OPEN Foundation

M. Yonamine

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

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Stability Evaluation of DMT and Harmala Alkaloids in Ayahuasca Tea Samples

Abstract

Ayahuasca tea is a hallucinogenic beverage used for religious purposes in Brazil and many other countries that has therapeutic potential in the treatment of some mental health disorders. In the context of psychedelic research, quantification of the tea’s main alkaloids prior to its administration in animal or human studies is essential. For this reason, this study aims to provide information regarding the stability of the main ayahuasca alkaloids (dimethyltryptamine, DMT; harmine, HRM; tetrahydroharmine, THH; harmaline, HRL) in three different conditions: (1) A year stored in a refrigerator either in plastic or glass containers, (2) seven days at 37 °C to reproduce usual mail transportation, and (3) after three freeze-thaw cycles. Samples were quantified after a dilute-and-shoot procedure using liquid chromatography tandem mass spectrometry (LC-ESI-MS/MS). There was no significant degradation of DMT concentration over time in all tested conditions. Harmala alkaloids (THH, HRL, and HRM) showed important variations after long-term and high-temperature storages. Although DMT has proven to be stable in all studied conditions, the harmala alkaloids revealed intense degradation and even concentration increment. This may be caused by degradation, alkaloid inter-conversion, and leaching from tea precipitate material. Therefore, ayahuasca quantification before administration in controlled sets is mandatory.

de Oliveira Silveira, G., Guimarães Dos Santos, R., Rebello Lourenço, F., Novak Rossi, G., Hallak, J., & Yonamine, M. (2020). Stability Evaluation of DMT and Harmala Alkaloids in Ayahuasca Tea Samples. Molecules (Basel, Switzerland), 25(9), 2072. https://doi.org/10.3390/molecules25092072

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Behavioral Changes Over Time Following Ayahuasca Exposure in Zebrafish

Abstract

The combined infusion of Banisteriopsis caapi stem and Psychotria viridis leaves, known as ayahuasca, has been used for centuries by indigenous tribes. The infusion is rich in NN-dimethyltryptamine (DMT) and monoamine oxidase inhibitors, with properties similar to those of serotonin. Despite substantial progress in the development of new drugs to treat anxiety and depression, current treatments have several limitations. Alternative drugs, such as ayahuasca, may shed light on these disorders. Here, we present time-course behavioral changes induced by ayahuasca in zebrafish, as first step toward establishing an ideal concentration for pre-clinical evaluations. We exposed adult zebrafish to five concentrations of the ayahuasca infusion: 0 (control), 0.1, 0.5, 1, and 3 ml/L (n = 14 each group), and behavior was recorded for 60 min. We evaluated swimming speed, distance traveled, freezing and bottom dwelling every min for 60 min. Swimming speed and distance traveled decreased with an increase in ayahuasca concentration while freezing increased with 1 and 3 ml/L. Bottom dwelling increased with 1 and 3 ml/L, but declined with 0.1 ml/L. Our data suggest that small amounts of ayahuasca do not affect locomotion and reduce anxiety-like behavior in zebrafish, while increased doses of the drug lead to crescent anxiogenic effects. We conclude that the temporal analysis of zebrafish behavior is a sensitive method for the study of ayahuasca-induced functional changes in the vertebrate brain.
Savoldi, R., Polari, D., Pinheiro-da-Silva, J., Silva, P. F., Lobao-Soares, B., Yonamine, M., … & Luchiari, A. C. (2017). Behavioral changes over time following ayahuasca exposure in zebrafish. Frontiers in behavioral neuroscience11. 10.3389/fnbeh.2017.00139
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Effects of Long-Term Ayahuasca Administration on Memory and Anxiety in Rats

Abstract

Ayahuasca is a hallucinogenic beverage that combines the action of the 5-HT2A/2C agonist N,N-dimethyltryptamine (DMT) from Psychotria viridis with the monoamine oxidase inhibitors (MAOIs) induced by beta-carbonyls from Banisteriopsis caapi. Previous investigations have highlighted the involvement of ayahuasca with the activation of brain regions known to be involved with episodic memory, contextual associations and emotional processing after ayahuasca ingestion. Moreover long term users show better performance in neuropsychological tests when tested in off-drug condition. This study evaluated the effects of long-term administration of ayahuasca on Morris water maze (MWM), fear conditioning and elevated plus maze (EPM) performance in rats. Behavior tests started 48h after the end of treatment. Freeze-dried ayahuasca doses of 120, 240 and 480 mg/kg were used, with water as the control. Long-term administration consisted of a daily oral dose for 30 days by gavage. The behavioral data indicated that long-term ayahuasca administration did not affect the performance of animals in MWM and EPM tasks. However the dose of 120 mg/kg increased the contextual conditioned fear response for both background and foreground fear conditioning. The tone conditioned response was not affected after long-term administration. In addition, the increase in the contextual fear response was maintained during the repeated sessions several weeks after training. Taken together, these data showed that long-term ayahuasca administration in rats can interfere with the contextual association of emotional events, which is in agreement with the fact that the beverage activates brain areas related to these processes.

Favaro, V. M., Yonamine, M., Soares, J. C. K., & Oliveira, M. G. M. (2015). Effects of Long-Term Ayahuasca Administration on Memory and Anxiety in Rats. PloS one, 10(12), e0145840. http://dx.doi.org/10.1371/journal.pone.0145840
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Gas chromatographic analysis of dimethyltryptamine and beta-carboline alkaloids in ayahuasca, an Amazonian psychoactive plant beverage

Abstract

Introduction: Ayahuasca is obtained by infusing the pounded stems of Banisteriopsis caapi in combination with the leaves of Psychotria viridis. P. viridis is rich in the psychedelic indole N,N-dimethyltryptamine, whereas B. caapi contains substantial amounts of β-carboline alkaloids, mainly harmine, harmaline and tetrahydroharmine, which are monoamine-oxidase inhibitors. Because of differences in composition in ayahuasca preparations, a method to measure their main active constituents is needed.

Objective: To develop a gas chromatographic method for the simultaneous determination of dimethyltryptamine and the main β-carbolines found in ayahuasca preparations.

Methodology: The alkaloids were extracted by means of solid phase extraction (C18) and detected by gas chromatography with nitrogen/phosphorous detector.

Results: The lower limit of quantification (LLOQ) was 0.02 mg/mL for all analytes. The calibration curves were linear over a concentration range of 0.02–4.0 mg/mL (r2 > 0.99). The method was also precise (RSD < 10%).

Conclusion: A simple gas chromatographic method to determine the main alkaloids found in ayahuasca was developed and validated. The method can be useful to estimate administered doses in animals and humans for further pharmacological and toxicological investigations of ayahuasca.

Pires, A. P. S., De Oliveira, C. D. R., Moura, S., Dörr, F. A., Silva, W. A. E., & Yonamine, M. (2009). Gas chromatographic analysis of dimethyltryptamine and β‐carboline alkaloids in ayahuasca, an amazonian psychoactive plant beverage. Phytochemical Analysis, 20(2), 149-153. 10.1002/pca.1110
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