![Response and remission rates as a function of time. Response (a) and remission (b) rates were high for both groups at D1 and D2. At D7, response rate was significantly higher for ayahuasca [OR 4.95 (95% CI 1.11-21.02); p = 0.04; NNT = 2.66], while remission rate showed a trend toward significance [OR 7.78 (95% CI 0.81-77.48); p = 0.054; NNT = 3.44].](https://www.researchgate.net/profile/Rafael-Dos-Santos-2/publication/325806001/figure/fig4/AS:638911382556673@1529339752420/Response-and-remission-rates-as-a-function-of-time-Response-a-and-remission-b-rates_Q320.jpg)
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Psychological Medicine
cambridge.org/psm
Original Article
Cite this article: Palhano-Fontes F et al (2018).
Rapid antidepressant effects of the
psychedelic ayahuasca in treatment-resistant
depression: a randomized placebo-controlled
trial. Psychological Medicine 1–9. https://
doi.org/10.1017/S0033291718001356
Received: 13 February 2018
Revised: 16 April 2018
Accepted: 24 April 2018
Key words:
Ayahuasca; depression; HRS; MEQ;
psychedelics; randomized controlled trial
(RCT)
Author for correspondence:
Dráulio B Araújo, E-mail: draulio@neuro.ufrn.br
© Cambridge University Press 2018. This is an
Open Access article, distributed under the
terms of the Creative Commons Attribution
licence (http://creativecommons.org/licenses/
by/4.0/), which permits unrestricted re-use,
distribution, and reproduction in any medium,
provided the original work is properly cited.
Rapid antidepressant effects of the psychedelic
ayahuasca in treatment-resistant depression:
a randomized placebo-controlled trial
Fernanda Palhano-Fontes1,2, Dayanna Barreto2,3, Heloisa Onias1,2,
Katia C. Andrade1,2, Morgana M. Novaes1,2, Jessica A. Pessoa1,2,
Sergio A. Mota-Rolim1,2, Flávia L. Osório4,5, Rafael Sanches4,5,
Rafael G. dos Santos4,5, Luís Fernando Tófoli6, Gabriela de Oliveira Silveira7,
Mauricio Yonamine7, Jordi Riba8, Francisco R. Santos9, Antonio A. Silva-Junior9,
João C. Alchieri10, Nicole L. Galvão-Coelho5,11, Bruno Lobão-Soares5,12,
Jaime E. C. Hallak4,5, Emerson Arcoverde2,3,5, João P. Maia-de-Oliveira2,3,5
and Dráulio B. Araújo1,2
1
Brain Institute, Federal University of Rio Grande do Norte (UFRN), Natal/RN, Brazil;
2
Onofre Lopes University
Hospital, UFRN, Natal/RN, Brazil;
3
Department of Clinical Medicine, UFRN, Natal/RN, Brazil;
4
Department of
Neurosciences and Behaviour, University of São Paulo (USP), Ribeirão Preto/SP, Brazil;
5
National Institute of
Science and Technology in Translational Medicine (INCT-TM), Ribeirão Preto/SP, Brazil;
6
Department of Medical
Psychology and Psychiatry, University of Campinas, Campinas/SP, Brazil;
7
Department of Clinical Analysis and
Toxicology, USP, São Paulo/SP, Brazil;
8
Sant Pau Institute of Biomedical Research, Barcelona, Spain;
9
Department
of Pharmacy, UFRN, Natal/RN, –Brazil;
10
Department of Psychology, UFRN, Natal/RN, Brazil;
11
Department of
Physiology, UFRN, Natal/RN, Brazil and
12
Department of Biophysics and Pharmacology, UFRN, Natal/RN, Brazil
Abstract
Background. Recent open-label trials show that psychedelics, such as ayahuasca, hold promise
as fast-onset antidepressants in treatment-resistant depression.
Methods. To test the antidepressant effects of ayahuasca, we conducted a parallel-arm, dou-
ble-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depres-
sion. Patients received a single dose of either ayahuasca or placebo. We assessed changes in
depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and
the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days
after dosing.
Results. We observed significant antidepressant effects of ayahuasca when compared with pla-
cebo at all-time points. MADRS scores were significantly lower in the ayahuasca group com-
pared with placebo at D1 and D2 ( p= 0.04), and at D7 ( p< 0.0001). Between-group effect
sizes increased from D1 to D7 (D1: Cohen’sd= 0.84; D2: Cohen’sd= 0.84; D7: Cohen’sd
= 1.49). Response rates were high for both groups at D1 and D2, and significantly higher
in the ayahuasca group at D7 (64% v. 27%; p= 0.04). Remission rate showed a trend toward
significance at D7 (36% v. 7%, p= 0.054).
Conclusions. To our knowledge, this is the first controlled trial to test a psychedelic substance
in treatment-resistant depression. Overall, this study brings new evidence supporting the
safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat
depression. This study is registered at http://clinicaltrials.gov (NCT02914769).
Introduction
The World Health Organization estimates that more than 300 million people suffer from
depression (World Health Organization, 2017), and about one-third do not respond to appro-
priate courses of at least three different antidepressants (Conway et al.,2017). Most currently
available antidepressants have a similar efficacy profile and mechanisms of action, based on
the modulation of brain monoamines, and usually, take about 2 weeks to start being effective
(Cai et al.,2015; Conway et al.,2017; Otte et al.,2016).
Recent evidence, however, shows a rapid and significant antidepressant effect of ketamine,
an N-methyl-D-aspartate (NMDA) antagonist frequently used in anesthesia. In recent rando-
mized placebo-controlled trials with ketamine in treatment-resistant depression, the anti-
depressant effects peaked 1 day after dosing and remained significant for about 7 days
(Berman et al.,2000; Zarate et al.,2006; Murrough et al.,2013; Lapidus et al.,2014).
Additionally, research with serotonergic psychedelics has gained momentum (Vollenweider
and Kometer, 2010). A few centers around the world are currently exploring how these
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substances affect the brain, and also probing their potential in
treating different psychiatric conditions, including mood disor-
ders (Grob et al.,2011; Osório et al.,2015; Carhart-Harris
et al.,2016; Griffiths et al.,2016; Ross et al.,2016; Sanches
et al.,2016). For instance, recent open-label trials show that psy-
chedelics, such as ayahuasca and psilocybin, hold promise as
fast-onset antidepressants in treatment-resistant patients (Osório
et al.,2015; Carhart-Harris et al.,2016; Sanches et al.,2016).
Ayahuasca is a brew traditionally used for healing and spiritual
purposes by indigenous populations of the Amazon Basin (Luna,
2011; Spruce and Wallace, 1908). In the 1930s, it began to be used
in religious settings of Brazilian small urban centers, reaching large
cities in the 1980s and expanding since then to several other parts
of the world (Labate and Jungaberle, 2011). In Brazil, ayahuasca
has a legal status for ritual use since 1987. Ayahuasca is most
often prepared by decoction of two plants (McKenna et al.,
1984): Psychotria viridis that contains the psychedelic N,
N-dimethyltryptamine (N,N-DMT), a serotonin and sigma-1 recep-
tors agonist (Carbonaro and Gatch, 2016), and Banisteriopsis caapi,
rich in reversible monoamine oxidase inhibitors (MAOi) such as
harmine, harmaline, and tetrahydroharmine (Riba et al.,2003).
The acute psychological effects of ayahuasca last around 4 h
and include intense perceptual, cognitive, emotional, and affective
changes (Shanon, 2002; Riba et al.,2003; Frecska et al.,2016).
Although nausea, vomiting, and diarrhea are often reported,
mounting evidence points to a positive safety profile of ayahuasca.
For instance, ayahuasca is not addictive and has not been
associated with psychopathological, personality, or cognitive
deterioration, and it promotes only moderate sympathomimetic
effects (Grob et al.,1996; Callaway et al.,1999; Dos Santos
et al.,2011; Bouso et al.,2012; Barbosa et al.,2016).
In a recent open-label trial, 17 patients with major depressive dis-
order attended a single dosing session with ayahuasca. Depression
severity was assessed before, during and after dosing, using the
Hamilton Depression Rating scale (HAM-D) and the
Montgomery–Åsberg Depression Rating Scale (MADRS) (Sanches
et al.,2016). Significant reduction in depression severity
was found already in the first hours after dosing, an effect that
remained significant for 21 days (Osório et al.,2015; Sanches
et al.,2016).
Although promising, these studies have not controlled for the
placebo effect, which can be remarkably high in clinical trials for
depression, reaching 30–40% of the patients (Sonawalla and
Rosenbaum, 2002). To address this issue, and to further test the
antidepressant effects of ayahuasca, we conducted a randomized
placebo-controlled trial in patients with treatment-resistant
depression. Additionally, we explored for correlations between
the antidepressant and the acute effects of ayahuasca.
Materials and methods
Study design and participants
This study is a double-blind parallel-arm randomized placebo-
controlled trial. Patients were recruited from psychiatrist referrals
at local outpatient psychiatric units or through media advertise-
ments. All procedures took place at the Onofre Lopes
University Hospital (HUOL), Natal-RN, Brazil. The University
Hospital Research Ethics Committee approved the study
(# 579.479), and all subjects provided written informed consent
before participation. This study is registered at http://clinical-
trials.gov (NCT02914769).
We recruited adults aged 18–60 years who met criteria for the
unipolar major depressive disorder as diagnosed by the Structured
Clinical Interview for Axis I (DSM-IV). Only treatment-resistant
patients were selected, defined herein as those with inadequate
responses to at least two antidepressant medications from differ-
ent classes (Conway et al.,2017). Selected patients were in a cur-
rent moderate-to-severe depressive episode at screening
(HAM-D⩾17). Patients were submitted to a full clinical evalu-
ation by a trained psychiatrist that included anamneses, mental
health evaluation, and screening for either personal or family his-
tory of mania or bipolar disorder. We adopted the following
exclusion criteria: previous experience with ayahuasca, current
medical disease based on history, pregnancy, current or previous
history of neurological disorders, personal or family history of
schizophrenia or bipolar affective disorder, personal or family his-
tory of mania or hypomania, use of substances of abuse, and sui-
cidal risk.
Randomization and masking
Patients were randomly assigned (1:1) to receive ayahuasca or pla-
cebo using permuted blocks of size 10. All investigators and
patients were blind to intervention assignment, which was kept
only in the database and with the pharmacy administrators.
Masking was further achieved by ensuring that all patients were
naïve to ayahuasca, and by randomly assigning, for each patient,
different psychiatrists for the dosing session and for the follow-up
assessments. Psychiatrists’blindness was not assessed.
Procedures
We used the MADRS and the HAM-D (Carneiro et al.,2015)to
access depression severity. MADRS assessments were at baseline
(one day before dosing), and at 1 (D1), 2 (D2), and 7 (D7)
days after dosing. HAM-D was applied only at baseline and D7,
as it was designed to access depression symptoms present in the
last week (Hamilton, 1960).
The liquid used as placebo was designed to simulate organo-
leptic properties (taste and color) of ayahuasca, such as a bitter
and sour taste, and a brownish color. It contained water, yeast, cit-
ric acid, zinc sulfate and caramel colorant. The presence of zinc
sulfate also produced low to modest gastrointestinal distress. A
single ayahuasca batch was used throughout the study, which
was prepared and provided free of charge by a branch of the
Barquinha church based at Ji-Paraná-RO, Brazil.
To assess alkaloids concentrations and stability of the batch,
samples of ayahuasca were quantified at two different time points
by mass spectroscopy analysis. On average, the ayahuasca used
contained (mean ± S.D.): 0.36 ± 0.01 mg/ml of N, N-DMT, 1.86
± 0.11 mg/ml of harmine, 0.24 ± 0.03 mg/ml of harmaline, and
1.20 ± 0.05 mg/ml of tetrahydroharmine (online Supplementary
Table S1).
After screening, patients underwent a washout period of 2
weeks on average and adjusted to the half-life time of the anti-
depressant medication in use. During dosing session, patients
were not under any antidepressant medication, and a new treat-
ment scheme was introduced only 7 days after dosing. If needed,
benzodiazepines were allowed as a supporting hypnotic and/or
2 Fernanda Palhano-Fontes et al.
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anxiolytic agents (online Supplementary Table S2 for demo-
graphic and clinical characteristics).
Dosing sessions lasted approximately 8 h, from 8:00 a.m. to
4:00 p.m., and intake usually occurred at 10:00 a.m. After a
light breakfast, patients were reminded about the effects they
could experience, and strategies to help alleviating eventual diffi-
culties. Patients were also told that they could receive ayahuasca
and feel nothing, or placebo and feel something. Sessions took
place in a quiet and comfortable living room-like environment,
with a bed, a recliner, controlled temperature, natural, and
dimmed light.
Patients received a single dose of 1 ml/kg of placebo or aya-
huasca adjusted to contain 0.36 mg/kg of N, N-DMT. They
were asked to remain quiet, with their eyes closed, while focusing
on their body, thoughts, and emotions. They were also allowed to
listen to a predefined music playlist. Patients received support
throughout the session from at least two investigators who
remained in a room next door, offering assistance when needed.
Acute effects were assessed with the Clinician-Administered
Dissociative States Scale (CADSS) (Bremner et al.,1998), the
Brief Psychiatric Rating Scale (BPRS) (Crippa et al.,2001), and
the Young Mania Rating Scale (YMRS) (Vilela et al.,2005),
applied at −10 min, +1:40 h, +2:40 h, and +4:00 h after intake.
When the acute psychedelic effects ceased, patients had a last
psychiatric evaluation, debriefed their experience, and responded
to the Hallucinogenic Rating Scale (HRS) (Strassman et al.,1994)
and Mystical Experience Questionnaire (MEQ30) (MacLean et al.,
2012). Around 4:00 p.m. they could go home accompanied by a
relative or friend. Only four patients presenting a more delicate
condition remained as inpatients in the hospital ward for an
entire week. Patients were asked to return for follow-up assess-
ments at 1, 2, and 7 days after dosing.
Outcomes
The primary outcome measure was the change in depression
severity assessed by the HAM-D scale, comparing baseline with
seven days (D7) after dosing. The secondary outcome was the
change in MADRS scores from baseline to 1 (D1), 2 (D2), and
7 (D7) days after dosing. We examined the proportion of patients
meeting response criteria, defined as a reduction of 50% or more
in baseline scores. Remission rates were also examined and were
defined as HAM-D⩽7 or MADRS⩽10. We assessed response
and remission rates using HAM-D (at D7) and MADRS (at D1,
D2, and D7) scores. Safety and tolerability were assessed with
the CADSS, the BPRS, and the YMRS applied during dosing ses-
sion. We used the HRS and the MEQ30 to assess specific aspects
of the psychedelic effects.
Statistical analysis
Analyses adhered to a modified intent-to-treat principle, includ-
ing all patients who completed assessments at baseline, dosing
and D7. An estimated sample size of 42 patients was estimated
in G*Power software to provide 80% power to detect a five-point
HAM-D difference (standardized effect size = 0.9) between
baseline and D7 with two-sided 5% significance. The initial esti-
mation was based on our previous open-label trial with ayahuasca
in treatment-resistant depression (Sanches et al.,2016). A
fixed-effects linear mixed model, with baseline scores as covariate,
examined changes in HAM-D at D7, and MADRS at D1, D2, and
D7. A Toeplitz covariance structure was the best fit to the data
according to Akaike’s information criterion. Missing data were
estimated using restricted maximum-likelihood estimation.
Main effects and treatment v. time interaction were evaluated.
Post-hoc t tests were performed for between-groups comparisons
at all time points, and Sidak’s test was used to control for multiple
comparisons. Cohen’sdeffect sizes were obtained for between
and within group comparisons. Between-group effect sizes were
calculated using the estimated means of each group at each
time point. For within-group comparisons, effect sizes of each
treatment were calculated separately, using the differences
between a time point and baseline values. Differences in the
proportion of responders/non-responders and remitters/non-
remitters were estimated using Fisher’s exact test. Odds ratio
(OR) and number needed to treat (NNT) were also calculated.
Data from patients whose HAM-D or MADRS scores were
reduced by 50% or more between washout onset and baseline,
or that were in remission at dosing, were not considered for stat-
istical analysis. Fisher’s exact test was used to assess differences in
the proportion of adverse events between the two treatments. We
used the Mann–Whitney test to evaluate between-group differ-
ences in BPRS+, CADSS, HRS, and MEQ30. We calculated
Pearson correlations between changes in MADRS scores from
baseline to D7, and the acute effects during dosing assessed by
BPRS, CADSS, MEQ30, and HRS. Multiple comparisons correc-
tion was based on the number of factors of each scale (N=6,
for the HRS; N= 5, for the MEQ30). Significance was set at p<
0.05, two-tailed. We used IBM SPSS Statistic 20 and Prism 7 to
run the analyses.
Results
From January 2014 to June 2016, we assessed 218 patients for eligi-
bility, and 35 met criteria for the trial. Six subjects had to be
excluded: five no longer met criteria for depression in the dayof dos-
ing, and one dropped out before dosing. Data from 29 patients were
included in the analysis: 14 in the ayahuasca group and 15 in the pla-
cebo group. Figure 1 shows the trial profile.
On average, patients met criteria for moderate-to-severe
depression (mean ± S.D.): HAM-D = 21.83 ± 5.35; MADRS =
Fig. 1. Trial profile.
Psychological Medicine 3
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33.03 ± 6.49. They had been experiencing depressive symptoms
for 11.03 ± 9.70 years and had tried 3.86 ± 1.66 different previous
unsuccessful antidepressants. Two patients had a previous history
of electroconvulsive therapy. Most patients (76%) had a comorbid
personality disorder, and 31% had a comorbid anxiety disorder.
All patients were under regular use of benzodiazepines during
the trial (online Supplementary Table S2 for clinical and
demographics).
Demographic and clinical characteristics are summarized in
Table 1 (online Supplementary Table S2). All patients were
Brazilian, most female (72%), adults (42.03 ± 11.66 yo) from
low socioeconomic status backgrounds: low educated (41% with
<8 years of formal education) and living in low household income
(41% earn <2 minimum wages).
Figure 2 shows changes in HAM-D scores from baseline to 7
days after dosing. We observed a significant between-groups dif-
ference at D7 (F
1
= 6.31; p= 0.019), and patients treated with aya-
huasca showed significantly reduced severity when compared
with patients treated with placebo (online Supplementary
Fig. S1 for individual HAM-D scores). Between-group effect
size was large at D7 (Cohen’sd= 0.98; 95% CI 0.21–1.75).
Within-group effect size (online Supplementary Table S3) was
large for the ayahuasca group (Cohen’sd= 2.22; 95% CI 1.28–
3.17), and medium for the placebo group (Cohen’sd= 0.46;
95% CI −0.27 to 1.18).
Figure 3 shows mean MADRS scores as a function of time.
Linear mixed model showed a significant effect for time (F
2,34.4
=
3.96; p= 0.028), treatment (F
1,27.7
= 10.52; p= 0.003), but no
treatment v. time interaction (F
2,34.4
= 1.77; p= 0.185). We observed
significant decreased depression severity already 1 day after dosing
with ayahuasca compared with placebo (F
1,49.7
= 4.58; p= 0.04).
Depression severity persisted lower in the ayahuasca group at
both D2 (F
1,50.3
= 4.67; p= 0.04) and D7 (F
1,47
= 14.81; p< 0.0001).
Between-groups effect size was large at D1 (Cohen’sd= 0.84;
95% CI 0.05–1.62) and D2 (Cohen’sd= 0.84; 95% CI 0.05–
1.63) and largest at D7 (Cohen’sd= 1.49; 95% CI 0.67–2.32).
Within-group effect sizes (online Supplementary Table S4) were
large for the ayahuasca at all time points: Cohen’sd= 2.78 at
D1 (95% CI 1.74–3.82), d= 3.05 at D2 (95% CI 1.94–4.16), and
d= 2.90 at D7 (95% CI 1.84–3.97).
HAM-D response rate was significantly different between-
groups at D7, with 57% of responders in the ayahuasca group
against 20% in the placebo group [OR 5.33 (95% CI 1.11–22.58);
p= 0.04; NNT = 2.69]. HAM-D remission rate showed a trend
toward significance at D7: 43% in ayahuasca v. 13% in placebo
[OR 4.87 (95% CI 0.77–26.73); p= 0.07; NNT = 3.39].
Figure 4ashows MADRS response rates as a function of time.
At D1, response rates were high for both groups: 50% in the aya-
huasca group, and 46% in the placebo group [OR 1.17 (95% CI
0.26–5.48); p= 0.87; NNT = 26]. At D2, they remained high in
both groups: 77% in the ayahuasca group and 64% in the placebo
[OR 1.85 (95% CI 0.29–8.40); p= 0.43; NNT = 7.91]. Response
rate was statistically different at D7: 64% of responders in the
ayahuasca group, and 27% in the placebo [OR 4.95 (95% CI
1.11–21.02); p= 0.04; NNT = 2.66]. Figure 4bshows the
MADRS remission rates as a function of time. At D1, the remis-
sion rate was of 42% in the ayahuasca group and 46% in the
placebo group ( p= 0.86), at D2, 31% in the ayahuasca group
and 50% in the placebo group ( p= 0.31). At D7 MADRS remis-
sion rate showed a trend toward significance: 36% of remitters in
the ayahuasca group and 7% in the placebo [OR 7.78 (95% CI
0.81–77.48); p= 0.054; NNT = 3.44].
Online Supplementary Figs. S1 and S2 show individual
MADRS scores %-changes from baseline, at all time points.
Although individual variance was high, we found improvement
in depression severity for all patients in the ayahuasca group 7
days after dosing, while four patients in the placebo group have
worsened their symptoms.
Table 1. Sociodemographic & clinical characteristics
Ayahuasca Placebo
Participants, n14 15
Age (years) 39.71 ± 11.26 44.2 ± 11.98
Gender (M/F) 3/11 5/10
Unemployed (%) 7/14 (50) 8/15 (53)
Household income
<2 minimum wages (%) 6/14 (43) 6/15 (40)
2–5 wages (%) 4/14 (28) 7/15 (47)
6–10 wages (%) 1/14 (7) 1/15 (6.6)
11 or more wages (%) 3/14 (21) 1/15 (6.6)
Education
Up to 8 years, n(%) 6/14 (43) 6/15 (40)
9–11 years, n(%) 3/14 (21) 5/15 (33)
12–16 years, n(%) 2/14 (14) 2/15 (13)
17 or more years, n(%) 3/14 (21) 2/15 (13)
Religion (%)
Catholic 7/14 (50) 5/15 (33)
Protestant 4/14 (28) 1/15 (6.6)
Other 0/14 (0) 4/15 (27)
No religion 3/14 (21) 5/15 (33)
Ethnicity (%)
Caucasian 9/14 (64) 8/15 (54)
Black 1/14 (7) 0/15 (0)
Pardo 4/14 (28) 7/15 (47)
Clinical characteristics
Age of depression onset ( years) 30.93 ± 10.19 30.87 ± 13.39
Illness duration ( years) 8.78 ± 6.25 13.13 ± 11.92
Number of previous episodes 2.71 ± 1.32 3.53 ± 1.76
Length of current episode (months) 14.71 ± 18.92 10.13 ± 9.15
Failed antidepressant medications 3.93 ± 1.44 3.8 ± 1.89
History of ECT (%) 1/14 (7) 1/15 (6.6)
History of psychotherapy (%) 11/14 (79) 12/15 (80)
Anxiety disorder (%) 5/14 (36) 5/15 (33)
Personality disorder (%) 10/14 (71) 12/15 (80)
Melancholic (%) 12/14 (83) 12/15 (80)
Atypical (%) 2/14 (14) 3/15 (20)
Baseline HAM-D 24.07 ± 5.34 19.73 ± 4.59
Baseline MADRS 36.14 ± 6.12 30.13 ± 5.55
M, male; F, female; ECT, electroconvulsive therapy.
Values are (mean ± S.D.).
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Patients exhibited transient acute changes in CADSS and BPRS+
scales, with slightly increased scores at +1:40 h after ayahuasca intake:
34.8% (BPRS+) and 21.6% (CADSS) (online Supplementary
Table S5). There was a trend increased toward significance observed
in CADSS scores at 1:40 h after ayahuasca intake ( p= 0.052). There
were no significant changes in BPRS+ scores at any time point
(online Supplementary Table S5). Changes in BPRS+ and CADSS
scores did not correlate with improvements in depression symptoms
(online Supplementary Fig. S3). We did not observe significant
increased manic symptoms as measured by the YMRS at 1:40 h
after ayahuasca intake ( p= 0.26). We also observed transient nausea
(Aya = 71%, Pla = 26%; p= 0.027), vomiting (Aya = 57%, Pla = 0%;
p= 0.0007),transient anxiety(Aya = 50%,Pla = 73%; p=0.263),rest-
lessness (Aya = 50%, Pla = 20%; p= 0.128), and transient headache
(Aya = 42%, Pla = 53%; p= 0.715) (online Supplementary Table S6).
The average and standard error of mean (S.E.M.) for each factor
of both scales (HRS and MEQ30) are presented in online
Supplementary Table S7, and in online Supplementary Figs. S4
and S5. Two patients did not respond to the HRS, leaving 27
respondents: 13 in the ayahuasca group, 14 in the placebo. The
MEQ30 was added to the study with the trial already ongoing,
and only 15 patients responded to it: eight in the ayahuasca
group, seven in the placebo.
Figure 5ashows the HRS average score for all six subscales. We
found significant differences between groups in five of them. The
ayahuasca group scored higher than the placebo group in percep-
tion ( p< 0.0001), somaesthesia ( p< 0.0001), cognition ( p<
0.0001), intensity ( p< 0.0001), and volition ( p= 0.0003). Only
affect was not significantly different between groups (p= 0.38).
Figure 5bshows scores for all factors of the MEQ30. We found
significant between-groups differences in mystical ( p= 0.049),
transcendence of time and space ( p= 0.0008), ineffability ( p=
0.003), and in total MEQ score ( p= 0.004). For all of these, the
ayahuasca group scored higher than the placebo group. The
only positive mood was not significantly different between groups
(p= 0.32).
Correlations between HRS and MADRS changes from baseline
to D7 were not statistically significant when assessing each group
separately, ayahuasca, or placebo (online Supplementary Fig. S6).
However, we observed a positive significant correlation between
MADRS changes at D7 with the HRS subscale ‘perception’(r=
0.90, p= 0.002), when considering the subgroup of ayahuasca
responders only (online Supplementary Fig. S7).
Despite the small number of patients, we found a negative
correlation between changes in MADRS scores and the MEQ30
factor transcendence of time and space in patients in the aya-
huasca group (r=−0.84, p= 0.009). The remaining three factors
(ineffability, mystical, and positive mood) and MEQ30 total
score were not significantly correlated with MADRS score
changes (online Supplementary Fig. S8).
Fig. 2. HAM-D scores at baseline and seven days after dosing. Statistical analysis
shows a significant difference between ayahuasca (squares) and placebo (circles)
seven days after dosing ( p= 0.019). Between-group effect size is high (Cohen’sd=
0.98). Values are (mean ± S.E.M.). HAM-D scores: mild depression (8–16), moderate
(17–23), severe (⩾24).
Fig. 3. MADRS scores as a function of time. Significant differences are observed
between ayahuasca (squares) and placebo (circles) at D1 ( p= 0.04), D2 ( p= 0.04)
and D7 ( p< 0.0001 ). Between groups effect sizes are high at all time points after dos-
ing: D1 (Cohen’sd= 0.84), D2 (Cohen’sd= 0.84), and D7 (Cohen’sd= 1.49). Values are
(mean ± S.E.M.). MADRS scores: mild depression (11–19), moderate (20–34), severe
(⩾35). *p< 0.05; ***p< 0.0001.
Fig. 4. Response and remission rates as a function of time. Response (a) and remission (b) rates were high for both groups at D1 and D2. At D7, response rate was
significantly higher for ayahuasca [OR 4.95 (95% CI 1.11–21.02); p= 0.04; NNT = 2.66], while remission rate showed a trend toward significance [OR 7.78 (95% CI
0.81–77.48); p= 0.054; NNT = 3.44 ].
Psychological Medicine 5
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Discussion
We found evidence of rapid antidepressant effect after a single
dosing session with ayahuasca when compared with placebo.
Depression severity changed significantly but differently for the
ayahuasca and placebo groups. Improvements in the psychiatric
scales in the ayahuasca group were significantly higher than
those of the placebo group at all time points after dosing, with
increasing between-group effect sizes from D1 to D7. Response
rates were high for both groups at D1 and D2 and were signifi-
cantly higher in the ayahuasca group at D7. Between-groups
remission rate showed a trend toward significance at D7.
The within-group effect size found for ayahuasca at D7
(Cohen’sd= 2.22) is compatible with our earlier open-label
study (Cohen’sdat D7 = 1.83) (Sanches et al.,2016), and compat-
ible with the one found in a recent open-label trial with psilocybin
for depression (Hedges’g= 3.1) (Carhart-Harris et al.,2016). Our
results are comparable with randomized controlled trials that used
ketamine in treatment-resistant depression. Although both keta-
mine and ayahuasca are associated with rapid antidepressant
effects, their response time-courses and mechanisms of action
seem to differ. Previous studies with ketamine have found the lar-
gest between-group effect size at D1 (Cohen’sd= 0.89), reducing
toward D7 (Cohen’sd= 0.41) (Berman et al.,2000; Zarate et al.,
2006; Murrough et al.,2013; Lapidus et al.,2014). In contrast,
the effect sizes observed herein were large, but smallest, at D1
(Cohen’sd= 0.84), and largest at D7 (Cohen’sd= 1.49). These
differences are also reflected in the response rates. At D1, the
response rate to ketamine lies between 37 and 70%, whereas in
our study 50% of the patients responded to ayahuasca. At D7,
the ketamine response rate ranges between 7 and 35% (Berman
et al.,2000; Zarate et al.,2006; Murrough et al.,2013; Lapidus
et al.,2014), while in our study 64% responded to ayahuasca.
The placebo effect was high in our study, and higher than most
studies with. While we find a response rate to placebo of 46% at
D1, and 26% at D7, ketamine trials have found a placebo effect of
the order of 0–6% at D1, and 0–11% at D7 (Berman et al.,2000;
Zarate et al.,2006; Murrough et al.,2013; Lapidus et al.,2014).
Several factors may account for the high placebo effect observed
herein. First, the higher placebo effect has been found in patients
with low socioeconomic status (Sonawalla and Rosenbaum, 2002),
which was the case of our study. Most patients were living under
significant psychosocial stressors, and during our trial, they stayed
at a ‘very comfortable and very supportive environment’,as
reported by the patients themselves. Therefore, part of the
increased placebo effects found in our study might be due to
this ‘care effect’. Second, patients with comorbid personality dis-
orders present higher placebo responses (Ripoll, 2013), and in our
study, most patients (76%) also suffered from personality disor-
ders, most of them in cluster B.
A growing body of evidence gives support to the observed
rapid antidepressant effects of ayahuasca (Palhano-Fontes et al.,
2014). For instance, sigma-1 receptors (σ1R) have been implicated
in depression, and it was reported to be activated by N, N-DMT
(Cai et al.,2015; Carbonaro and Gatch, 2016). Moreover, it has
been shown that the administration of σ1R agonists results in
antidepressant-like effects, which are blocked by σ1R antagonism
(Cai et al.,2015). Furthermore, σ1R upregulates neurotrophic fac-
tors such as brain-derived neurotrophic factor (BDNF) and nerve
growth factor (NGF), proteins whose regulation and expression
seem to be involved in the pathophysiology of depression (Cai
et al.,2015). Nevertheless, it is worth mentioning that antidepres-
sants with σ1R agonist profile do not present clinically significant
antidepressant effect. For instance, the antidepressant fluvox-
amine, which has a high affinity for σ1R do not present response
rates compatible to that was found herein (Delgado et al.,1988;
Hashimoto, 2009).
The effects observed might be in part due to the presence of
MAOi in the brew. In fact, studies in animal models reported
that chronic administration of harmine reduces immobility
time, increases climbing and swimming time, reverses anhedonia,
increases adrenal gland weight, and increases BDNF levels in the
hippocampus (Fortunato et al.,2010a,2010b). All of these are
compatible with antidepressant effects. Likewise, harmine seems
to stimulate neurogenesis of human neural progenitor cells,
derived from pluripotent stem cells (Dakic et al.,2016), and pro-
genitor cells from adult mice brains (Morales-García et al.,2017),
a mechanism also observed in rodents following antidepressant
treatment. In addition, a recent study in rodents found that a
Fig. 5. HRS subscales and MEQ30 factors during the dosing session. (a) Significantly higher scores in the ayahuasca group in five HRS subscales: perception ( p<
0.0001), somaesthesia ( p< 0.0001), cognition ( p< 0.0001), intensity ( p< 0.0001), and volition ( p= 0.0003). Only affect was not significantly different between groups
(p= 0.38). ( b) Significantly higher MEQ30 scores in the ayahuasca group in the total MEQ30 score (p= 0.004), and three of its factors: mystical ( p= 0.049), tran-
scendence of time and space ( p= 0.00 08), and ineffability ( p= 0.003), except for the positive mood ( p= 0.32). Values are expressed as a percentage of maximum
possible score.
6 Fernanda Palhano-Fontes et al.
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single ayahuasca dose increases swimming time in a forced-swim
test (Pic-Taylor et al.,2015).
Brain circuits modulated by psychedelics show great overlap
with those involved in mood disorders (Vollenweider and
Kometer, 2010). We recently found that a single ayahuasca session
in patients with depression increases blood flow in brain regions
consistently implicated in the regulation of mood and emotions,
such as the left nucleus accumbens, right insula and left subgenual
area (Otte et al.,2016; Sanches et al.,2016). Moreover, we have
shown that ayahuasca reduces the activity of the Default Mode
Network (Palhano-Fontes et al.,2015), a brain network found to
be hyperactive in depression (Sheline et al.,2009).
Over the last two decades, mental health evaluations of regular
ayahuasca consumers have shown preserved cognitive function,
increased well-being, reduction of anxiety, and depressive symp-
toms when compared to non-ayahuasca consumers (Grob et al.,
1996; Bouso et al.,2012; Barbosa et al.,2016). Moreover, a recent
study observed that a single dose of ayahuasca enhanced
mindfulness-related capacities (Soler et al.,2016), and meditation
practices have been associated with antidepressant effects (Segal
et al.,2010).
Prior studies suggest that elements of the psychedelic experi-
ence, such as experiences of mystical-type, account for the thera-
peutic benefit (Bogenschutz et al.,2015; Garcia-Romeu et al.,
2015; Majićet al.,2015; Griffiths et al.,2016; Ross et al.,2016).
We found significant increased MEQ30 scores during the effects
of ayahuasca. We also observed an inverse correlation between
MADRS score changes at D7 with ‘transcendence of time and
space’MEQ30 factor.
Furthermore, HRS dimensions seem important to the clinical
outcome, particularly ‘perception’, a subscale that comprehends
changes in visual, auditory, and body sensations. Visions are com-
mon during the effects of ayahuasca, and are most frequent with
the eyes closed (Shanon, 2002; De Araujo et al.,2012). It has been
suggested that visions may play an important role in the thera-
peutic effect of ayahuasca, as they may help bringing clarity to
introspective events (Frecska et al.,2016). It is interesting to
observe that changes in perception taken alone are not sufficient
to predict the positive clinical outcome, as for instance, we find
that some patients presented increased scores in ‘perception’with-
out significant clinical response.
No serious adverse events were observed during or after dos-
ing. Although 100% of the patients reported feeling safe, the aya-
huasca session was not necessarily a pleasant experience. In fact,
some patients reported the opposite, as the experience was accom-
panied by much psychological distress. Most patients reported
nausea, and about 57% have vomited, although vomiting is trad-
itionally not considered a side effect of ayahuasca, but rather part
of a purging process (Tafur, 2017).
Although promising, this study has some caveats and limita-
tions worth mentioning. The number of participants is modest,
and therefore randomized trials in larger populations are neces-
sary. The study was limited to patients with treatment-resistant
depression, with a long course of illness, and high comorbid per-
sonality disorder, which altogether precludes a simple extension
of these results to other classes of depression. Another challenge
of the research with psychedelics is maintaining double blindness,
as the effects of psychedelics are unique. We were particularly
keen to ensure blindness throughout the entire experiment, and
to that end, we adopted a series of additional measures to preserve
blindness. All patients were naïve to ayahuasca, with no previous
experience with any other psychedelic substance. Clinical
evaluations involved a team of five psychiatrists. For every patient,
one psychiatrist was responsible for clinical evaluation during the
dosing session and a different one for the follow-up assessments.
The substance used as placebo increased anxiety and induced
nausea. In fact, five patients misclassified placebo as ayahuasca,
and two of them showed a response at D7 (online
Supplementary Table S2). Therefore, we believe blindness was
adequately preserved in our study.
Since the prohibition of psychedelics in the late 1960s, research
with these substances has almost come to a halt. Before research
restrictions, psychedelics were at early stage testing for many psy-
chiatric conditions, including obsessive-compulsive disorder and
alcohol dependence. By mid-1960s, over 40.000 subjects had par-
ticipated in clinical research with psychedelics, most of them in
uncontrolled settings (Vollenweider and Kometer, 2010). To our
knowledge, this is the first randomized placebo-controlled trial
to investigate the antidepressant potential of a psychedelic in a
population of patients with treatment-resistant depression.
Overall, this study brings new evidence supporting the safety
and therapeutic value of psychedelics, dosed within an appropri-
ate setting, to help treat depression.
Supplementary material. The supplementary material for this article can
be found at https://doi.org/10.1017/S0033291718001356
Acknowledgements. The authors would like to express their gratitude to all
patients who volunteered for this experiment. To the Brain Institute and to the
Hospital Universitário Onofre Lopes (HUOL), both from the Federal
University of Rio Grande do Norte (UFRN) for always giving the necessary
institutional support. To the laboratory of Pharmacognosy for helping with
placebo preparation. To Edilsom Fernandes, for carefully preparing the
Ayahuasca batch used in our study, and for the fruitful discussion, particularly
about the dosing session. To Sidarta Ribeiro, for the enthusiastic support
throughout the study. To Dr Ricardo Lagreca, for the unconditional support.
To Beatriz Labate, for the fruitful discussions. To Altay Souza and João Sato
for assistance with statistical analysis. To Deborah Maia, Ranna Brito,
Tayrine Lopes, Lízie Brasileiro, Artur Morais, Isaac Campos, Brígida
Albuquerque, Marianna Lucena, Fernanda Araújo, Raíssa Nóbrega, Marina
Leonardo, Kaique Andrade, Rodolfo Lira, Giuliana Travassos, for helping
with data acquisition. To Prof. Octávio Pontes-Neto and Adriano Tort for crit-
ical review of the manuscript. To the Brazilian federal funding agencies CNPq
(grants #466760/2014 & #479466/2013) and CAPES (grants #1677/2012 &
#1577/2013) for providing financial support.
Author contributions. FPF, KCA, NGC, BLS, JR, JCA, LFT, SAMR, FO, RS,
JAC, JH, EA, JPMO, and DBA contributed to study design and conception.
FRRS and AASJ conceived and developed the substance used as placebo.
GOS and MY conducted the analysis to determine alkaloid concentrations.
JA coordinated the psychology team. NGC coordinated the biochemistry
team. DB, EA, and JPMO recruited the patients. FPF, HO, KCA, MN, JP,
BA, and DBA coordinated data acquisition. DBA coordinated the trial. FPF,
HO, KCA, MN, JP, JPMO, and DBA analyzed data and interpreted the results.
FPF, HO, KCA, MN, JP, and DBA were responsible for the first draft of the
manuscript. All authors read, critically revised, and approved the manuscript.
Financial support. This study was funded by the Brazilian National Council
for Scientific and Technological Development (CNPq, grants #466760/2014 &
#479466/2013), and by the CAPES Foundation within the Ministry of
Education (grants #1677/2012 & #1577/2013). The authors declare no compet-
ing financial interests.
Conflict of interest. None.
Ethical standards. The authors assert that all procedures contributing to
this work comply with the ethical standards of the relevant national and insti-
tutional committees on human experimentation and with the Helsinki
Declaration of 1975, as revised in 2008.
Psychological Medicine 7
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