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Study 1 was conducted from November 2017 to May 2019 and had as the primary outcome the effects of ayahuasca on emotion face recognition, and as secondary outcomes subjective effects, safety, and personality measures [the results were recently published (12). Study 2 was conducted from September 2018 to March 2020 and had as the primary outcomes the effects of ayahuasca on emotion face recognition and empathy, and as secondary outcomes subjective effects, safety, and personality measures (manuscript in preparation).

In study 1, 49 participants were screened through the Structured Clinical Interview for Mental Disorders (SCID-5-CV, DSM-5) via telephone (13) with an experienced psychologist to verify eligibility for participation in the study. After the interview, 22 participants were included in the study, with 11 randomized to the placebo group and 11 in the ayahuasca group. One volunteer completed the experimental session but was excluded from further analysis in the ayahuasca group due to loss of baseline data for an emotion face recognition task (primary outcome in the original trial). Another volunteer was excluded in the placebo group due to hypoglycemia at the last blood collection point in the experimental session. Therefore, 20 volunteers were included in the final sample (10 per group). The mean age was 31.8 years (range 21–55), and the mean weight was 72.8 kg (range 53–101) [see details in (12)]. Of these 20 volunteers, personality data for day 21 was lost for five volunteers (errors and/or unanswered items). Therefore, 15 volunteers were included in the final personality analysis of study 1 (eight in the ayahuasca group and seven in the placebo group). In study 2, 35 participants were screened using the same procedures of study 1 (SCID-5-CV), and 17 were included in the trial. Nine volunteers were randomly included in the cannabidiol (CBD) plus ayahuasca group and eight in the placebo plus ayahuasca group. The mean age was 25.3 years (range 20–36), and the mean weight was 68.1 kg (range 49–110). All volunteers completed the experimental sessions. However, two volunteers were excluded in the placebo plus ayahuasca group due to home use of ayahuasca bought on the Internet 2 weeks after their experimental session. Thus, 15 volunteers were included in the final personality analysis (nine in the CBD plus ayahuasca group and six in the placebo plus ayahuasca group). The flowchart for study participants in both trials is shown in the Online Resource 1.

In both trials, volunteers were invited through contact with researchers or other study participants. Eligibility criteria in both trials included age between 18 and 65 years. However, studies differed regarding drug use. In study 1, eligibility criteria included the absence of prior use of ayahuasca and ≤ 2 uses in life of other hallucinogens (LSD, psilocybin, DMT, mescaline, other tryptamines and phenethylamines). In study 2, eligibility criteria included ≤ 2 lifetime uses of hallucinogens (including ayahuasca) and ≤ 20 lifetime uses of other recreational drugs. In both studies, exclusion criteria included a current or past history of cardiovascular, liver and/or neurological diseases, any psychiatric diagnosis (SCID-5), use of psychoactive medications (antidepressants, mood stabilizers, anxiolytics and antipsychotics), recurrent use (> twice a month) of drugs of abuse (cannabis and cocaine confirmed by urinalysis and other drugs as reported by volunteers), and pregnant or lactating women.

Groups were homogeneous in terms of sociodemographic characteristics (the sociodemographic characteristics of the volunteers are shown in the Online Resource 2). Regarding clinical characteristics, all volunteers included in both trials were considered healthy, that is, none had a history of mental disorders, chronic diseases, or other clinical conditions. In addition, none of the participants were using psychotropic medications. In study 1, none of the volunteers had a history of drug use (including ayahuasca and other hallucinogens). In study 2, volunteers had a mean lifetime use of cannabis of 7.3 uses (range 2–20), with the last use at least 1.5 months (mean 15.3 months) before the trial. Cocaine was used by only one volunteer, 4 years before the trial. Methylenedioxy methamphetamine (MDMA) was used by four volunteers a mean of 3.75 lifetime uses (range 1–6), with the last use at least 3 months (mean 7.25 months) before the trial. LSD was used once by one volunteer, 6 months before the trial. Ayahuasca was used by three volunteers, with a mean of 1.3 lifetime uses (range 1–2), with the last use at least 6 months before the trial (mean 20 months). Solvents were used by two volunteers with a mean of 7.5 lifetime uses (range 5–10), with the last use at least 5 months before the trial (range 5–48 months).

The trials were approved by the Research Ethics Committee of the Hospital das Clínicas, Faculty of Medicine of Ribeirão Preto, University of São Paulo (HC-FMRP-USP). All procedures were conducted in accordance with the Declaration of Helsinki and the ethical standards of the Ministry of Health (Resolution No. 466/12 of the National Health Council). Volunteers received detailed information on the nature of ayahuasca, the general psychological effects of hallucinogens/psychedelics and their possible adverse effects, as reported in the psychiatric literature. All volunteers gave their written informed consent to participate.

In study 1, the administered drugs were placebo and ayahuasca (both 1 mL/kg). In study 2, the treatments were 600 mg CBD (99% purity diluted in sunflower oil, administered in two 00 capsules containing 300 mg of CBD each; BioSynthesis Pharma Group Ltd, United Kingdom) plus ayahuasca, and placebo plus ayahuasca (ayahuasca dose of 1 ml/kg). The ayahuasca dose administered was chosen based on previous work by our group in which it caused psychotropic effects (14–16). The ayahuasca batches used during the study were donated by the Santo Daime church Rainha do Céu (“Queen of heaven”) (Ribeirão Preto, Brazil), which uses ayahuasca in their religious rituals. The religious use of ayahuasca is permitted in Brazil, as well as for scientific research. Ayahuasca was prepared via the prolonged decoction of the bark of the Banisteriopsis caapi vine (rich in the β-carbolines harmine, tetrahydroharmine/THH, and harmaline) together with the leaves of the Psychotria viridis bush (rich in DMT). The Brazilian legislation demands that ayahuasca must be made using only these two species, but the quantity of each plant used, and the time of decoction vary substantially from group to group. The ayahuasca batch in study 1 was prepared in October 2017, and the batch used in study 2 was prepared in July 2018. After preparation, ayahuasca was cooled and stored according to the religious institution guidelines (at room temperature protected from light) until the first experimental session (November 2017 in study 1 and September 2018 in study 2). Alkaloid stability was assessed in study 1 from November 2017 until the end of the trial 18 months later (May 2019), and from September 2018 until the end of the trial 16 months later (March 2020) in study 2, using ultra-performance liquid chromatography-electrospray tandem mass spectrometry (UPLC-ESI-MS/MS) [see [12] for detailed method description]. In study 1, the average concentration and variation of alkaloids was 1.58 (range: 0.45–3.04) mg/mL for DMT, 1.15 (range: 0.30–1.57) mg/ml for harmine, 0.73 (range: 0.59–0.81) mg/ml for THH, and 7.38 (range: 2.07–11.80) mg/ml for harmaline. In study 2, the average concentration and variation of alkaloids was 0.67 (range 0.45–1.00) mg/ml for DMT, 0.87 (range: 0.30–1.50) mg/ml for harmine, 0.52 (range: 0.35–0.80) mg/mL for THH, and 0.05 (range: 0.03–0.57) mg/ml for harmaline. Considering previous evidence of dose-dependent effects of ayahuasca [especially regarding DMT; (17)], these alkaloid differences seem to be relevant and, therefore, could influence the results.

In study 1, the placebo was a non-psychoactive substance intended to produce in the participant the sensation of drinking a nauseous and bitter medicine. Since all volunteers were naive to the use of ayahuasca in this study, they did not know the organoleptic properties of ayahuasca. Placebo was prepared with substances that are commonly used as food additives and in pharmaceutical formulations: mineral water (500 mL), glycerin 5% (E422), purchased from Galena (Campinas, SP, Brazil), propylene glycol 5% (E1520), purchased from Fagron (São Paulo, SP, Brazil), and methylparaben 0.1% (E218), purchased from Ely Martins (Cravinhos, SP, Brazil). For study 2, where the blinding procedure was done regarding CBD administration, the placebo was two 00 capsules identical to the ones that contained CBD plus sunflower oil, but with just the oil. Ayahuasca and placebo were administered in brownish/opaque glass bottles of 200 mL so that participants and researchers could not see the color of the liquid. Moreover, in the experimental session volunteers were instructed to ingest the full content of the bottle without smelling or visually examining its content. To avoid an accidental identification of the substance via smell by the authors in study 1, volunteers were instructed to open the bottle and drink the contents at least two meters away from researchers.

Both studies used a randomized, double-blind, placebo-controlled, parallel-group design. Simple randomization was performed in both trials by a researcher who did not participate directly in the experimental sessions and did not have access to the raw data of the study. We recommended abstention from alcohol, tobacco, and caffeinated drinks 24 h prior to the experimental sessions. Volunteers were instructed to fast before the session and to not ingest tyramine containing foods/drinks 24 h before and 12 h after the experimental session to avoid possible interactions with the β-carbolines in ayahuasca, which are reversible inhibitors of the monoamine oxidase enzyme type A (MAO-A). It was suggested for volunteers to wear comfortable clothes and to avoid using cell phones/social media during the experimental sessions. Reading was allowed (we offered some magazines with themes related to nature and science, but volunteers could bring their own reading). Music and movies were not allowed so that the environment during the effects of ayahuasca was kept as quiet and neutral as possible.

No specific psychotherapeutic intervention was used before, during, or after the experiments, as in our previous studies (14–16). Our protocol included general principles described in the psycholytic and psychedelic models of the 1960–1970s and in recent guidelines for safety in human hallucinogen research (18). These include (i) creation of trust with the volunteers before the experiment, (ii) use of a non-directive, supportive approach during drug sessions, and (iii) follow-up encounters from some days to several weeks after the session. There were no pre-dose visits, and the volunteers encountered the personnel directly involved in the trial (JMR, GNR, RGS) only in the day of the experimental session. Before the session, volunteers were informed about the general effects of ayahuasca and could express any doubts about the experimental session. During the sessions, simple instructions were given: “remain as quiet and introspective as possible, with your eyes opened or closed, while focusing on your body, thoughts, and emotions.” Volunteers remained seated in a comfortable reclining chair in a quiet dimly-lit room. Researchers stayed in a room next to the room where the volunteers were and assessed their well-being during the data collection points. Researchers only remained with volunteers in cases when it was requested by the volunteer or if researchers judged it necessary due to the intensity of psychoactive effects. At the end of the experimental session (4 h after ayahuasca intake), the general condition of the volunteers was evaluated, and if the volunteers were feeling well, they were discharged.

In the days to weeks after the experimental session, volunteers freely described their experiences, but no specific integration technique was used. In study 1, follow-ups occurred 1, 7, 14, and 21 days and 3 months after drug intake [see (12) for results not related to personality]. In study 2, follow-ups occurred 1, 7, and 21 days after drug intake (results not related to personality in preparation). In both trials, personality was assessed at day 21. Follow-up encounters were standardized for both studies.

Volunteers were offered R$ 20.00 (~$4.00) for going to the laboratory in the experimental and follow-up sessions.