Ayahuasca and its major component harmine promote antinociceptive effects in mouse models of acute and chronic pain.

ETHNOPHARMACOLOGICAL RELEVANCE: Ayahuasca (AYA) is a psychedelic brew used in religious ceremonies. It is broadly used as a sacred medicine for treating several ailments, including pain of various origins. AIM OF THE STUDY: To investigate the antinociceptive effects of AYA and its mechanisms in preclinical models of acute and chronic pain in mice, in particular during experimental neuropathy. MATERIALS AND METHODS: The antinociceptive effects of AYA administered orally were assessed in the following models of pain: formalin test, Complete Freund's Adjuvant (CFA)-induced inflammation, tail flick test, and partial sciatic nerve ligation model of neuropathic pain. Antagonism assays and Fos immunohistochemistry in the brain were performed. AYA-induced toxicity was investigated. AYA was chemically characterized. The antinociceptive effect of harmine, the major component present in AYA, was investigated. RESULTS: AYA (24-3000 µL/kg) dose-dependently reduced formalin-induced pain-like behaviors and CFA-induced mechanical allodynia but did not affect CFA-induced paw edema or tail flick latency. During experimental neuropathy, single treatments with AYA (24-3000 µL/kg) reduced mechanical allodynia; daily treatments once or twice a day for 14 days promoted consistent and sustained antinociception. The antinociceptive effect of AYA (600 µL/kg) was reverted by bicuculline (1 mg/kg) and methysergide (5 mg/kg), but not by naloxone (5 mg/kg), phaclofen (2 mg/kg), and rimonabant (10 mg/kg), suggesting the roles of GABAA and serotonergic receptors. AYA increased Fos expression in the ventrolateral periaqueductal gray and nucleus raphe magnus after 1 h, but not after 6 h or 14 days of daily treatments. AYA (600 µL/kg) twice a day for 14 days did not alter mice's motor function, spontaneous locomotion, body weight, food and water intake, hematological, biochemical, and histopathological parameters. Harmine (3.5 mg/kg) promoted consistent antinociception during experimental neuropathy. CONCLUSIONS: AYA promotes consistent antinociceptive effects in different mouse models of pain without inducing detectable toxic effects. Harmine is at least partially accountable for the antinociceptive properties of AYA.

Ayahuasca, Personality and Acute Psychological Effects in Neo-Shamanic and Religious Settings in Uruguay.

This study is an interdisciplinary research into Uruguayan ayahuasca users belonging to one neo-shamanic and one Santo Daime group. The study involved the chemical analysis of ayahuasca samples, an ethnographic description of the two traditions and rituals, and the application of psychometric scales to measure personality differences, and the acute psychological effects during an ayahuasca ritual. Personality measurements showed lower scores for Santo Daime in Neuroticism-Anxiety, Dependence, Low Self-Esteem, Anger and Restlessness. These differences may be related to the presence of participants under treatment in the neo-shamanic group and/or to the protective effects of a church religion such as Santo Daime. Regarding acute effects, the neo-shamanic group showed higher scores in Somesthesia and Perception, which can be related to the high-arousal ritual setting. Chemical analysis for the ayahuasca samples showed a typical composition of alkaloids. No adulterants were found. The sample from the neo-shamanic group displayed a higher ß-carbolines:DMT ratio compared to the Santo Daime sample, which could be related to the higher effects observed for Somesthesia for the neo-shamanic group. Significant positive correlations between some personality traits and acute effects were found only in the neo-shamanic group, which may be related to the more individualistic approach of this tradition.

Altered State of Consciousness and Mental Imagery as a Function of N, N-dimethyltryptamine Concentration in Ritualistic Ayahuasca Users.

Consumption of the psychedelic brew ayahuasca is a central ritualistic aspect of the Santo Daime religion. The current observational, baseline controlled study was designed to assess whether members (n = 24) of the Santo Daime church would show enhanced capacity for mental imagery during an ayahuasca experience. In addition, this study assessed whether the effects of ayahuasca on consciousness and mental imagery were related to peak serum concentration of N, N-dimethyltryptamine (DMT), the main psychoactive component. Measures of altered states of consciousness (5-Dimensional Altered States of Consciousness Questionnaire) and ego dissolution (Ego Dissolution Inventory [EDI]) as well as measures of mental imagery (visual perspective shifting, vividness of visual imagery, cognitive flexibility, associative thinking) were taken on two subsequent days on which members of Santo Daime were sober or drank a self-selected volume of ayahuasca. Measures of altered states of consciousness revealed that feelings of oceanic boundlessness, visual restructuralization, and EDI increased most prominently after drinking and shared a positive correlation with peak DMT concentration. Measures of mental imagery did not noticeably differ between the baseline and ayahuasca condition, although subjective ratings of cognitive flexibility were lower under ayahuasca. Two measures related to mental imagery, that is, perspective shifts and cognitive flexibility, were significantly correlated to peak DMT concentrations. Peak concentrations of DMT and other alkaloids did not correlate with ayahuasca dose. These findings confirm previous notions that the primary phenomenological characteristics of ayahuasca are driven by DMT. Compensatory or neuroadaptive effects associated with long-term ayahuasca intake may have mitigated the acute impact of ayahuasca in Santo Daime members on mental imagery.

Ayahuasca Ritual, Personality and Sociality: Observational Research Conducted in a Substance Use Disorder Rehabilitation Center in Uruguay.

The current article presents a mixed qualitative-quantitative observational study of the effect of ayahuasca ritual on subjective experiences and personality traits on participants of a center specialized in the treatment of substance use disorder in Uruguay. When comparing the psychological traits of ayahuasca participants to a control group, quantitative results using the Zuckerman-Kuhlman-Aluja Personality Questionnaire showed statistically significant higher scores in Impulsive Sensation Seeking, Boredom Susceptibility, and Social Warmth scales. Qualitative analysis of ayahuasca experiences resulted in five main categories: emotional experiences (including social emotions such as love and empathy), corporal experiences, spiritual/transcendental experiences, personal experiences, and visions. Last, qualitative descriptions provide support for the importance of social interactions in the phenomenological manifestations of the psychedelic experience. Both quantitative and qualitative results suggest that the combination of social interactions and the pharmacological action of ayahuasca could facilitate the manifestation of social emotions during the ritual, and may contribute to the long-term increase of empathic and social aspects of personality.

Application of machine learning and complex network measures to an EEG dataset from ayahuasca experiments.

Ayahuasca is a blend of Amazonian plants that has been used for traditional medicine by the inhabitants of this region for hundreds of years. Furthermore, this plant has been demonstrated to be a viable therapy for a variety of neurological and mental diseases. EEG experiments have found specific brain regions that changed significantly due to ayahuasca. Here, we used an EEG dataset to investigate the ability to automatically detect changes in brain activity using machine learning and complex networks. Machine learning was applied at three different levels of data abstraction: (A) the raw EEG time series, (B) the correlation of the EEG time series, and (C) the complex network measures calculated from (B). Further, at the abstraction level of (C), we developed new measures of complex networks relating to community detection. As a result, the machine learning method was able to automatically detect changes in brain activity, with case (B) showing the highest accuracy (92%), followed by (A) (88%) and (C) (83%), indicating that connectivity changes between brain regions are more important for the detection of ayahuasca. The most activated areas were the frontal and temporal lobe, which is consistent with the literature. F3 and PO4 were the most important brain connections, a significant new discovery for psychedelic literature. This connection may point to a cognitive process akin to face recognition in individuals during ayahuasca-mediated visual hallucinations. Furthermore, closeness centrality and assortativity were the most important complex network measures. These two measures are also associated with diseases such as Alzheimer's disease, indicating a possible therapeutic mechanism. Moreover, the new measures were crucial to the predictive model and suggested larger brain communities associated with the use of ayahuasca. This suggests that the dissemination of information in functional brain networks is slower when this drug is present. Overall, our methodology was able to automatically detect changes in brain activity during ayahuasca consumption and interpret how these psychedelics alter brain networks, as well as provide insights into their mechanisms of action.

Molecular Pathways of the Therapeutic Effects of Ayahuasca, a Botanical Psychedelic and Potential Rapid-Acting Antidepressant.

Ayahuasca is a psychoactive brew traditionally used in indigenous and religious rituals and ceremonies in South America for its therapeutic, psychedelic, and entheogenic effects. It is usually prepared by lengthy boiling of the leaves of the bush Psychotria viridis and the mashed stalks of the vine Banisteriopsis caapi in water. The former contains the classical psychedelic N,N-dimethyltryptamine (DMT), which is thought to be the main psychoactive alkaloid present in the brew. The latter serves as a source for ß-carbolines, known for their monoamine oxidase-inhibiting (MAOI) properties. Recent preliminary research has provided encouraging results investigating ayahuasca's therapeutic potential, especially regarding its antidepressant effects. On a molecular level, pre-clinical and clinical evidence points to a complex pharmacological profile conveyed by the brew, including modulation of serotoninergic, glutamatergic, dopaminergic, and endocannabinoid systems. Its substances also interact with the vesicular monoamine transporter (VMAT), trace amine-associated receptor 1 (TAAR1), and sigma-1 receptors. Furthermore, ayahuasca's components also seem to modulate levels of inflammatory and neurotrophic factors beneficially. On a biological level, this translates into neuroprotective and neuroplastic effects. Here we review the current knowledge regarding these molecular interactions and how they relate to the possible antidepressant effects ayahuasca seems to produce.

Evaluation of the In Vitro Wound-Healing Potential of Ayahuasca.

Ayahuasca is an Amazonian drink, which contains ß-carboline alkaloids and N,N-dimethyltryptamine. The aim of this study was to evaluate the healing potential of decoctions of a commercial mixture, four individual plants and four mixtures of two plants used in the ayahuasca preparation. Thus, the cytotoxic potential of the samples was evaluated and a wound-healing assay was performed with a NHDF cell line. Subsequently, a parallel artificial membrane permeability assay was also performed, to verify if any psychoactive compound could be absorbed by skin fibroblasts. The integrity and permeability of the cell layer were also evaluated, using the transepithelial electrical resistance assay and Lucifer yellow permeability assay, respectively. The compounds absorbed by the cell layer were quantified by high-performance liquid chromatography coupled to a diode array detector. The results showed that only one sample showed cytotoxicity and all the others promoted the migration of skin fibroblasts. Additionally, it was also verified that ß-carbolynic alkaloids and N,N-dimethyltriptamine were not absorbed by the cell layer, and in general, did not interfere with its permeability and integrity. To the best of our knowledge, this is the first study where ayahuasca's wound-healing potential was evaluated.

Immunological Modulation and Control of Parasitaemia by Ayahuasca Compounds: Therapeutic Potential for Chagas's Disease.

Ayahuasca is a psychoactive and psychedelic decoct composed mainly of Banisteriopsis caapi and Psychotria viridis plant species. The beverage is rich in alkaloids and it is ritualistically used by several indigenous communities of South America as a natural medicine. There are also reports in the literature indicating the prophylaxis potential of Ayahuasca alkaloids against internal parasites. In the present study, Ayahuasca exhibited moderate in vitro activity against Trypanosoma cruzi trypomastigotes (IC50 95.78 µg/mL) compared to the reference drug benznidazole (IC50 2.03 µg/mL). The ß-carboline alkaloid harmine (HRE), isolated from B. caapi, was considered active against the trypomastigotes forms (IC50 6.37), and the tryptamine N, N-dimethyltryptamine (DMT), isolated from P. viridis was also moderately active with IC50 of 21.02 µg/mL. Regarding the in vivo evaluations, no collateral effects were observed. The HRE alone demonstrated the highest trypanocidal activity in a dose-responsive manner (10 and 100 mg/kg). The Ayahuasca and the association between HRE and DMT worsened the parasitaemia, suggesting a modulation of the immunological response during the T. cruzi infection, especially by increasing total Immunoglobulin (IgG) and IgG1 antibody levels. The in silico molecular docking revealed HRE binding with low energy at two sites of the Trypanothione reductase enzyme (TR), which are absent in humans, and thus considered a promissory target for drug discovery. In conclusion, Ayahuasca compounds seem to not be toxic at the concentrations of the in vivo evaluations and can promote trypanocidal effect in multi targets, including control of parasitaemia, immunological modulation and TR enzymatic inhibition, which might benefit the treatments of patients with Chagas' disease. Moreover, the present study also provides scientific information to support the prophylactic potential of Ayahuasca against internal parasites.

Components of Banisteriopsis caapi, a Plant Used in the Preparation of the Psychoactive Ayahuasca, Induce Anti-Inflammatory Effects in Microglial Cells.

Banisteriopsis caapi is used to prepare the psychoactive beverage ayahuasca, and both have therapeutic potential for the treatment of many central nervous system (CNS) conditions. This study aimed to isolate new bioactive compounds from B. caapi extract and evaluate their biological activity, and that of the known ß-carboline components of the plant (harmine, harmaline, and tetrahydroharmine), in BV-2 microglial cells, the in vivo activation of which is implicated in the physiopathology of CNS disorders. B. caapi extract was fractionated using semipreparative liquid chromatography (HPLC-DAD) and the exact masses ([M + H]+m/z) of the compounds in the 5 isolated fractions were determined by high-resolution LC-MS/MS: F1 (174.0918 and 233.1289), F2 (353.1722), F3 (304.3001), F4 (188.1081), and F5 (205.0785). Harmine (75.5-302 µM) significantly decreased cell viability after 2 h of treatment and increased the number of necrotic cells and production of reactive oxygen species at equal or lower concentrations after 24 h. F4 did not impact viability but was also cytotoxic after 24 h. Most treatments reduced proinflammatory cytokine production (IL-2, IL-6, IL-17, and/or TNF), especially harmaline and F5 at 2.5 µM and higher concentrations, tetrahydroharmine (9.3 µM and higher), and F5 (10.7 µM and higher). The results suggest that the compounds found in B. caapi extract have anti-inflammatory potential that could be explored for the development of treatments for neurodegenerative diseases.

Prospective examination of the therapeutic role of psychological flexibility and cognitive reappraisal in the ceremonial use of ayahuasca.

BACKGROUND: Evidence suggests that psychedelic-assisted therapy carries transdiagnostic efficacy in the treatment of mental health conditions characterized by low mood and the use of avoidance coping strategies. AIMS: While preliminary evidence suggests that psychological flexibility and emotion regulation processes play an important role within psychedelic therapy, this prospective study addressed methodological gaps in the literature and examined the ability of ayahuasca to stimulate acute states of cognitive reappraisal and long-term changes in psychological flexibility and mood. The study also explored whether moderating factors predisposed participants to experience therapeutic changes. METHODS: Participants (N = 261) were recruited from three Shipibo ayahuasca retreat centers in Central and South America and completed assessments on mood, psychological flexibility, and acute ceremonial factors. Expectancy, demand characteristics, and invalid responding were controlled for with several validity scales. RESULTS/OUTCOMES: Participants reported significant reductions in negative mood after three months, as well as increases in positive mood and psychological flexibility. Acute experiences of reappraisal during the ayahuasca ceremony exerted the strongest moderating effects on increases in positive mood and psychological flexibility. Increases in psychological flexibility statistically mediated the effects of acute psychological factors, including reappraisal, on changes in positive mood. CONCLUSIONS/INTERPRETATION: These results highlight the role of acute psychological processes, such as reappraisal, and post-acute increases in psychological flexibility as putative mechanisms underlying positive outcomes associated with psychedelics. These results also provide support for the integration of third-wave and mindfulness-based therapy approaches with psychedelic-assisted interventions.

N,N-dimethyltryptamine and Amazonian ayahuasca plant medicine.

OBJECTIVE: Reports have indicated possible uses of ayahuasca for the treatment of conditions including depression, addictions, post-traumatic stress disorder, anxiety and specific psychoneuroendocrine immune system pathologies. The article assesses potential ayahuasca and N,N-dimethyltryptamine (DMT) integration with contemporary healthcare. The review also seeks to provide a summary of selected literature regarding the mechanisms of action of DMT and ayahuasca; and assess to what extent the state of research can explain reports of unusual phenomenology. DESIGN: A narrative review. RESULTS: Compounds in ayahuasca have been found to bind to serotonergic receptors, glutaminergic receptors, sigma-1 receptors, trace amine-associated receptors, and modulate BDNF expression and the dopaminergic system. Subjective effects are associated with increased delta and theta oscillations in amygdala and hippocampal regions, decreased alpha wave activity in the default mode network, and stimulations of vision-related brain regions particularly in the visual association cortex. Both biological processes and field of consciousness models have been proposed to explain subjective effects of DMT and ayahuasca, however, the evidence supporting the proposed models is not sufficient to make confident conclusions. Ayahuasca plant medicine and DMT represent potentially novel treatment modalities. CONCLUSIONS: Further research is required to clarify the mechanisms of action and develop treatments which can be made available to the general public. Integration between healthcare research institutions and reputable practitioners in the Amazon is recommended.

Therapeutic effect of an ayahuasca analogue in clinically depressed patients: a longitudinal observational study.

RATIONALE: Studies have suggested mental health improvements following the use of the psychotropic plant concoction ayahuasca in non-clinical and clinical samples. OBJECTIVES: The present observational study assessed depressive symptomatology in 20 clinically depressed patients (symptom score > 13 on the Beck's Depression Inventory) before attendance of an ayahuasca ceremony and 1 month and 1 year after. Secondary measures included ratings of altered states of consciousness and ego dissolution during the ayahuasca ceremony as well as global measures of mindfulness, satisfaction with life, depression, anxiety, and stress. RESULTS: Twenty participants completed baseline and 1-day follow-up, 19 completed measures at 1-month follow-up, and 17 completed measures at 1-year follow-up. BDI scores reduced from baseline (M = 22.7) to all post-ceremony measures (Ms 11.45, 12.89, and 8.88, for 1-day, 1-month, and 1-year follow-up, respectively). After 1 day, 12/20 participants were in remission (BDI < 13). Remission rates after 1 month and 1 year were 13/19 and 12/17, respectively. Three participants remained mildly depressed (BDI 14-19) at the 1-month and 1-year follow-up. Two participants did not respond and remained at a moderate/severe level of depression at 1-year follow-up. Reductions on the secondary mental health measures and increases in mindfulness and satisfaction with life were found up to 1 year post-ceremony. Improvements in clinical depression and mental health correlated with levels of experienced ego dissolution and oceanic boundlessness during the ceremony up to 1 month after the ceremony. Engagement in additional mental health treatments or use of another psychedelic during study participation may have contributed to improved mental health ratings at 1-year follow-up. CONCLUSION: Ayahuasca produces long-term mental health improvements in clinically depressed patients, which highlights its therapeutic potential.

Overcoming epistemic injustices in the biomedical study of ayahuasca: Towards ethical and sustainable regulation.

After decades of biomedical research on ayahuasca's molecular compounds and their physiological effects, recent clinical trials show evidence of therapeutic potential for depression. However, indigenous peoples have been using ayahuasca therapeutically for a very long time, and thus we question the epistemic authority attributed to scientific studies, proposing that epistemic injustices were committed with practical, cultural, social, and legal consequences. We question epistemic authority based on the double-blind design, the molecularization discourse, and contextual issues about safety. We propose a new approach to foster epistemically fair research, outlining how to enforce indigenous rights, considering the Brazilian, Peruvian, and Colombian cases. Indigenous peoples have the right to maintain, control, protect, and develop their biocultural heritage, traditional knowledge, and cultural expressions, including traditional medicine practices. New regulations about ayahuasca must respect the free, prior, and informed consent of indigenous peoples according to the International Labor Organization Indigenous and Tribal Peoples Convention no. 169. The declaration of the ayahuasca complex as a national cultural heritage may prevent patenting from third parties, fostering the development of traditional medicine. When involving isolated compounds derived from traditional knowledge, benefit-sharing agreements are mandatory according to the United Nations' Convention on Biological Diversity. Considering the extremely high demand to treat millions of depressed patients, the medicalization of ayahuasca without adequate regulation respectful of indigenous rights can be detrimental to indigenous peoples and their management of local environments, potentially harming the sustainability of the plants and of the Amazon itself, which is approaching its dieback tipping point.

Ayahuasca Lyophilization (Freeze-drying) Protocol with Pre- and Post-procedure Alkaloids Quantification.

Ayahuasca is a psychoactive brew from the decoction of different Amazonian plants, traditionally used in several cultures, religions, and rituals. Scientific studies with ayahuasca are rapidly increasing due to its subjective effects and therapeutic potential. Although ayahuasca is traditionally used in its liquid presentation, lyophilized (freeze-dried) ayahuasca is often used in scientific experimentation settings. However, there is no standard process or guideline to freeze-dry ayahuasca nor comparison of the chemical profile between the liquid and freeze-dried presentations. Therefore, we describe a reproducible five-day protocol for ayahuasca lyophilization with alkaloids quantification by liquid chromatography coupled to tandem mass spectrometry of both the liquid and the final freeze-dried ayahuasca. By the end of the protocol, approximately 295 g of freeze-dried extract with similar alkaloids concentration were obtained from two liters of ayahuasca (dry matter: 14.75 %). The final extract was stored for three years inside a vacuum desiccator (approximately 6°C) with its texture quality preserved. Further studies should address the impact of different storage conditions and the lyophilization on the alkaloids' quantity of the freeze-dried ayahuasca, especially the use of heat in regards to the ß-carbolines.

Ayahuasca may help to improve self-compassion and self-criticism capacities.

OBJECTIVE: Ayahuasca is a psychedelic brew that originated in the Amazon basin. The psychological effects of this drug are becoming better understood due to the growing research interest in identifying new potential therapeutic agents for the treatment of emotion dysregulation and other disorders. Previous studies suggest that ayahuasca enhances mindfulness-related capacities (decentering, non-judging, non-reacting and acceptance) and emotion regulation. The aim of the present exploratory study was to determine the effects of ayahuasca on self-compassion in a community sample. METHODS: We administered validated questionnaires (the Self-Compassion Scale-Short Form and Forms of Self-Criticism and Self-Reassurance) to evaluate pre-post changes in self-compassion and self-criticism/self-reassurance in 45 volunteers (27 women; 60%) before and after (≤24 h) an ayahuasca ceremony. Most participants (n = 29; 67.4%) had previously used ayahuasca. RESULTS: Ayahuasca resulted in significant improvements, with medium to large effect sizes (η2  = 0.184-0.276), in measures of self-compassion (p < 0.05), self-criticism (p < 0.01) and self-reassurance (p < 0.01). CONCLUSIONS: The findings of this study suggest that ayahuasca promotes well-being and self-compassion, which could have a therapeutic effect on individuals with negative affect and other psychopathological conditions. Large, controlled studies are needed to confirm these findings.

Ayahuasca blocks ethanol preference in an animal model of dependence and shows no acute toxicity.

ETHNOPHARMACOLOGICAL RELEVANCE: Ayahuasca, a psychoactive beverage prepared from Banisteriopsis caapi and Psychotria viridis, is originally used by Amazon-based indigenous and mestizo groups for medicinal and ritualistic purposes. Nowadays, ayahuasca is used in religious and shamanic contexts worldwide, and preliminary evidence from preclinical and observational studies suggests therapeutic effects of ayahuasca for the treatment of substance (including alcohol) use disorders. AIM OF THE STUDY: To investigate the initial pharmacological profile of ayahuasca and its effects on ethanol rewarding effect using the conditioned place preference (CPP) paradigm in mice. MATERIALS AND METHODS: Ayahuasca beverage was prepared using extracts of B. caapi and P. viridis, and the concentration of active compounds was assessed through high performance liquid chromatography (HPLC). The following behavioral tests were performed after ayahuasca administration: general pharmacological screening (13, 130, or 1300 mg/kg - intraperitoneally - i.p., and 65, 130, 1300, or 2600 mg/kg - via oral - v.o.); acute toxicity test with elevated doses (2600 mg/kg - i.p., and 5000 mg/kg - v.o.); motor activity, motor coordination, and hexobarbital-induced sleeping time potentiation (250, 500, or 750 mg/kg ayahuasca or vehicle - v.o.). For the CPP test, the animals received ayahuasca (500 mg/kg - v.o.) prior to ethanol (1.8 g/kg - i.p.) or vehicle (control group - i.p.) during conditioning sessions. RESULTS: Ayahuasca treatment presented no significant effect on motor activity, motor coordination, hexobarbital-induced sleeping latency or total sleeping time, and did not evoke signs of severe acute toxicity at elevated oral doses. Ayahuasca pre-treatment successfully inhibited the ethanol-induced CPP and induced CPP when administered alone. CONCLUSIONS: Our results indicate that ayahuasca presents a low-risk acute toxicological profile when administered orally, and presents potential pharmacological properties that could contribute to the treatment of alcohol use disorders.