Lack of Acute Agomelatine Effect in a Model of Social Anxiety in Healthy Volunteers: A Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Agomelatine is an antidepressant drug that acts as an agonist of melatoninergic MT1/2 receptors and an antagonist of serotonergic 5-HT2C receptors. Studies suggest that agomelatine has anxiolytic properties in social anxiety, but there are no studies that assessed the effects of this compound in human experimental anxiety induced by a public speaking test. The objective of our investigation was to assess the effects of agomelatine on human experimental anxiety using the Simulation Public Speaking Test (SPST). METHODS: Agomelatine (25 mg, n = 14), citalopram (20 mg, n = 14), venlafaxine (75 mg, n = 14), or placebo (n = 14) were administered in single doses to healthy volunteers in a double-blind study. Subjective anxiety was assessed with the Visual Analogue Mood Scale. Arterial blood pressure, heart rate, and blood levels of prolactin and cortisol were also recorded, as well as plasma levels of the 3 drugs. RESULTS: The SPST induced significant subjective, physiological, and hormonal effects in all groups. The SPST also increased the anxiety and decreased mental sedation Visual Analogue Mood Scale factors during the anticipatory and performance phases of the test. Citalopram increased anxiety during the test in females, whereas agomelatine and venlafaxine were not different from placebo. CONCLUSIONS: Confirming previous results, a serotonin selective reuptake inhibitor, citalopram, caused an anxiogenic effect in the SPST only in females. Acute administration of a low dose of agomelatine failed to modify the behavioral and physiological changes caused by this test. Future studies using higher doses and repeated administration should investigate if agomelatine behavioral and physiological effects could be detected in human experimental anxiety models.

Genetic ablation of the isoform γ of PI3K decreases antidepressant efficacy of ketamine in male mice.

About one-third of major depressive disorder (MDD) patients demonstrate unresponsiveness to classic antidepressants, and even the clinical efficacy of fast-acting drugs such as ketamine varies significantly among patients with treatment-resistant depression. Nevertheless, the lack of suitable animal models that mimic a possible ketamine-resistant phenotype challenges the understanding of resistance to drug treatment. In this study, we showed that PI3Kγ knock-out (KO) mice do not respond to classical doses of ketamine and classical antidepressants. PI3Kγ KO mice were unresponsive to both the rapid and sustained antidepressant-like effects of a single dose of ketamine in the forced swimming test. Additionally, they were unresponsive to the antidepressant-like effects induced by the tricyclic antidepressant imipramine and the selective serotonin reuptake inhibitor fluoxetine. However, acute pharmacological inhibition of PI3Kγ did not block the antidepressant-like effect of ketamine, showing that a chronic deficiency of the PI3Kγ-mediated pathway is necessary for the effects of classic doses of ketamine and antidepressants. Therefore, we propose that PI3Kγ participates in the antidepressant activity and is likely implicated in the neurobiology and phenotype observed in patients with MDD who demonstrate treatment resistance.

Long-term ayahuasca use is associated with preserved global cognitive function and improved memory: a cross-sectional study with ritual users.

Although several studies have been conducted to elucidate the relationship between psychedelic consumption and cognition, few have focused on understanding the long-term use influence of these substances on these variables, especially in ritualistic contexts.  To verify the influence of ritualistic ayahuasca consumption on the cognition of experienced ayahuasca religious users (> 20 years) and beginners (< 3 years), which participated in rituals of the Centro Luz Divina (CLD), a Santo Daime church in Brazil. Observational, descriptive, and cross-sectional study was carried out in which 48 people participated divided into three groups: (a) experienced ayahuasca users (n = 16), (b) beginner ayahuasca users (n = 16) and (c) control group (n = 16). All groups were matched by sex, age, and education and contained 8 women and 8 men. Cognition was assessed with the WASI (intelligence quotient), Digit Span (verbal working memory), Corsi Block-Tapping Task (visuospatial-related and working memory), Rey-Osterrieth Complex Figure test (visual perception, immediate memory), and Wisconsin Card Sorting and Five Digit Test (executive functions). Groups were homogenous in terms of sociodemographic characteristics, with participants presenting average intellectual performance. There was no evidence of cognitive decline amongst ayahuasca users. The experienced group showed higher scores compared to the less experienced group in the Digit Span and Corsi Block-Tapping tasks, which assess working verbal and visuospatial memories respectively. We confirmed the botanical identities of Psychotria viridis and Banisteriopsis caapi and the presence of the alkaloids both in the plants and in the brew. Short and long-term ayahuasca consumption does not seem to alter human cognition, while long-term use seems to be associated with improvements in aspects of working memory when compared with short-term use.

Fiber-in-tube SPME-CapLC-MS/MS method to determine Aß peptides in cerebrospinal fluid obtained from Alzheimer's patients.

Mass spectrometry is characterized by its high sensitivity, ability to measure very low analyte concentrations, specificity to distinguish between closely related compounds, availability to generate high-throughput methods for screening, and high multiplexing capacity. This technique has been used as a platform to analyze fluid biomarkers for Alzheimer's disease. However, more effective sample preparation procedures, preferably antibody-independent, and more automated mass spectrometry platforms with improved sensitivity, chromatographic separation, and high throughput are needed for this purpose. This short communication discusses the development of a fiber-in-tube SPME-CapLC-MS/MS method to determine Aß peptides in cerebrospinal fluid obtained from Alzheimer's disease patients. To obtain the fiber-in-tube SPME capillary, we longitudinally packed 22 nitinol fibers coated with a zwitterionic polymeric ionic liquid into the same length of the PEEK tube. In addition, this communication compares this fiber-in-tube SPME method with the conventional HPLC scale (HPLC-MS/MS) and when directly coupled to CapESI-MS/MS without chromatographic separation, and, as a case study, discusses the benefits and challenges inherent in miniaturizing the flow scale of the sample preparation technique (fiber-in-tube SPME) to the CapLC-MS/MS system. Fiber-in-tube SPME-CapLC-MS/MS provided LLOQ ranging from 0.09 to 0.10 ng mL-1, accuracy ranging from 91 to 117 % (recovery), and reproducibility of less than 18 % (RSD). Analysis of the cerebrospinal fluid samples obtained from Alzheimer's disease patients evidenced that the method is robust. At the capillary scale (10 µL min-1), this innovative method presented higher analytical sensitivity than the conventional HPLC-MS/MS scale. Although fiber-in-tube SPME directly coupled to CapESI-MS/MS offers advantages in terms of high throughput, the sample was dispersed and non-quantitatively desorbed from the capillary at low flow rate. These results highlighted that chromatographic separation is important to decrease the matrix effect and to achieve higher detectability, which is indispensable for bioanalysis.

Solvent-free parallel artificial liquid membrane extraction for drugs of abuse in plasma samples using LC-MS/MS.

BACKGROUND: Parallel artificial liquid membrane extraction (PALME) is a 96-well plate setup variant of liquid-phase microextraction. Basic or acidic analytes are extracted in neutral form from the sample, through a supported liquid membrane (SLM), and into aqueous acceptor. PALME is already considered a green extraction technique, but in the current conceptual work, we sought to make it even greener by replacing the use of organic solvents with essential oils (EO). PALME was combined with LC-MS/MS for analysis of plasma samples and multiple drugs of abuse with toxicological relevance (amphetamines, phenethylamines, synthetic cathinones, designer benzodiazepines, ayahuasca alkaloids, lysergic acid diethylamide, and ketamine). RESULTS: Fourteen EO were compared to organic solvents frequently used in PALME. The EO termed smart & sassy yielded the best analyte recovery for all drugs studied and was thus selected as SLM. Then, factorial screening and Box-Behnken were employed to optimize the technique. The extraction time, concentration of base, sample volume, and percentage of trioctylamine significantly impacted analyte recovery. The optimum values were defined as 120 min, 10 mmol/L of NaOH, 150 µL, and 0%, respectively. Once optimized, validation parameters were 1-100 ng mL-1 as linear range, accuracy ±16.4%, precision >83%, 1 ng mL-1 as limit of quantitation, 0.1-0.75 ng mL-1 as limit of detection, matrix effect <20%, and recovery 20-106%. Additionally, EO purchased from different production batches were tested and achieved acceptable reproducibility. Data were in compliance with requirements set by internationally accepted validation guidelines and the applicability of the technique was proven using authentic samples. SIGNIFICANCE: In this study, the use of an EO provided a solvent-free sample preparation technique suited to extract different classes of drugs of abuse from plasma samples, dismissing the use of hazardous organic solvents. The method also provided excellent sample clean-up, thus being a simple and efficient tool for toxicological applications that is in agreement with the principles of sustainable chemistry.

Cannabidiol modulates hippocampal genes involved in mitochondrial function, ribosome biogenesis, synapse organization, and chromatin modifications.

BACKGROUND: Cannabidiol (CBD) is one of the main cannabinoids present in Cannabis sativa female flowers. Previous investigation has already provided insights into the CBD molecular mechanism; however, there is no transcriptome data for CBD effects on hippocampal subfields. Here, we investigate transcriptomic changes in dorsal and ventral CA1 of adult mice hippocampus after 100 mg/kg of CBD administration (i.p.) for one or seven consecutive days. METHODS: C57BL/6JUnib mice were treated with either vehicle or CBD for 1 or 7 days. The collected brains were sectioned, and the hippocampal sub-regions were laser microdissected for RNA-Seq analysis. RESULTS: The transcriptome analysis following 7 days of CBD administration indicates the differential expression of 1559 genes in dCA1 and 2924 genes in vCA1. Furthermore, GO/KEGG analysis identified 88 significantly enriched biological process and 26 significantly enriched pathways for dCBD7, whereas vCBD7 revealed 128 enriched BPs and 24 pathways. CONCLUSION: This dataset indicates a widespread decrease of electron transport chain and ribosome biogenesis transcripts in CA1, while chromatin modifications and synapse organization transcripts were increased following CBD administration for 7 days.

Ayahuasca-enhanced extinction of fear behaviour: Role of infralimbic cortex 5-HT2A and 5-HT1A receptors.

BACKGROUND AND PURPOSE: Ayahuasca (AYA) is a botanical psychedelic with promising results in observational and small clinical trials for depression, trauma and drug use disorders. Its psychoactive effects primarily stem from N,N-dimethyltryptamine (DMT). However, there is a lack of research on how and where AYA acts in the brain. This study addressed these questions by examining the extinction of aversive memories in AYA-treated rats. EXPERIMENTAL APPROACH: We focused on the 5-HT1A and 5-HT2A receptors, as DMT exhibits a high affinity for both of them, along with the infralimbic cortex in which activity and plasticity play crucial roles in regulating the mnemonic process under analysis. KEY RESULTS: A single oral treatment with AYA containing 0.3 mg·kg-1 of DMT increased the within-session extinction of contextual freezing behaviour without affecting its recall. This protocol, when repeated twice on consecutive days, enhanced extinction recall. These effects were consistent for both 1- and 21-day-old memories in males and females. AYA effects on fear extinction were independent of changes in anxiety and general exploratory activity: AYA- and vehicle-treated animals showed no differences when tested in the elevated plus-maze. The 5-HT2A receptor antagonist MDL-11,939 and the 5-HT1A receptor antagonist WAY-100635 infused into the infralimbic cortex respectively blocked within- and between-session fear extinction effects resulting from repeated oral administration of AYA. CONCLUSION AND IMPLICATIONS: Our findings highlight complementary mechanisms by which AYA facilitates the behavioural suppression of aversive memories in the rat infralimbic cortex. These results suggest potential beneficial effects of AYA or DMT in stress-related disorders.

Cannabidiol as an Adjunctive Treatment for Acute Bipolar Depression: A Pilot Study: Le cannabidiol comme traitement d'appoint de la dépression bipolaire aiguë : une étude pilote.

OBJECTIVE: The treatment of bipolar depression remains challenging due to the limited effective and safe therapeutic options available; thus, developing newer treatments that are effective and well tolerable is an urgent unmet need. The objective of the present trial was to test 150 to 300 mg/day of cannabidiol as an adjunctive treatment for bipolar depression. METHOD: A randomized, double-blind, placebo-controlled pilot study to assess the efficacy of adjunctive cannabidiol in bipolar depression was used. Efficacy parameters were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 8. Secondary outcomes included response and remission rates, changes in anxiety and psychotic symptoms, and changes in functioning. Patients continued double-blind treatment until week 12 to monitor for adverse effects, laboratory analysis, and manic symptoms. Study registry: NCT03310593. RESULTS: A total of 35 participants were included. MADRS scores significantly decreased from baseline to the endpoint (placebo, -14.56; cannabidiol, -15.38), but there was no significant difference between the groups. Similarly, there were no other significant effects on the secondary outcomes. However, an exploratory analysis showed a significant effect of cannabidiol 300 mg/day in reducing MADRS scores from week 2 to week 8 (placebo, -6.64; cannabidiol, -13.72). There were no significant differences in the development of manic symptoms or any other adverse effects. CONCLUSION: Cannabidiol did not show significantly higher adverse effects than placebo. Despite the negative finding on the primary outcome, an exploratory analysis suggested that cannabidiol should be further studied in bipolar depression in higher doses of at least 300 mg/day and under research designs that could better control for high placebo response.

Longitudinal and transcultural assessment of the relationship between hallucinogens, well-being, and post-traumatic growth during the COVID-19 pandemic.

The COVID-19 pandemic has had a devastating impact on the health and wellbeing of the global population. This paper presents the results of a longitudinal transcultural study that was begun at the peak of the pandemic (in April, 2020). An online survey was used to collect data from English-, Spanish-, and Portuguese-speaking participants. The survey collected information about sociodemographics, lifestyle activities, COVID-19-related circumstances, and drug use (with an emphasis on hallucinogenic drugs), as well as involving psychometric questionnaires. Users of hallucinogenic drugs had higher psychological well-being and lower scores on psychopathology scales, both at baseline and during follow-ups. This difference was larger when users were distinguished by frequency of use, as regular users scored higher on psychological well-being and lower on psychopathology scales. Subjects with more psychological distress had lower scores for all scales of post-traumatic growth, but if they were regular hallucinogens users, they had higher scores for post-traumatic growth. When comparing the results between cultural contexts, heterogeneous results were obtained. There were more English-speaking regular users of hallucinogenic drugs. Further research should analyse the potential role of hallucinogens in large-scale catastrophes, with a special focus on post-traumatic growth.

Biases in affective attention tasks in posttraumatic stress disorder patients: A systematic review of neuroimaging studies.

INTRODUCTION: Posttraumatic stress disorder (PTSD) is characterized by alterations in emotional and cognitive processing. The current neurobiological model of PTSD posits that amygdala and prefrontal cortex functioning impairment underpins symptoms, such as altered emotional and cognitive processing. Additionally, these structures are key components of emotional and attention regulation. AIM: This review sought to evaluate studies comparing PTSD group to non-PTSD controls performance in affective attention tasks during neuroimaging. RESULTS: PTSD group behavioral performance when responding to affective stimuli differed from controls only in stroop-based tasks. However, neuroimaging techniques were able to identify brain activation differences even when behavioral differences were not present. Amygdala hyperactivation in PTSD patients was confirmed in most cases, but cortical networks results were not as consistent. More than a general reduction in activity, PTSD group data points out to impaired recruitment of ventral cortical structures and increased reliance on dorsal cortical structures during task performance. CONCLUSION: Stroop-based tasks seem to be better at identifying differences in behavioral performance of PTSD individuals. PTSD individuals seems to present an altered brain activation pattern in affective attention tasks when compared to controls, where PTSD individuals seem to present enhanced amygdala activation and rely more on dorsal anterior cingulate cortex and posterior insula activation during tasks. The PROSPERO ID for this study is CRD42022355471.

Cannabidiol modulates chronic neuropathic pain aversion behavior by attenuation of neuroinflammation markers and neuronal activity in the corticolimbic circuit in male Wistar rats.

Chronic neuropathic pain (CNP) is a vast world health problem often associated with the somatosensory domain. This conceptualization is problematic because, unlike most other sensations that are usually affectively neutral and may present emotional, affective, and cognitive impairments. Neuronal circuits that modulate pain can increase or decrease painful sensitivity based on several factors, including context and expectation. The objective of this study was to evaluate whether subchronic treatment with Cannabidiol (CBD; 0.3, 3, and 10 mg/kg intraperitoneal route - i.p., once a day for 3 days) could promote pain-conditioned reversal, in the conditioned place preference (CPP) test, in male Wistar rats submitted to chronic constriction injury (CCI) of the sciatic nerve. Then, we evaluated the expression of astrocytes and microglia in animals treated with CBD through the immunofluorescence technique. Our results demonstrated that CBD promoted the reversal of CPP at 3 and 10 mg/kg. In CCI animals, CBD was able to attenuate the increase in neuronal hyperactivity, measured by FosB protein expression, in the regions of the corticolimbic circuit: anterior cingulate cortex (ACC), complex basolateral amygdala (BLA), granular layer of the dentate gyrus (GrDG), and dorsal hippocampus (DH) - adjacent to subiculum (CA1). CBD also prevented the increased expression of GFAP and IBA-1 in CCI animals. We concluded that CBD effects on CNP are linked to the modulation of the aversive component of pain. These effects decrease chronic neuronal activation and inflammatory markers in regions of the corticolimbic circuit.

Systemic Chronic Treatment with Cannabidiol in Carioca High- and Low-Conditioned Freezing Rats in the Neuropathic Pain Model: Evaluation of Pain Sensitivity.

Studies have shown high comorbidity of anxiety disorder and chronic pain; generalized anxiety disorder (GAD) and neuropathic pain are among these pathologies. Cannabidiol (CBD) has been considered a promising treatment for these conditions. This study investigated whether chronic systemic treatment with CBD alters pain in high- (CHF) and low-freezing (CLF) Carioca rats (GAD model) and control rats (CTL) submitted to chronic neuropathic pain. The rats were evaluated in the sensory aspects (von Frey, acetone, and hot plate tests) before the chronic constriction injury of the ischiatic nerve (CCI) or not (SHAM) and on days 13 and 23 after surgery. Chronic treatment with CBD (5 mg/kg daily) was used for ten days, starting the 14th day after surgery. The open field test on the 22nd also evaluated locomotion and anxiety-like behavior. CBD treatment had an anti-allodynic effect on the mechanical and thermal threshold in all lineages; however, these effects were lower in the CHF and CLF lineages. Considering emotional evaluation, we observed an anxiolytic effect in CTL+CCI and CHF+CCI after CBD treatment and increased mobility in CLF+SHAM rats. These results suggest that the CBD mechanical anti-allodynic and emotional effects can depend on anxiety level.

Interactive Effects of Ayahuasca and Cannabidiol in Social Cognition in Healthy Volunteers: A Pilot, Proof-of-Concept, Feasibility, Randomized-Controlled Trial.

BACKGROUND: Serotonergic hallucinogens and cannabinoids may alter the recognition of emotions in facial expressions (REFE). Cannabidiol (CBD) attenuates the psychoactive effects of the cannabinoid-1 agonist tetrahydrocannabinol. Ayahuasca is a dimethyltryptamine-containing hallucinogenic decoction. It is unknown if CBD may moderate and attenuate the effects of ayahuasca on REFE. PROCEDURES: Seventeen healthy volunteers participated in a 1-week preliminary parallel-arm, randomized controlled trial for 18 months. Volunteers received a placebo or 600 mg of oral CBD followed by oral ayahuasca (1 mL/kg) 90 minutes later. Primary outcomes included REFE and empathy tasks (coprimary outcome). Tasks were performed at baseline and 6.5 hours, 1 and 7 days after the interventions. Secondary outcome measures included subjective effects, tolerability, and biochemical assessments. RESULTS: Significant reductions (all P values <0.05) only in reaction times were observed in the 2 tasks in both groups, without between-group differences. Furthermore, significant reductions in anxiety, sedation, cognitive deterioration, and discomfort were observed in both groups, without between-group differences. Ayahuasca, with or without CBD, was well tolerated, producing mainly nausea and gastrointestinal discomfort. No clinically significant effects were observed on cardiovascular measurements and liver enzymes. CONCLUSIONS: There was no evidence of interactive effects between ayahuasca and CBD. The safety of separate and concomitant drug intake suggests that both drugs could be applied to clinical populations with anxiety disorders and in further trials with larger samples to confirm findings.

DNA methylation in regulatory elements of the FKBP5 and NR3C1 gene in mother-child binomials with depression.

BACKGROUND: The FKBP5 and NR3C1 genes play an important role in stress response, thus impacting mental health. Stress factor exposure in early life, such as maternal depression, may contribute to epigenetic modifications in stress response genes, increasing the susceptibility to different psychopathologies. The present study aimed to evaluate the DNA methylation profile in maternal-infant depression in regulatory regions of the FKBP5 gene and the alternative promoter of the NR3C1 gene. METHODS: We evaluated 60 mother-infant pairs. The levels of DNA methylation were analyzed by the MSRED-qPCR technique. RESULTS: We observed an increased DNA methylation profile in the NR3C1 gene promoter in children with depression and children exposed to maternal depression (p < 0.05). In addition, we observed a correlation of DNA methylation between mothers and offspring exposed to maternal depression. This correlation shows a possible intergenerational effect of maternal MDD exposure on the offspring. For FKBP5, we found a decrease in DNA methylation at intron 7 in children exposed to maternal MDD during pregnancy and a correlation of DNA methylation between mothers and children exposed to maternal MDD (p < 0.05). LIMITATIONS: Although the individuals of this study are a rare group, the sample size of the study was small, and we evaluated the DNA methylation of only one CpG site for each region. CONCLUSION: These results indicate changes in DNA methylation levels in regulatory regions of FKBP5 and NR3C1 in the mother-child MDD context and represent a potential target of studies to understand the depression etiology and how it occurs between generations.

Identifying setting factors associated with improved ibogaine safety: a systematic review of clinical studies.

Ibogaine is a psychoactive alkaloid derived from the west-African shrub Tabernanthe iboga. Western cultures are increasing the interest for the substance due to its claimed anti addictive properties, although the evidence supporting this effect is still preliminary. The use of ibogaine often occurs with no medical supervision in uncontrolled settings, and its use has been associated with several reports of severe adverse events. This review aims to evaluate the clinical studies of ibogaine, with a focus on administration settings, to elucidate specific criteria that may promote safer contexts for ibogaine use. A systematic review of the literature was conducted based on PRISMA guidelines. PubMed, Scielo, ClinicalTrials.gov and Core.ac.uk electronic databases were searched, and clinical studies published until November 17, 2022, were retrieved. The final synthesis included 12 sources. Information about general characteristics of the studies, adverse effects, screening of participants and setting characteristics were summarized and discussed. It is concluded that the use of controlled settings, supported by trained professionals and equipment allowing for rigorous medical, psychiatric, and cardiac monitoring, are essential to promote the safety of patients receiving ibogaine.

Hallucinations and Hallucinogens: Psychopathology or Wisdom?

Hallucinations are currently associated almost exclusively with psychopathological states. While it is evident that hallucinations can indicate psychopathology or neurological disorders, we should remember that hallucinations also commonly occur in people without any signs of psychopathology. A similar case occurs in the case of hallucinogenic drugs, which have been long associated with psychopathology and insanity. However, during the last decades a huge body of research has shown that certain kinds of hallucinations, exerted by hallucinogenic drugs, may serve to improve mental health. We propose that, in light of historical, epidemiological, and scientific research, hallucinations can be better characterized as a common phenomenon associated sometimes with psychopathology but also with functional and even beneficial outcomes. In the last sections of the manuscript, we extend our argument, suggesting that hallucinations can offer a via regia to knowledge of the mind and the world. This radical shift in the cultural interpretation of hallucinations could have several implications for fields such as drug policy, civil law, and psychiatry, as well as for the stigma associated with mental disorders.

Ayahuasca and Public Health II: Health Status in a Large Sample of Ayahuasca-Ceremony Participants in the Netherlands.

Ayahuasca is a plant decoction in traditional Amazonian medicine. Its ritual use has been internationalized, leading to policy challenges that countries should address. This study evaluates the impact of regular ayahuasca ceremony participation on health by assessing the health status of 377 participants in ayahuasca ceremonies in the Netherlands using validated health indicators. A questionnaire was developed and administered to study participants. The questionnaire included several health indicators with public health relevance (e.g., BMI, diet, physical activity) and psychometrically validated questionnaires (ELS and COPE-easy). The data retrieved through health indicators was compared to normative Dutch data. Participants (50.1% women) were mostly Dutch (84.6%) with a mean age of 48.8 years (SD = 11.6). Compared to normative Dutch data, regular participants in ayahuasca ceremonies showed better general well-being, fewer chronic or lifestyle-related diseases, more physical activity, and a more balanced diet. Participants also used less alcohol during the COVID-19 pandemic, and although they used more illegal drugs than the general population, they did not report associated harms. Our findings suggest that regular participation in ayahuasca ceremonies is not linked to relevant health harms. This data could help drug policymakers to develop and implement evidence-based public policies.