psychotria viridis and MAO-inhibiting β-carbolines from Banisteriopsis caapi. Preclinical and clinical evidence suggests its antidepressant effects involve complex modulation of serotoninergic, glutamatergic, dopaminergic, and endocannabinoid systems, along with interactions with VMAT, TAAR1, and sigma-1 receptors. The brew also appears to beneficially modulate inflammatory and neurotrophic factors, leading to neuroprotective and neuroplastic effects. This review summarizes current knowledge of these molecular interactions and their relation to ayahuasca's potential antidepressant properties.
Journal of Psychoactive Drugs
May 28, 2022
Maja Kohek, Genís Ona, Michiel van Elk et al.
25 citations
Regular participation in ayahuasca ceremonies is not linked to relevant health harms. Compared to normative Dutch data, 377 participants (50.1% women, mean age 48.8 years) showed better general well-being, fewer chronic or lifestyle-related diseases, more physical activity, and a more balanced diet. During the COVID-19 pandemic, they used less alcohol. Although they used more illegal drugs than the general population, they did not report associated harms. This evidence could inform drug policymakers in developing evidence-based public policies.
Expert Opinion on Drug Safety
April 15, 2022
Giordano Novak Rossi, Jaime E. C. Hallak, José Carlos Bouso Saiz et al.
24 citations
In the reviewed studies, no serious adverse events were linked to psilocybin or LSD administration. Most side effects were anticipated, manageable, and temporary. However, concerns persist about certain effects like dissociation, paranoia, and confusion. The authors conclude that larger randomized controlled trials are needed to confirm therapeutic benefits and further assess safety and tolerability.
Journal of Clinical Psychopharmacology
María Gómez-sousa, Daniel Jiménez‐garrido, Genís Ona et al.
24 citations
Among 40 first-time ayahuasca ceremony participants, 7 reported intense challenging psychological effects. Four of those 7 had a pre-existing psychiatric diagnosis; one month after the ceremony, two no longer met diagnostic criteria and the other two showed considerably reduced symptoms, with effects persisting at six months. Poor setting and guidance contributed to some reactions. Six of the seven did not use ayahuasca again during the study. The findings suggest that acute negative psychological reactions during ayahuasca ceremonies can sometimes be followed by positive long-term effects, highlighting the need for prospective research on safety and contextual factors.
bioRxiv (Cold Spring Harbor Laboratory)
January 27, 2017
Fernanda Palhano-Fontes, Dayanna Barreto, Heloisa Onias et al.
22 citations
preprint
A single dose of ayahuasca produced significant antidepressant effects in patients with treatment-resistant depression compared to placebo. Depression severity, measured by the Montgomery–Åsberg Depression Rating Scale (MADRS), was significantly lower in the ayahuasca group at one, two, and seven days after dosing. Effect sizes increased over time, reaching a Cohen's d of 1.49 at day seven. Response rates were significantly higher in the ayahuasca group at day seven (64% vs. 27%), and remission rates were marginally significant (36% vs. 7%). This controlled trial supports the safety and therapeutic value of ayahuasca in treating depression.
British Journal of Pharmacology
June 1, 2024
Isabel Werle, Laura M M Nascimento, Aymee L A Dos Santos et al.
21 citations
A single oral dose of ayahuasca containing 0.3 mg/kg of DMT increased within-session extinction of contextual freezing behavior in rats without affecting recall; two consecutive daily doses enhanced extinction recall. These effects occurred for both 1- and 21-day-old memories in males and females, independent of changes in anxiety or general exploratory activity. Blocking 5-HT2A receptors in the infralimbic cortex prevented within-session extinction, while blocking 5-HT1A receptors prevented between-session extinction. The findings highlight complementary mechanisms by which ayahuasca facilitates behavioral suppression of aversive memories, suggesting potential benefits for stress-related disorders.
European Archives of Psychiatry and Clinical Neuroscience
October 1, 2023
Juliana Mendes Rocha, José A S Reis, José Carlos Bouso et al.
21 citations
Ibogaine, a psychoactive alkaloid from the west-African shrub Tabernanthe iboga, is increasingly sought in Western cultures for its claimed anti-addictive properties, though evidence remains preliminary. Its use often occurs without medical supervision in uncontrolled settings and has been linked to severe adverse events. This systematic review evaluated clinical studies of ibogaine, focusing on administration settings to identify criteria promoting safer use. Following PRISMA guidelines, searches in PubMed, Scielo, ClinicalTrials.gov, and Core.ac.uk retrieved clinical studies published through November 17, 2022; 12 sources were synthesized. The review concludes that controlled settings with trained professionals and equipment for rigorous medical, psychiatric, and cardiac monitoring are essential for patient safety.
Human Psychopharmacology Clinical and Experimental
February 2, 2022
Rafael G. Dos Santos, Juliana Mendes Rocha, Giordano Novak Rossi et al.
20 citations
A post-hoc analysis of two small randomized placebo-controlled trials measured endocannabinoid (anandamide, AEA; 2-arachidonoylglycerol, 2-AG) plasma levels in healthy volunteers and in volunteers with social anxiety disorder (SAD) after a single oral dose of ayahuasca or placebo. In the SAD group, ayahuasca intake was associated with a significant difference in AEA concentrations over time, and near-significant increases in AEA were observed at 90 and 240 minutes after intake. No definitive conclusions could be drawn due to high interindividual variability and small sample sizes. Larger studies are needed to clarify ayahuasca's effects on the endocannabinoid system.
Journal of Psychedelic Studies
July 25, 2018
Rafael G. Dos Santos, Scotty Enyart, José Carlos Bouso et al.
18 citations
A man who had long experienced aphantasia (the inability to form voluntary mental images) reported modest but sustained improvements in his visual imagery after a single dose of ayahuasca, a botanical hallucinogen rich in DMT. The improvements were attributed to possible biological and psychological processes, including stimulation of cortical 5-HT2A receptors, increased activity in the visual cortex, and resolution of psychological trauma from a difficult relationship with his father. The case suggests that 5-HT2A agonists like ayahuasca may offer a path to explore treatments for aphantasia, though further trials are needed.
Drug and Alcohol Review
February 1, 2023
Borja J Rodríguez-cano, Maja Kohek, Genís Ona et al.
17 citations
Ibogaine, a psychoactive alkaloid from the Tabernanthe iboga plant traditionally used in Bwiti culture, has been used experimentally to treat substance use disorders (SUD) since 1962. Interviews with 13 people who self-treated their SUD with ibogaine revealed that the drug's therapeutic benefits arise not only from its pharmacology but also from the subjective experience it induces. Participants reported that ibogaine evoked interpersonal and transpersonal experiences, autobiographical memories, and personal insights. These effects, along with preparation, integration, and motivation for lifestyle change, appear to help individuals cope with their SUD, particularly given limited alternative treatment options.