A placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats

This double-blind placebo-controlled study (n=30) controlled for expectation bias in a naturalistic ayahuasca ceremony. The use of ayahuasca led to more emotional empathy, but both groups improved as much on symptoms of depression, anxiety, and stress. Noted should be that the dosage of ayahuasca was relatively low (14-21mg DMT, 2-4x lower than usual).


“Ayahuasca is a plant concoction containing N,N-dimethyltryptamine (DMT) and certain β-carboline alkaloids from South America. Previous research in naturalistic settings has suggested that ingestion of ayahuasca can improve mental health and well-being; however, these studies were not placebo-controlled and did not control for the possibility of expectation bias. This naturalistic observational study was designed to assess whether mental health changes were produced by ayahuasca or by set and setting. Assessments were made pre- and post-ayahuasca sessions in 30 experienced participants of ayahuasca retreats hosted in the Netherlands, Spain, and Germany. Participants consumed ayahuasca (N = 14) or placebo (N = 16). Analysis revealed a main effect of time on symptoms of depression, anxiety, and stress. Compared to baseline, symptoms reduced in both groups after the ceremony, independent of treatment. There was a main treatment × time interaction on implicit emotional empathy, indicating that ayahuasca increased emotional empathy to negative stimuli. The current findings suggest that improvements in mental health of participants of ayahuasca ceremonies can be driven by non-pharmacological factors that constitute a placebo response but also by pharmacological factors that are related to the use of ayahuasca. These findings stress the importance of placebo-controlled designs in psychedelic research and the need to further explore the contribution of non-pharmacological factors to the psychedelic experience.”

Authors: Malin V. Uthaug, Natasha L. Mason, Stefan W. Toennes, Johannes T. Reckweg, Elizabeth B. de Sousa Fernandes Perna, Kim P. C. Kuypers, Kim van Oorsouw, Jordi Riba & Johannes G. Ramaekers


A double-blind, placebo-controlled study (n=30) by Malin Uthaug and colleagues adds even more evidence to the power of set and setting. The expectation of participants, and the ceremonial environment of ayahuasca retreats (in Spain, The Netherlands, and Germany) led to lower scores on scales of depression, anxiety, and stress.

And you may have guessed it already, this reduction in scores was the same for the group that received ayahuasca or placebos. Both groups received pills, and those for the placebo group contained cacao and other substances to still taste the same when someone burbs. A clever study that once again shows the power of the environment when studying psychedelics.

What was found in this study?

  • Ayahausca, versus placebo, did have a significant effect on implicit arousal to negative stimuli, a measure that indicates increased empathy. Still, this effect was relatively small (not going higher than the baseline for the placebo group).
  • The placebo group came into this study with much higher depression and stress scores, and improved more than the ayahuasca group.
  • Of the participants, 57% and 69% guessed correctly that they were in the ayahuasca or placebo group (with 50% being chance). But, the dosage of ayahuasca was relatively low, coming in at 2 to 4 times lower than a (very) high dose.

Doing this type of analysis can provide information on what factors contribute to the beneficial effects of psychedelics. They don’t only show the power of psychedelics, but also highlight the need for a set and setting that is beneficial for participants.


A naturalistic observational study was conducted in 30 experienced participants of ayahuasca retreats in the Netherlands, Spain, and Germany. Results suggest that improvements in mental health can be driven by non-pharmacological factors that constitute a placebo response but also by pharmacological factors related to the use of ayahuasca.


Ayahuasca is a plant concoction used by shamans in the Amazon region for communication with spirits, magical experiences, rites of initiation, and healing rituals. It is also sought after by Westerners for various reasons such as “spiritual enlightenment,””self-actualization,””mystical experiences,””

Ayahuasca has been demonstrated to have an antidepressant effect in patients with treatment-resistant depression, but has not yet been developed into a regular medicine for the treatment of depression.

The use of ayahuasca in non-clinical settings has become increasingly popular, and research has indicated that it is associated with improvements in mental functioning in healthy individuals, as well as in people with mental health problems.

No study has controlled for the placebo effect, which is a strong possibility because many factors can influence the experience of taking ayahuasca, including the person taking the ayahuasca, the setting in which the ayahuasca ceremony takes place, and the set of those taking the ayahuasca.

In ayahuasca ceremonies, individual intentions and expectations of healing play a prominent role, and group dynamics are controlled and guided by facilitators or hosts who aim to maximize the setting in which the session takes place.

A naturalistic, placebo-controlled, observational study was set up to address the knowledge gap regarding psychological effects observed after participation in a non-clinical ayahuasca ceremony.


We visited 6 ayahuasca retreats, hosted by a single organization, all taking place in Europe. The ceremonies were all structured in the same way, and most participants were first-time visitors.

The “students” exposed themselves repeatedly to ayahuasca ceremonies of the host organization, and drank ayahuasca or placebo capsules as part of their training program. They were invited to participate in a study in which they were offered ayahuasca or a placebo substance.

Participants completed a 30-min test battery prior to and after the ayahuasca session, and were not compensated for their participation. The study was approved by the Ethics Review Committee Psychology and Neuroscience at Maastricht University, the Netherlands.

Dose administration

Study participants were randomly assigned to receive either ayahuasca or placebo from a facilitator at a retreat, and were blind to the actual treatments. They received 7 capsules with the option of taking 3 additional ones as a booster, after about 2 h of the first dose.

During one of the ceremonies, capsules were not available, so a drink mixture was administered instead, which included coffee, coco powder, and balsamic vinegar.


The alkaloid concentrations in the ayahuasca capsules were determined using high-performance liquid chromatography-electrospray ionization-time-of-flight mass spectrometry. The doses per individual subject are shown in Table 1.

Setting of the retreat

After registration, all ceremony participants were welcomed to the room where the session would start around midnight. The facilitators guided the session, and a member of the host organization distributed the capsules or drink to the study participants.

Test battery

A demographic section, the multifaceted empathy test, five questionnaires, the Ego Dissolution Inventory, the 5-Dimensional Altered States of Consciousness Rating Scale, the Depression, Anxiety, and Stress Scale 21, and the Brief Symptom Inventory 18 were used.

Multifaceted empathy test

The MET consists of 40 pictures of people in various emotional states. Participants were asked to select the emotion word that matched the depicted emotion, and to rate how concerned they felt for the person in the picture.

Ego Dissolution Inventory

The EDI is an 8-item self-report scale that assesses the participant’s experience of ego dissolution. The higher the total score, the stronger the experience of ego dissolution.

5-Dimensional Altered States of Consciousness Rating Scale

The 5D-ASC is a 94-item self-report scale that assesses 11 subscales, including experience of unity spiritual experience, blissful state, insightfulness, disembodiment, impaired control and cognition, anxiety, complex imagery, elementary imagery, audio-visual synesthesia, and changed meaning of perception.

Depression, Anxiety, and Stress Scale 21

The DASS-21 is a shorter version of the original self-report questionnaire Depression, Anxiety, and Stress Scale 42 with a Cronbach’s alpha of 0.93. It measures constructs of depression, anxiety, and stress ranging from 0 (normal) to 42 (extremely severe).

Brief Symptom Inventory 18

The BSI-18 is a self-report scale that contains subscales on somatization, depression, and anxiety. The scales have strong internal consistency.

Five Facets Mindfulness Questionnaire 15

The FFMQ-15 is a 15-item self-report questionnaire that measures five different factors: observe, describe, act with awareness, nonjudgment, and non-reaction. The results range from 8 to 40, except for the non-reaction facet, which ranges from 7 to 35.


The statistical analysis was conducted in IBM SPSS Statistics 24 using a mixed model ANOVA, with time and treatment as between group factors, and ayahuasca experience as covariate.

Study participants

There was no statistical difference in demographics between groups, and all participants reported previous experience with ayahuasca. Most participants used alcohol, smoked, and had a contemplative practice, and most participants had relatives suffering from a mental disorder.

Treatment guess

The frequency of correct vs incorrect guesses among facilitators and study participants was similar, but there was a significant correlation between their correct and incorrect guesses.

Subjective effects and MET

Mixed model ANOVA revealed significant main effects of time on ratings of stress, depression, and anxiety, and an interaction between treatment and time was observed for the measure of implicit arousal to negative stimuli. None of the FFMQ measures were affected by time or treatment.

The psychedelic experience

There were no group differences in ratings of ego dissolution, and mean ratings of 5D-ASC dimensions varied between 10 and 27% in the ayahuasca group and 6 and 23% in the placebo group.

The EDI and total 5D-ASC did not significantly differ between conditions or interact with ayahuasca use experience. However, the EDI and total 5D-ASC were higher in the ayahuasca group.

Correlational analysis

After removing a single outlier, the only correlations between depression, stress, anxiety, and emotional empathy were between the EDI and 5D-ASC ratings of anxious ego dissolution and auditory alterations.


Participants and facilitators were blind to the treatment randomization in the present study, and the frequency of correct and incorrect guesses did not significantly differ among participants and facilitators.

In this study, participants did not experience a significant psychedelic effect after consuming ayahuasca. This may be because the alkaloid doses were low, or because the participants were not exposed to high levels of DMT. Previous placebo-controlled studies have administered oral doses containing 0.36mg/kg DMT to depressed patients and freeze-dried oral doses containing 0.75mg/kg DMT and 1 mg/kg DMT to experienced users of ayahuasca. The psychedelic experience of the depressed patients was higher than the psychedelic experience of the experienced users.

The low ratings of the psychedelic experience may have been due to participants lowering their expectancies or to the presence of a group ceremony in which most attendants drank ayahuasca and expressed their emotions and experiences.

Subjective ratings of depression, stress, and anxiety were significantly less after the ceremony as compared to baseline, across both treatment groups. These positive changes did not differ between participants in the ayahuasca and placebo group, although depression symptoms were more prominent in the placebo group.

Additionally, it is known that expectancies are modeled through verbal suggestions and instructions. It has been demonstrated that repeated suggestion of the positive mental health effects of ayahuasca may have contributed to the positive changes in mental health parameters observed after the ceremony.

The setting of the ceremony, such as the physical, social, and cultural environment, may alter the mental experience of a pharmacological agent. Additionally, psychedelics like LSD may enhance suggestibility by temporarily suspending the drive to maintain control of one’s mind and environment. This study focused on the general impact of set and setting per se, and did not distinguish between a moderating effect of ayahuasca on set and setting experience.

The present findings do not mean that ayahuasca’s effect on mental health is always based on expectation. Ayahuasca has been shown to reduce symptoms of depression in treatment resistant patients and increase empathy toward negative emotions. The present finding is important because low-level empathy has been found in stress-related psychopathologies like depression, anxiety disorders, and post-traumatic stress disorder (PTSD). Treatments that increase empathy may be very relevant for patients that suffer from mood disorders and psychopathy.

The magnitude of the psychedelic experience was related to the magnitude of subjective mental health changes across the two treatment groups. This finding suggests that also a placebo response can elicit significant clinical benefits on mental health outcomes.

The present study has limitations. It is not clear whether expectancy effects contributed strongly to outcome measures in both groups, and whether pharmacological and non-pharmacological contributions to changes in mental health outcomes would have become more prominent at higher doses of ayahuasca.

The current findings demonstrate that non-pharmacological factors can contribute to the mental health effects of ayahuasca, as well as pharmacological factors related to the use of ayahuasca.

Study details

Topics studied
Anxiety Depression

Study characteristics
Placebo-Controlled Double-Blind Randomized


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