Effects of Ayahuasca on the Recognition of Facial Expressions of Emotions in Naive Healthy Volunteers: A Pilot, Proof-of-Concept, Randomized Controlled Trial

This randomized, double-blind, placebo-controlled, pilot study (n=22) investigated the acute and prolonged effects of ayahuasca (9.36mg of DMT, 79.62mg of harmine, 50.71mg of tetrahydroharmine, 7.38mg of harmaline) on social cognition amongst healthy volunteers. Contrary to previous studies which indicate that psychedelics reduce the recognition of fearful face stimuli, this study yielded null results in the absence of ayahuasca-induced effects on the recognition of emotions in facial expressions.

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.”

Authors: Juliana M. Rocha, Giordano N. Rossi, Flávia de Lima Osório, José Carlos Bouso, Gabriela de Oliveira Silveira, Mauricio Yonamine, Alline Cristina Campos, Giuliana Bertozi, Hallak Jaime E. Cecílio & Rafael G. Dos Santos

Summary

Ayahuasca reduced the recognition of negative facial expressions in healthy volunteers.

Social cognition involves several psychological processes, such as the theory of mind and empathy.

Recent studies with lysergic acid diethylamide (LSD) and psilocybin showed contradictory results regarding REFE. Some studies found significant reductions in amygdala activation during the presentation of fear expressions, while others found no significant effects.

These studies suggest that hallucinogens/psychedelics may have beneficial effects in mood disorders, such as depression, and that preliminary trials suggest that LSD, psilocybin, and ayahuasca have antidepressant effects.

Previous articles have assessed the pharmacokinetics and subjective effects of oral ayahuasca when ingested by healthy volunteers. These studies have demonstrated that even at relatively low doses (32 mg), DMT still reaches the systemic circulation, causing psychoactive effects and biological changes to the human body.

A pilot study was conducted to assess the effects of ayahuasca on the REFE. Other variables included subjective effects, tolerability measures, and brain-derived neurotrophic factor plasma levels.

Volunteers

The trial was conducted from November 2017 to May 2019 on 22 participants. 11 volunteers were randomly included in the placebo group and 11 in the ayahuasca group, and 1 volunteer was excluded in the placebo group because of hypoglycemia.

Eligibility criteria included age between 18 and 65 years, absence of prior use of ayahuasca, and 2 uses in life of other hallucinogens. Exclusion criteria included a history of cardiovascular, liver, or neurological diseases, and any psychiatric diagnosis.

Groups were homogeneous in terms of sociodemographic characteristics and clinical characteristics. None of the participants were using psychotropic medications.

Ayahuasca was studied in accordance with the Declaration of Helsinki and the ethical standards of the Ministry of Health. All volunteers gave their written informed consent to participate.

Drugs

The administered drugs were placebo and ayahuasca (both 1 mL/kg), and the ayahuasca dose was chosen based on previous work by our group in which it had been proven to elicit psychotropic effects. The ayahuasca batch was prepared in October 2017 and stored at room temperature protected from light.

A pharmacist prepared a placebo with similar (as possible) organoleptic properties to ayahuasca, but without any relationship with the study investigators or participants. The placebo was intended to produce in the participant the sensation of drinking a nauseous and bitter medicine.

Investigators with previous experience with ayahuasca and one without tested and approved the placebo. Volunteers were instructed to ingest the full content of the bottle without smelling or visually examining its content.

Study Design

We conducted an experiment with 6 time points and 5 follow-up time points with ayahuasca using a randomized, double-blind, placebo-controlled, parallel-group design. Volunteers were instructed to fast before the session and avoid ingesting tyramine containing foods/drinks 24 hours before and 12 hours after the experimental session.

No specific psychotherapeutic intervention was used before, during, or after the experiments, and volunteers were informed about the general effects of ayahuasca. Researchers stayed in a room next to the room where the volunteers were and assessed their well-being during the 6 data collection points.

At the end of the experimental session, volunteers were offered R$20.00 for going to the laboratory, totaling R $140.00.

Tolerability

Systolic blood pressure, diastolic blood pressure, and heart rate were measured before and after drug administration. Adverse effects were not systematically collected.

Brain-Derived Neurotrophic Factor

We took three blood samples to assess plasma BDNF levels (baseline, 120 minutes, and 240 minutes). The results were expressed in picograms per milliliter according to calculations obtained after plotting the optical density of the samples against the line equation generated by the standard curve.

Blinding Efficacy

The effectiveness of blinding procedures was assessed by asking the volunteers which substance they thought they had received.

Statistical Analyses

Ayahuasca was used to assess the effects of ayahuasca on the REFE task, cardiovascular variables, and BDNF. A 2-way repeated-measures analysis of variance was performed with time and group as factors, and an effect size was calculated using 2.

Feasibility and Adherence

Twenty-two volunteers completed the full experimental session and most of the study protocol, and there were no serious adverse events or dropouts in the ayahuasca group.

In the placebo group, 11 experimental sessions were performed, with 1 male volunteer being excluded from analysis because of hypoglycemia. This episode was probably linked to the fact that he had fasted in the last 12 hours, but no previous similar episode was reported by this volunteer.

REFE Task

For faces of happiness, there were no significant differences in accuracy, but a significant effect of time was found in reaction time. For faces of anger, there were significant effects of time in accuracy, but not in the interaction between time group. For the faces of disgust, sadness, and fear, there was a significant effect of time on accuracy and reaction time, but not on group. No significant differences were found between groups.

Subjective Effects

All volunteers gave positive reports regarding the experiment, and most appreciated the opportunity to observe their body and breathing.

During the experimental session, 40% of the volunteers reported visual effects, and 2 volunteers reported increased well-being and increased creativity. The other 2 volunteers reported feeling more electric and motivated in the afternoon after the experimental session.

Some volunteers reported feelings of tranquility, relaxation, well-being, increased flow of thoughts, and difficulty in describing verbally what they were feeling. Some volunteers reported being more anxious and nervous but related this state to being unemployed.

Tolerability

The following adverse effects were reported by the volunteers and/or observed by the researchers: vomiting, gastrointestinal discomfort and nausea, difficulty in concentrating, headache, and drowsiness. No serious adverse effects were observed.

Analyses for cardiovascular variables were performed without using the T6 data points of 2 volunteers from the ayahuasca group because of problems with the equipment. No significant differences were observed in the time group interaction and between groups. Volunteers in the ayahuasca group presented with hypertension at baseline, T2, and T3, while volunteers in the placebo group presented with hypertension at baseline, T2, and T3. Tachycardia was not reported in any group.

Brain-Derived Neurotrophic Factor

The analysis of BDNF levels was performed without data from 5 volunteers in the ayahuasca group because of technical problems. No significant differences were found between groups.

Stability of Ayahuasca Alkaloids

Over 18 months, the levels of DMT, harmine, THH, and harmaline decreased, and the average concentration of DMT was 1.58 mg/mL, 1.15 mg/mL, 0.73 mg/mL, and 7.38 mg/mL, respectively.

DISCUSSION

The results of this pilot study showed that ayahuasca was feasible and that there were no significant effects on the REFE task. However, previous studies have reported inconsistent results on the effects of psychedelics/hallucinogens on REFE task performance.

The absence of significant effects of ayahuasca could be due to several reasons, such as a lack of effect of ayahuasca on the REFE task or a lack of effects at the doses used. The high educational level of the sample could also be a factor.

The lack of effects of ayahuasca on the REFE could be related to the small sample size, increasing the probability of type II errors. However, future trials with larger samples will help clarify the findings.

Ayahuasca has good cardiovascular tolerability in healthy volunteers, with no significant results found in the cardiovascular variables.

In this trial, no significant differences were found between the groups in plasma BDNF levels, a proxy of neuroplasticity. However, future trials should try to use similar methods of BDNF analysis to overcome this important gap in our knowledge regarding the effects of hallucinogens on this measure.

The results of this study could be explained by the small number of samples in the ayahuasca group and by differences in sample storage time and centrifugation strategy.

We observed significant ayahuasca alkaloid degradation over time, which may have influenced the absence of significant effects between placebo and ayahuasca groups. Furthermore, many clinical studies have used alkaloid dosages within the current study’s range and have demonstrated significant subjective and biological effects. Given the results of previous studies and the fact that volunteers and researchers correctly guessed what volunteers had taken (placebo or ayahuasca) at the end of each experimental session, it is reasonable to expect that there would be a significant difference in the outcomes tested. A recent study evaluated the stability of ayahuasca alkaloids under 3 distinct conditions: 1 year stored in a refrigerator, 7 days at 37°C, and 3 cycles of freezing and thawing.

Blinding efficacy was 65% for volunteers and 75% for researchers in a double-blind study with the administration of psilocybin and active placebo (methylphenidate).

Although we used a placebo with organoleptic characteristics like those of ayahuasca, the psychoactive effects of this substance render effective blinding a challenge. The high rate of correct answers is notable for both the volunteers and the researchers involved.

CONCLUSIONS

The effects of ayahuasca on the REFE task were not significant, and the drug’s alkaloids degraded over time, which could have influenced the results. The drug produced typical psychedelic/hallucinogenic effects and was well tolerated, producing transitory nausea, gastrointestinal discomfort, and vomiting.