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Suicide is a major public health problem. Given increasing suicide rates and limitations surrounding current interventions, there is an urgent need for innovative interventions for suicidality. Although ayahuasca has been shown to target mental health concerns associated with suicidality (i.e., depression and hopelessness), research has not yet explored the impact of ayahuasca on suicidality. Therefore, we conducted secondary analyses of a randomized placebo-controlled trial in which individuals with treatment-resistant depression were administered one dose of ayahuasca (n=14) or placebo (n=15). Suicidality was assessed by a trained psychiatrist at baseline, as well as 1 day, 2 days, and 7 days after the intervention. A fixed-effects linear mixed model, as well as between and within-groups Cohen’s d effect sizes were used to examine changes in suicidality. Controlling for baseline suicidality, we found a significant effect for time (p <.05). The effect of the intervention (i.e., ayahuasca vs. placebo) trended toward significance (p = .088). At all time points, we found medium between-group effect sizes (i.e., ayahuasca vs. placebo; day 1 Cohen’s d = 0.58; day 2 d = 0.56; day 7 d = 0.67), as well as large within-group (ayahuasca; day 1 Cohen’s d = 1.33; day 2 d = 1.42; day 7 d = 1.19) effect sizes, for decreases in suicidality. Conclusions: This research is the first to explore the impact of ayahuasca on suicidality. The findings suggest that ayahuasca may show potential as an intervention for suicidality. We highlight important limitations of the study, potential mechanisms, and future directions for research on ayahuasca as an intervention for suicidality.
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Edited by:
Liana Fattore,
Italian National Research Council
(CNR), Italy
Reviewed by:
Manish Kumar Jha,
UT Southwestern Medical Center,
United States
Jan Ramaekers,
Maastricht University, Netherlands
Draulio B. Araujo
Specialty section:
This article was submitted to
a section of the journal
Frontiers in Pharmacology
Received: 24 July 2019
Accepted: 15 October 2019
Published: 19 November 2019
ZeifmanRJ, Palhano-FontesF,
HallakJ, ArcoverdeE,
Maia-OliveiraJPand AraujoDB
(2019) The Impact of Ayahuasca
on Suicidality: Results From a
Randomized Controlled Trial.
Front. Pharmacol. 10:1325.
doi: 10.3389/fphar.2019.01325
The Impact of Ayahuasca on
Suicidality: Results From a
Randomized Controlled Trial
Richard J. Zeifman 1, Fernanda Palhano-Fontes 2,3, Jaime Hallak 4, EmersonArcoverde 3,
João Paulo Maia-Oliveira 3 and Draulio B. Araujo 2,3*
1 Centre for Psychedelic Research, Department of Brain Sciences, Faculty of Medicine, Imperial College London, London,
United Kingdom, 2 Brain Institute, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil, 3 Onofre Lopes
University Hospital, UFRN, Natal, Brazil, 4 Department of Neurosciences and Behaviour, University of São Paulo (USP),
Ribeirão Preto, Brazil
Suicide is a major public health problem. Given increasing suicide rates and limitations
surrounding current interventions, there is an urgent need for innovative interventions
for suicidality. Although ayahuasca has been shown to target mental health concerns
associated with suicidality (i.e., depression and hopelessness), research has not yet explored
the impact of ayahuasca on suicidality. Therefore, we conducted secondary analyses of a
randomized placebo-controlled trial in which individuals with treatment-resistant depression
were administered one dose of ayahuasca (n = 14) or placebo (n = 15). Suicidality was
assessed by a trained psychiatrist at baseline, as well as 1 day, 2 days, and 7 days after
the intervention. A fixed-effects linear mixed model, as well as between and within-groups
Cohen's d effect sizes were used to examine changes in suicidality. Controlling for baseline
suicidality, we found a significant effect for time (p < .05). The effect of the intervention
(i.e., ayahuasca vs. placebo) trended toward significance (p = .088). At all time points, we
found medium between-group effect sizes (i.e., ayahuasca vs. placebo; day 1 Cohen's
d= 0.58; day 2 d = 0.56; day 7 d = 0.67), as well as large within-group (ayahuasca; day 1
Cohen's d= 1.33; day 2 d = 1.42; day 7 d = 1.19) effect sizes, for decreases in suicidality.
Conclusions: This research is the first to explore the impact of ayahuasca on suicidality. The
findings suggest that ayahuasca may show potential as an intervention for suicidality. We
highlight important limitations of the study, potential mechanisms, and future directions for
research on ayahuasca as an intervention for suicidality.
Clinical Trial Registration:, identifier NCT02914769.
Keywords: suicidality, ayahuasca, psychedelics, randomized controlled trial, novel intervention
Suicide is a public health issue of major concern: it is a leading cause of premature death, accounting
for nearly one million deaths annually (World Health Organization, 2014). For every completed
suicide, it is estimated that 20–30 suicide attempts occur (Wasserman, 2001). Furthermore, suicide
rates have been increasing within the United States (Curtin et al., 2016).
Suicide occurs most commonly among individuals with major depressive disorder (MDD)
(Cavanagh et al., 2003; World Health Organization, 2014) and individuals with comorbid MDD
Frontiers in Pharmacology | November 2019 | Volume 10 | Article 1325
doi: 10.3389/fphar.2019.01325
published: 19 November 2019
Impact of Ayahuasca On SuicidalityZeifman et al.
and borderline personality disorder (BPD) exhibit especially
heightened levels of suicidality (Soloff et al., 2000; Galione and
Zimmerman, 2010; Perugi et al., 2013; Zeng et al., 2015). Given
the drastic consequences of suicide and suicide attempts, effective
suicide interventions are of great importance.
A number of interventions are effective for treating suicidality
(i.e., suicide attempts, suicide planning, and suicidal ideation; for
a review, see Zalsman et al., 2016), including electroconvulsive
therapy, psychotherapy (e.g., cognitive behavior therapy,
dialectical behavior therapy), and pharmacological interventions
(e.g., antidepressants, lithium, clozapine). However, there
remain a number of important limitations surrounding current
interventions for suicidality, including (a) non-immediate
effects (e.g., weeks to months; Griffiths et al., 2014), (b) limited
treatment availability (Bateman, 2012), (c) negative side-effects
(e.g., increased suicidality with antidepressant use among
adolescents; Vitiello and Ordóñez, 2016), (d) the need for
ongoing administration (Kellner et al., 2005), and (e) high rates
of non-responsiveness (Stone et al., 2009; Pompili et al., 2010).
Individuals who do not respond to conventional interventions
(i.e., individuals with treatment-resistant depression) show
especially heightened levels of suicidality (Nelsen and Dunner,
1995; Malhi et al., 2005; Souery et al., 2007) and are, therefore,
especially in need of novel interventions for suicidality.
Novel Interventions for Suicidality
One novel intervention that has recently received attention for
the treatment of suicidality is ketamine, a dissociative that acts
as an antagonist of N-methylD-aspartate (NMDA). A recent
meta-analysis (k = 10; N = 167; Wilkinson et al., 2018) of
randomized controlled trials on the impact of a single dose of
ketamine (vs. saline or midazolam) on suicidality found medium
to large between-group effect sizes both 1 day [effect size (ES) =
0.85], 2 (ES = 0.85), and 7 days (ES = 0.61) aer administration.
Importantly, this meta-analysis suggests that the impact of
ketamine on suicidality may begin to decrease within a week
aer administration. Moreover, there is no evidence that the
antisuicidal effects of ketamine are long-lasting (Zalsman et al.,
2016; Dadiomov and Lee, 2019) and there are signicant concerns
surrounding repeated administration of ketamine, including the
potential for abuse and cognitive impairment (Schak et al., 2016;
Strong and Kabbaj, 2018). us, there is a need for identifying
alternative novel interventions for suicidality with less potential
for abuse and a longer-lasting impact on suicidality.
One potentially promising novel intervention for suicidality,
which has shown promise for a wide range of mental health concerns
(for a review, see dos Santos et al., 2018) are psychedelics. Psychedelics
are a class of pharmacological agents, including psilocybin and
ayahuasca (a brew which contains N,N-dimethyltryptamine and
beta-carboline alkaloids), that induce changes in affect, cognition,
and perception, as well as non-ordinary states of consciousness at
high doses (Griffiths et al., 2006; Hamill et al., 2019).
Cross-sectional and longitudinal research indicates that lifetime
use of psychedelics is associated with lower levels of suicidality. For
instance, among adult males (N = 190,000), lifetime psychedelic
use was associated with lower levels of past-year suicide ideation,
planning, and attempts (Hendricks et al., 2015). Furthermore,
within a community-based cohort of marginalized women,
lifetime psychedelic use was predictive of reduced risk of suicidality
(Argento et al., 2017), as well as buffered the relationship between
opioid use and suicidality (Argento et al., 2018). However, given
that these studies were non-experimental, they leave open the
question of whether these effects are due to factors associated with
psychedelic use, such as personality, or whether administration of
psychedelics leads to decreases in suicidality.
To date, only a single study has experimentally explored
the impact of psychedelics on suicidality. Carhart-Harris and
colleagues (2018) conducted an open-label trial in which
individuals with treatment-resistant MDD received two doses
of psilocybin with psychological support. Results indicated
signicant decreases in self-reported suicidality 1 and 2 weeks
aer the intervention. is study was limited by reliance upon
self-reported suicidality and the open-label design. Accordingly,
additional experimental research on the impact of psychedelics
on suicidality, using clinician assessed suicidality and a placebo-
controlled design, is necessary.
Additional support for the impact of psychedelics on
suicidality comes from clinical research indicating that
interventions that include administration of psilocybin (Carhart-
Harris et al., 2016; Griffiths et al., 2016; Ross et al., 2016;
Carhart-Harris et al., 2018) and ayahuasca (Santos et al., 2007;
omas et al., 2013; Osório et al., 2015; Sanches et al., 2016;
Palhano-Fontes et al., 2019; Uthaug et al., 2018) lead to acute
and sustained reductions in mental health concerns associated
with suicidality, such as depression and hopelessness (Brown
et al., 2000; Nock et al., 2009). For instance, among individuals
with treatment-resistant MDD, a recent randomized placebo-
controlled trial showed large decreases in depressive symptoms
1, 2, and 7 days administration of ayahuasca (Palhano-Fontes
et al., 2019). However, extant research suggests that suicidality
can occur independent from depressive symptoms (Brent etal.,
2005; Brent, 2010; Brent and Mann, 2010; Dutta et al., 2017;
Batterham et al., 2019) and decreases in depressive symptoms are
not always associated with decreases in suicidality (Christensen
etal., 2013). For instance, compared with placebo, even rst-line
interventions for depression (i.e., selective serotonin reuptake
inhibitors; SSRIs) lead to limited to no decreases in suicidality
(intent to treat ES = –0.04–0.20; Näslund et al., 2018). erefore,
there is a need for research on the impact of ayahuasca directly
on suicidality.
In sum, suicide is an increasingly problematic mental health
concern and there are important limitations surrounding current
interventions for suicidality. Lifetime psychedelic use is associated
with lower levels of suicidality. Furthermore, ayahuasca and
psilocybin have shown promise as interventions for a wide range
of mental health issues associated with suicidality. However,
research has not yet explored whether the administration of
ayahuasca leads to reductions in suicidality. In order to ll this
gap in the literature, we conducted secondary analyses of data
from a randomized placebo-controlled trial, in which individuals
with treatment-resistant MDD were administered a single dose of
ayahuasca or placebo (see primary analysis: Palhano-Fontes et al.,
2019). We hypothesized that ayahuasca would lead to decreases
Frontiers in Pharmacology | November 2019 | Volume 10 | Article 1325
Impact of Ayahuasca On SuicidalityZeifman et al.
in suicidality that are sustained (i.e., from 1 to 7 days aer the
intervention). We also conducted exploratory analyses in order
to determine whether changes in suicidality were associated with
changes in non-suicide-related depressive symptoms.
We conducted secondary analyses of a double-blind, parallel-
arm, randomized placebo-controlled trial for individuals with
treatment-resistant MDD (for primary outcomes, see Palhano-
Fontes et al., 2019). Participants were recruited via referral
from outpatient psychiatric units and advertisement. Interested
participants received a full clinical assessment by a psychiatrist
in order to determine eligibility. To be eligible to participate in
the study, participants needed to be: between ages 18 and 60,
meeting criteria for a unipolar MDD, which was assessed using
the Portuguese version (Del-Ben et al., 2001) of the Structured
Clinical Interview for DSM-IV (SCID-IV; First et al., 1997),
and treatment-resistant (i.e., inadequate response to 2 or more
antidepressant medications from different classes; Conway et al.,
2017). Exclusion criteria for the study included: prior experience
using psychedelics, current medical disease, pregnancy,
imminent suicidal risk, or use of substances of abuse, current
or previous neurological disorders, and personal or family
history of schizophrenia, bipolar affective disorder, mania, or
hypomania. Eligible participants were randomly assigned (1:1)
to either the ayahuasca or placebo group, randomized in blocks
of 10. Investigators and participants were blind to the treatment
condition. Blindness was enhanced through the exclusion of
individuals with past experience with ayahuasca, the use of an
active placebo, as well as through randomly assigning participants
to different assessors following the intervention.
Antidepressant medication was discontinued prior to
intervention (average 2 weeks, dependant on the half-life of
the antidepressant) and for 7 days post-intervention. Daily
benzodiazepine use was permitted, excluding during the acute
phases of the intervention. On the morning of the intervention,
participants were reminded with information regarding potential
experiences and strategies for dealing with difficult experiences
during the ayahuasca inebriation. Participants were also
instructed to focus on their bodies, thoughts, and emotions. e
intervention occurred in a quiet and dimly lit environment with
a bed and a recliner. Participants listened to a predened music
playlist throughout the intervention.
Within an individual setting, participants were administered a
single 1 ml/kg dose of either ayahuasca (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)
or placebo (per 1 ml of water: 0.1 g of yeast, 0.02 g of zinc sulfate,
and 0.02 g of citric acid). e placebo was designed to imitate
the bitter/sour taste, brownish color, and gastrointestinal distress
oen present during the effects of ayahuasca. During the session,
two investigators remained next door to provide support when
needed. Sessions lasted approximately 8 h, aer which participants
were permitted to return home. Following the intervention, four
participants opted to remain as inpatients throughout the 7-day
period. Suicidality was assessed at (a) baseline, (b) 1 day, (c) 2
days, and (d) 7 days aer the intervention. e study adhered
to recommended clinical guidelines for safely conducting
psychedelic administration (Johnson et al., 2008), it occurred at
the Onofre Lopes University Hospital (HUOL), Natal-RN, Brazil,
and was approved by the University Hospital Research ethics
committee. For additional details regarding study procedures,
including a CONSORT diagram of the trial prole, as well as
the impact of ayahuasca on depressive symptoms, not including
analyses of suicidality, see Palhano-Fontes and colleagues (2019).
Montgomery-Åsberg Depression Rating Scale—The
Montgomery-Åsberg Depression Rating Scale (MADRS;
Montgomery and Asberg, 1979) is a 10-item, clinician-
administered measure of depression severity. The measure
includes one item (item 10; MADRS-suicidality item; MADRS-SI)
that assesses current suicidality. MADRS-SI is rated on a scale
from 0 to 6. e ratings are as follows: 0 (“Enjoys life or takes it
as it comes.”), 2 (“Weary of life. Only eeting suicidal thoughts.”),
4 (“Probably better off dead. Suicidal thoughts are common, and
suicide is considered as a possible solution but without specic
plans or intention.”), and 6 (“Explicit plans for suicide when there
is an opportunity. Active preparations for suicide.”). Odd ratings
(i.e., 1, 3, and 5) may be used but are not specically dened.
Past research has dened clinically signicant suicidality as
MADRS-SI≥ 4 (Ballard et al., 2015). Assessment of suicidality
using the MADRS-SI is common in suicidality research (e.g., Price
et al., 2009; Larkin and Beautrais, 2011; Perroud et al., 2011; Price
et al., 2014; Ballard et al., 2015) and is considered a valid approach
for the assessment of suicidality (Desseilles et al., 2012). In line with
past research (e.g., Price et al., 2014; Ballard et al., 2015), we used
the sum of the remaining nine items of the MARDS to measure
non-suicide-related depressive symptoms (MADRS-totalnonSI).
Statistical Analysis
We used a modified intention-to-treat analysis, in which all
participants that received the intervention (i.e., ayahuasca
or placebo) were included in analyses. We ran a fixed-
effects linear mixed model, examining MARDS-SI scores 1
day, 2 days, and 7 days after the intervention, with baseline
MADRS-SI scores as a covariate. We used an unstructured
covariance structure and estimated missing data (1 and 2
days after the intervention two participants failed to attend
assessments) with restricted maximum-likelihood estimation.
We evaluated the main effects of time and intervention, as
well as a time x intervention interaction. For MADRS-SI
and MADRS-totalnonSI scores, we calculated between-group
Cohen's d effect sizes by dividing estimated marginal means (1
day, 2 days, and 7 days after the intervention) for each group
by pooled standard deviations. We also calculated within-
group Cohen's d effect sizes by dividing change scores (time
point—baseline) at each time point (1 day, 2 days, and 7 days
after the intervention) by the standard deviation of the change
Frontiers in Pharmacology | November 2019 | Volume 10 | Article 1325
Impact of Ayahuasca On SuicidalityZeifman et al.
score. For within-group effect sizes, missing values were not
imputed. For the relationship between changes in MADRS-SI
and MADRS-totalnonSI scores 7 days after the intervention,
within both the ayahuasca and placebo groups, we calculated
Pearson correlation coefficients. We set the alpha level
indicating significance at p < 0.05, two-tailed. All analyses
were conducted using IBM SPSS Statistics (Version 25).
Participant mean age was 42.04 (SD = 11.66). The majority
of participants were female (72%), Caucasian (59%),
unemployed (52%), had a lifetime suicide attempt (55%),
and a comorbid personality disorder (76%). Nine individuals
(31%) had a diagnosis of BPD. At baseline, participant
mean MADRS-SI score was 2.35 (SD = 1.91). For additional
details regarding participants' characteristics by condition,
see Table 1. For individual participant details related to the
presence of a personality disorder and MADRS-SI at each
time point, see Tabl e 2.
Clinical Response
For changes in suicidality (MADRS-SI) by group, see Figure 1.
Results of the linear mixed model showed a signicant effect for
time, F(2,25.72 = 3.38; p < .05) and a trend toward signicance
for the intervention (i.e., ayahuasca vs. placebo), F(1,27.44 =
3.13; p = .088). e interaction between time and intervention
was not signicant, F(3,25.72 = .395; p = .678).
TABLE 1 | Sample characteristics and treatment history by study condition.
Variable Ayahuasca group
(n = 14)
Placebo group
(n = 15)
Age M (SD)39.71 (11.26) 44.2 (11.98)
Sex-Female 11 5
Black 1 0
Pardo 4 7
Caucasian 9 8
Incomplete Primary Education 5 4
Completed Primary Education 1 2
Completed Secondary Education 4 7
Completed Undergraduate Education 1 0
Completed Postgraduate Education 3 2
Employment status
Employed-working 3 3
Employed-leave of absence 2 4
Unemployed 7 8
Student 2 0
Presence of personality disorder 10 12
Borderline personality disorder 5 4
Dependant personality disorder 1 0
Histrionic personality disorder 4 7
Narcissistic personality disorder 1 0
Schizoid personality disorder 0 1
Cluster B (undefined) 1 0
Depression duration (years)
Baseline MADRS-SI M (SD) 3.36 (1.65) 1.40 (1.68)
Lifetime suicide attempt 10 6
Number of failed antidepressant
medications M (SD)
3.93 (1.44) 3.80 (1.90)
History of psychotherapy 11 12
History of electroconvulsive therapy 1 1
Inpatient during the intervention 2 2
Cluster B personality disorders include antisocial personality disorder, borderline
personality disorder, histrionic personality disorder, and narcissistic personality disorder.
TABLE 2 | Participant clinical characteristics.
Condition Personality disorder Suicidality (MARDS-SI)
Baseline 1 day
post 2 days
post 7 days
A1 Histrionic 4 4 4 4
A2 Histrionic 2 0 0 0
A3 Borderline 4 3 * 2
A4 Histrionic + Dependent 3 0 0 0
A5 Cluster B (undefined) 0 0 0 0
A6 None 3 0 0 0
A7 Borderline + Narcissistic 5 1 1 1
A8 Histrionic 4 2 0 2
A9 None 5 1 0 0
A10 None 0 0 0 0
A11 Borderline 5 0 0 0
A12 None 4 3 3 0
A13 Borderline 4 2 0 0
A14 Borderline 4 0 1 5
P1 Schizoid 2 0 0 0
P2 Histrionic 0 0 0 0
P3 Borderline 5 2 2 2
P4 None 0 4 0 2
P5 Borderline 3 * 3 3
P6 Histrionic 1 0 0 0
P7 None 0 0 0 0
P8 Borderline 3 1 1 1
P9 None 2 1 1 1
P10 Histrionic 0 0 0 0
P11 Histrionic 0 0 0 0
P12 Histrionic 0 0 0 2
P13 Histrionic 4 * * 4
P14 Borderline 1 2 1 5
P15 Histrionic 0 3 0 0
MADRS-SI, Montgomery-Asberg Depression Rating Scale-Suicidality Item; A,
ayahuasca; P, placebo; *, Failed to attend assessment.
FIGURE 1 | Changes in suicidality (MADRS-SI) over time. Baseline values
are means (± standard error of the mean) for MADRS-SI. Day 1, Day 2,
and Day 7 values are estimated marginal means (±standard error of the
mean) for MADRS-SI.
Frontiers in Pharmacology | November 2019 | Volume 10 | Article 1325
Impact of Ayahuasca On SuicidalityZeifman et al.
We found medium between-group (ayahuasca vs. placebo)
effect sizes for decreases in MADRS-SI 1 day (Cohen's d = 0.58;
95% CI –1.32–0.17), 2 days (Cohen's d = 0.56; 95% CI –1.30–
0.18), and 7 days (Cohen's d = 0.67; 95% CI –1.42–0.08) aer the
intervention (see Tab le 3). Within the ayahuasca group, we found
large within-group effect sizes for decreases in MADRS-SI 1 day
(Cohen's d = 1.33; 95% CI 1.25–3.18; n = 14), 2 days (Cohen's
d = 1.42; 95% CI 1.50–3.74; n = 13), and 7 days (Cohen's d =
1.19; 95% CI 1.21–3.50; n = 14) aer the intervention. Within
the placebo group, we found small within-group effect sizes for
decreases in MADRS-SI 1 day (Cohen's d = 0.00; 95% CI –1.09–
1.63; n = 13) and 7 days (Cohen's d = 0.04; 95% CI –0.90–1.04;
n = 15) aer the intervention, as well as a medium effect size
2 days (Cohen's d = 0.64; 95% CI 0.06–1.23; n = 14) aer the
intervention (see Tab le 4). Overall, these effect sizes suggest that
ayahuasca leads to decreases in suicidality that are sustained
from 1 to 7 days aer administration. For between and within-
group effect sizes for changes in non-suicide-related depressive
symptoms (MADRS-totalnonSI), see Tables 3 and 4, respectively.
Association Between Changes in
Suicidality and Depressive Symptoms
Seven days aer the intervention, within the ayahuasca group,
the association between changes in changes in suicidality
(MADRS-SI) and changes in non-suicide-related depressive
symptoms (MADRS-totalnonSI) approached signicance, r = .53,
p = .053. Within the placebo group, the association between
changes in suicidality (MADRS-SI) and changes in non-suicide-
related depressive symptoms (MADRS-totalnonSI) was not
signicant, r = .16, p = .579.
Given the limitations surrounding current interventions, there
is an urgent need for innovative interventions for suicidality
(Research Prioritization Task Force, 2014). To date, experimental
research had not yet directly explored the impact of ayahuasca on
suicidality. erefore, this study aimed to ll this gap by being the
rst to explore the impact of ayahuasca on suicidality.
We hypothesized that ayahuasca would lead to decreases
in suicidality that are sustained (i.e., from 1 to 7 days aer the
intervention). Our results are mixed. Although across groups
there was a signicant decrease in suicidality over time, the effect
for the treatment group (i.e., ayahuasca vs. placebo) trended
toward but did not reach signicance. ere are a number of
potential explanations for these results. First, compared with
placebo, ayahuasca may not lead to signicant decreases in
suicidality. Given that research has not yet explored the direct
impact of ayahuasca on suicidality, this is a plausible explanation.
Alternatively, given that large effects may not be detected by
statistical tests, especially within small sample sizes (Greenland et
al., 2016), our study was likely underpowered to detect the impact
of ayahuasca (compared with placebo) on suicidality. erefore,
consideration of effect sizes is essential for the interpretation of
our ndings. In support of this possibility, we found medium
between-group effect sizes for decreases in suicidality at all time
points. Furthermore, within the ayahuasca group, we found large
effect sizes for decreases in suicidality at all time points. ese
ndings are in line with past research on the impact of psilocybin
on suicidality (Carhart-Harris et al., 2018), as well as cross-
sectional (Hendricks et al., 2015) and longitudinal (Argento
etal., 2017) research indicating that lifetime use of psychedelics
is associated with reduced levels of suicidality and decreased risk
of becoming suicidal. Furthermore, these results are in line with
TABLE 4 | Mean scores and within-group effect sizes (Cohen's d) for suicidality (MADRS-SI) and non-suicide-related depressive symptoms (MADRS-totalnonSI).
Baseline Day 1 Day 2 Day 7
Aya Pla Aya Pla Aya Pla Aya Pla
n14 15 14 13 13 14 14 15
Mean 3.36 1.40 1.14 1.00 0.69 0.57 1.00 1.33
SD 1.65 1.68 1.41 1.35 1.32 0.94 1.66 1.63
Cohen's d 1.33 0.00 1.42 0.64 1.19 0.04
95% CI 1.25–3.18 –1.09–1.63 1.50–3.74 0.06–1.23 1.21–3.50 –0.90–1.04
Mean 32.79 28.73 15.57 15.00 13.54 13.86 14.64 22.20
SD 4.93 5.08 12.68 11.16 10.07 10.04 8.64 9.87
Cohen's d 1.46 1.61 2.17 1.57 2.20 0.91
95% CI 10.42–24.02 8.06–17.78 14.03–24.89 8.94–19.35 13.38–22.92 2.55–0.51
Aya, ayahuasca; Pla, placebo.
TABLE 3 | Between-group effect sizes (Cohen's d) for suicidality (MADRS-SI)
and non-suicide-related depressive symptoms (MADRS-totalnonSI)
Day 1 Day 2 Day 7
Cohen's d0.58 0.56 0.67
95% CI –1.32–0.17 –1.30–0.18 –1.42–0.08
Cohen's d0.59 0.65 1.55
95% CI –1.33–0.16 –1.40–0.10 –2.38–0.72
Frontiers in Pharmacology | November 2019 | Volume 10 | Article 1325
Impact of Ayahuasca On SuicidalityZeifman et al.
past research indicating that the administration of ayahuasca
is associated with improvement in mental health concerns
associated with suicidality (e.g., depression and hopelessness;
Santos et al., 2007; Palhano-Fontes et al., 2019). Interestingly,
7 days aer the intervention, between and within-group effect
sizes for decreases in non-suicide-related depressive symptoms
were larger than those found for suicidality, which may suggest
that ayahuasca has a greater impact on non-suicide-related
depressive symptoms than suicidality. Alternatively, these results
may be due to a oor effect as a result of low levels of baseline
suicidality. Nonetheless, overall, these results suggest that the
therapeutic benets of ayahuasca may extend to suicidality and
that investigation of the impact on ayahuasca on suicidality using
a larger sample is warranted.
ese ndings are also important as they indicate that
ayahuasca may have a fast-acting impact on suicidality (i.e.,
as soon as 1 day aer the intervention). Given that the time
between the emergence of suicidality and suicide can be very
short (Deisenhammer et al., 2009), there is a need for fast-
acting interventions for suicidality. Currently, recommended
interventions for suicidality are limited by the duration of time
they take to be effective. For instance, individuals with MDD that
are treated with antidepressants remain at high risk of suicide
for at least 10–14 days aer treatment begins (Jick et al., 2004;
Simon et al., 2006). Furthermore, compared with nonsuicidal
individuals, individuals with moderate to high levels of suicidality
show slower responses to antidepressants (Baldessarini et al.,
2006). Similarly, among individuals receiving ECT three times
a week, suicidality oen persists for 1–2 weeks aer intervention
(Kellner et al., 2005). Similar to the fast-acting effects of ketamine
on suicidality (Bartoli et al., 2017), ayahuasca may also show
promise as a fast-acting intervention for suicidality.
We found similar medium between-group and large within-
group effect sizes for decreases in suicidality at all time points,
with the largest between-group effect size 7 days aer the
intervention. ese results suggest that the impact of ayahuasca
on suicidality may last beyond the acute and post-acute effects of
ayahuasca. ese ndings are in line with past research indicating
that ayahuasca (e.g., Sampedro et al., 2017; Sanches et al., 2016;
Palhano-Fontes et al., 2019); and psilocybin (e.g., Griffiths et al.,
2016; Ross et al., 2016; Carhart-Harris et al., 2018) lead to mental
health improvements that last beyond their acute effects. ese
results are especially important in light of the need for ongoing
treatment in interventions for suicidality. For instance, ECT
(Tanney, 1986; Prudic and Sackeim, 1999; Kellner et al., 2005)
and traditional interventions for suicidality require ongoing
administration in order to maintain their antisuicidal effects
(Valuck et al., 2009). Similarly, research suggests that ketamine
also requires repeated administration in order to maintain its
efficacy (Zalsman et al., 2016; Dadiomov and Lee, 2019), which
is problematic given the potential for cognitive impairment
and abuse with repeated administration of ketamine (Schak et
al., 2016; Strong and Kabbaj, 2018). Importantly, ayahuasca is
associated with a low abuse and dependence potential (Hamill
et al., 2019). erefore, these ndings suggest that ayahuasca
may show promise as an intervention for suicidality that does
not require repeated administration. Additional research with
longer-term follow-up will be necessary to determine the long-
term impact of ayahuasca on suicidality.
Interestingly, within the ayahuasca group, the relationship
between changes in suicidality and changes in non-suicide-
related depressive symptoms approached signicance, with a large
effect size (i.e., r = .53). ese ndings suggest that the impact of
ayahuasca on suicidality may, in part, be due to its impact on non-
suicide-related depressive symptoms or mechanisms overlapping
both non-suicide-related depressive symptoms and suicidality.
Research suggests that suicide functions as a means of escaping
intense emotional distress (Baumeister, 1990; Shneidman,
1998). Extant research indicates that psychedelics in general,
and ayahuasca in particular, leads to decreases in emotional
distress (for a review, see dos Santos etal., 2018). Similarly, a
recent study found that the administration of ayahuasca led to
decreases in emotion dysregulation, within a community sample
and among individuals with BPD traits (Domínguez-Clavé et al.,
2019). Similarly, among males in a community sample, lifetime
use of psychedelics was associated with lower levels of emotion
dysregulation (iessen et al., 2018). One particular means
through which ayahuasca may decrease emotion dysregulation
is via increased mindfulness-related capacities (e.g., acceptance
and decentering), which have been shown to increase aer
administration of ayahuasca (omas et al., 2013; Soler et al., 2016;
Sampedro et al., 2017; Domínguez-Clavé et al., 2019; Soler etal.,
2018; Uthaug et al., 2018). Neurobiological research similarly
suggests that ayahuasca may impact suicidality via decreases in
emotion dysregulation. For instance, among individuals with
MDD, a single dose of ayahuasca led to increased blood ow in
regions of the brain associated with emotion regulation (e.g., le
nucleus accumbens, right insula and le subgenual area; Sanches
et al., 2016). Furthermore, research has found that administering
psychedelics to rats promotes neuroplasticity (Ly et al., 2018), and
markers of neuroplasticity (Nichols and Sanders-Bush, 2002),
within the prefrontal cortex, a region of the brain implicated
in emotion dysregulation (Vollenweider and Kometer, 2010)
and suicidality (Ding et al., 2015). erefore, the impact of
ayahuasca on suicidality may be accounted for by its impact on
psychological and neurobiological mechanisms associated with
emotion dysregulation. Additional research is necessary in order
to understand the mechanisms that account for the impact of
ayahuasca on suicidality.
Ayahuasca and Borderline
Personality Disorder
One psychiatric disorder that ayahuasca may show promise as an
intervention for is BPD, a severe psychiatric disorder associated
with especially high rates of suicide (i.e., 3%–10%; Links 2009)
and suicide attempts (i.e., 60%–78%; Links 2009). Importantly,
there is limited evidence for the efficacy of treating BPD with
pharmacological agents and a pressing need for innovative
pharmacological interventions for BPD (Chanen, 2015; Starcevic
and Janca, 2018). Interestingly, among individuals with BPD
traits, a recent study found that the administration of ayahuasca
led to decreases in components of emotion dysregulation
(Domínguez-Clavé et al., 2019), which is considered the core
Frontiers in Pharmacology | November 2019 | Volume 10 | Article 1325
Impact of Ayahuasca On SuicidalityZeifman et al.
dysfunction in BPD (Linehan, 1993; Carpenter and Trull, 2013).
However, they did not include a sample of individuals that
met diagnostic criteria for BPD and the impact of ayahuasca
on suicidality was not assessed. e present study was the rst
clinical trial with psychedelics to report including individuals
with BPD. It is noteworthy that no serious adverse events
occurred among individuals with BPD. Furthermore, while
all ve individuals with BPD that received ayahuasca showed
clinically signicant suicidality at baseline (i.e., MADRS-SI ≥ 4),
none (i.e., 0%) reported clinically signicant suicidality 1 and 2
days aer administration and only 1 (i.e., 20%) reported clinically
signicant suicidality 7 days aer administration (see Table 2).
Given the limited number of individuals with BPD included
in the sample, these results must be interpreted with caution.
However, given the pressing need for innovative pharmacological
interventions for BPD, the wide-ranging mental health concerns
for which psychedelics have shown promise, and our results
related to the impact of ayahuasca on suicidality, additional
research exploring the safety, tolerability, and clinical utility of
ayahuasca as an intervention for BPD may be warranted.
Strengths, Limitations, and
Future Direction
is study includes a number of strengths and limitations that
are important to consider. e study utilized a double-blind
randomized placebo-controlled design, a gold-standard for
suicide research (Zalsman et al., 2016). Furthermore, in order to
increase blinding, the study only included individuals without past
experience with psychedelics and used an active placebo designed
to imitate characteristics of ayahuasca. Additionally, the sample
used in the present study showed severe psychiatric comorbidity,
with the majority of the sample (76%) meeting criteria for a
comorbid DSM-IV axis II disorder. Furthermore, all individuals
had treatment-resistant MDD and some had failed to respond to as
many as 10 interventions. e impact of ayahuasca on suicidality
among individuals with such high rates of non-responsiveness to
conventional interventions is especially promising.
e primary limitation surrounding the present study is that,
despite the use of randomization, suicidality among those in the
placebo group was low. erefore, although, we controlled for
baseline differences in suicidality, the possibility that our results
may be inuenced by the placebo effect or regression to the mean,
cannot be ruled out. Nonetheless, given the large within-group
effects we found, we suggest that additional placebo-controlled
research on the impact of ayahuasca on suicidality will be
important. Relatedly, our study is limited by the use of a small
sample size, which limits the extent to which inferential statistics
are able to identify signicant changes. Furthermore, due to the
small sample size, potentially important covariates (e.g., use
of benzodiazepines) were not included in our analyses. Future
research would benet from studies with larger samples that are
better powered to detect the impact of ayahuasca on suicidality.
Second, due to safety concerns, the study did not include
individuals with imminent suicide risk. Accordingly, it is difficult
to determine from the present study whether ayahuasca would lead
to reductions in suicidality among individuals with higher levels
of suicidality. Past research on pharmacological interventions
for suicidality has employed similar exclusion criteria (e.g., Price
et al., 2009) and the suicidality exclusion criteria employed in
this study were less strict than past studies on pharmacological
interventions for suicidality (e.g., MADRS-SI > 4; Ballard et al.,
2015). Future research would benet from exploring the impact
of ayahuasca on individuals with higher levels of suicidality.
ird, we did not conduct a qualitative analysis of participants
descriptions of why ayahuasca impacted suicidality. Future
research would benet from using a mixed-methods approach, as
well as analysis of potential mediators of the impact of ayahuasca
on suicidality. Finally, similar to all research on psychedelics, due to
the psychological experience induced by ayahuasca, ensuring that
participants are blind to treatment condition is difficult (Barnby
and Mehta, 2018). In order to improve blinding procedures in
psychedelic research, future research should continue to develop
increasingly convincing placebos.
is study was the rst to explore the impact of ayahuasca
on suicidality and our ndings suggest that ayahuasca may
show promise as a fast-acting and innovative intervention for
suicidality. Given important limitations of our study (e.g., small
sample size, low levels of baseline suicidality), additional research
will be necessary in order to determine the long-term impact of
ayahuasca on suicidality, as well as the safety, tolerability, and
clinical outcomes associated with administration of ayahuasca
among highly suicidal individuals.
e datasets generated for this study are available on request to
the corresponding author.
e studies involving human participants were reviewed and
approved by Onofre Lopes University Hospital (HUOL),
Natal-RN, Brazil, University Hospital Research Ethics Committee.
e patients/participants provided their written informed consent
to participate in this study.
FP-F, JH, EN, JM-O, and DA contributed to study design and
conception. FP-F and DA coordinated data acquisition. RZ,
FP-F, and DA analyzed data and interpreted the results. RZ was
responsible for the rst dra of the manuscript. All authors read,
critically revised, and approved the manuscript.
Funded by the Brazilian National Council for Scientic and
Technological Development (CNPq, grants #466760/2014
& #479466/2013), and by the CAPES Foundation (grants
#1677/2012 & #1577/2013).
Frontiers in Pharmacology | November 2019 | Volume 10 | Article 1325
Impact of Ayahuasca On SuicidalityZeifman et al.
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Conict of Interest: e authors declare that the research was conducted in the
absence of any commercial or nancial relationships that could be construed as a
potential conict of interest.
Copyright © 2019 Zeifman, Palhano-Fontes, Hallak, Arcoverde, Maia-Oliveira and
Araujo. is is an open-access article distributed under the terms of the Creative
Commons Attribution License (CC BY). e use, distribution or reproduction in
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Frontiers in Pharmacology | November 2019 | Volume 10 | Article 1325
... An additional secondary analysis evaluated reduction in suicidal thoughts with medium between-group effect sizes favouring ayahuasca at all time points (ayahuasca vs. placebo; day 1: d = 0.58; day 2: d = 0.56; day 7: d = 0.67). 80 Overall, evidence from these two small trials supports acute antidepressant efficacy following a single dose of oral ayahuasca. Given the small sample sizes, methodological limitations and lack of replication from independent centres, there is Level 3 evidence for acute antidepressant efficacy of single-dose oral ayahuasca for TRD. ...
... Preliminary evidence also supports potential benefits for the reduction in suicidality. 78,80 Is Psychotherapy Necessary for Psychedelic Treatments? ...
Objective Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence and provide a consensus recommendation for the clinical use of psychedelic treatments for major depressive disorder. Methods A systematic review was conducted to identify contemporary clinical trials of serotonergic psychedelics for the treatment of major depressive disorder and cancer-related depression. Studies published between January 1990 and July 2021 were identified using combinations of search terms, inspection of bibliographies and review of other psychedelic reviews and consensus statements. The levels of evidence for efficacy were graded according to the Canadian Network for Mood and Anxiety Treatments criteria. Results Only psilocybin and ayahuasca have contemporary clinical trials evaluating antidepressant effects. Two pilot studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator (escitalopram with supportive psychotherapy) in major depressive disorder, with additional randomized controlled trials showing efficacy specifically in cancer-related depression (Level 3 evidence). There was only one open-label trial of psilocybin in treatment-resistant unipolar depression (Level 4 evidence). Small sample sizes and functional unblinding were major limitations in all studies. Adverse events associated with psychedelics, including psychological (e.g., psychotomimetic effects) and physical (e.g., nausea, emesis and headaches) effects, were generally transient. Conclusions There is currently only low-level evidence to support the efficacy and safety of psychedelics for major depressive disorder. In Canada, as of 2022, psilocybin remains an experimental option that is only available through clinical trials or the special access program. As such, Canadian Network for Mood and Anxiety Treatments considers psilocybin an experimental treatment and recommends its use primarily within clinical trials, or, less commonly, through the special access program in rare, special circumstances.
... While response rates were higher in the ayahuasca group compared to placebo at day 7 (64% v. 27%; p = 0.04), the difference in remission rates did not reach statistical significance (36% v. 7%; p = 0.054) [16]. An additional secondary analysis evaluated reduction in suicidal thoughts with medium between-group effect sizes favoring ayahuasca at all time points (ayahuasca vs. placebo; day 1: d = 0.58; day 2: d -= 0.56; day 7: d = 0.67) [17]. Finally, the same investigators also conducted a pilot placebo-controlled RCT of ayahuasca in 17 adults with social anxiety disorder (SAD). ...
... However, recent clinical trials suggest that these serious adverse events are very rare and can be prevented with adequate participant screening, monitoring, and safety protocols. Except for the small placebo-controlled RCT of ayahuasca that showed a larger reduction in suicidality with ayahuasca than with placebo [17], all published contemporary trials described above have excluded participants with active suicidal ideation. Although treatment-emergent suicidality has not been reported, there was one suicide in a participant treated for end-of-life distress, 2 weeks after receiving a subtherapeutic 1-mg dose of psilocybin [8]. ...
... são importantes as pesquisas com alternativas farmacológicas para estes transtornos. A Ayahuasca aparece como uma destas alternativas, uma vez que vem apresentando resultados positivos e com efeito rápido. (Almeida et. al., 2019;Galvão et. al., 2018;Galvão-Coelho et. al., 2020;Osório et. al., 2015;Palhano-Fontes et. al., 2018;Sanches et. al., 2016;Zeifman et. al., 2019Zeifman et. al., , 2020. ...
... articipantes em relação à tendência suicida, os resultados foram semelhantes. Nos dois estudos houve diminuição da tendência suicida, embora em um deles a diferença entre os participantes que receberam a Ayahuasca e os que receberam placebo não tenha sido significativamente expressiva, o que pode indicar importância dos fatores não farmacológicos. (Zeifman et. al., 2019;2020) ...
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Objetivo: Investigar evidências terapêuticas da Ayahuasca, que é uma bebida psicoativa obtida da decocção de duas plantas de origem amazônica: Banisteriospsis caapi (cipó Mariri) e Psychotria viridis (Chacrona), comprovadas em estudos clínicos controlados em pacientes com transtornos psiquiátricos. Metodologia: Trata-se de uma revisão integrativa da literatura focada em ensaios clínicos disponíveis nas bases de dados eletrônicas MEDLINE (Pubmed-AdvancedSearch), Trip data base e Lilacs por meio dos descritores “Ayahuasca, tratamento”; “Ayahuasca, estudo clínico”; “Ayahuasca, tratamento psiquiátrico”. Resultados: Foram selecionados 8 artigos publicados entre 2015 e 2021. Seis estudos avaliaram o uso da Ayahuasca no tratamento do transtorno depressivo recorrente, e dois verificaram a relação entre a Ayahuasca e a redução do risco de suicídio em pacientes com depressão recorrente. A bebida apresentou efeitos antidepressivos rápidos e sustentados, melhorando sintomas de depressão, ligados ou não a pensamentos suicidas. Considerações Finais: Considerando os efeitos colaterais e o tempo necessário para a remissão dos sintomas dos tratamentos atuais, é preciso considerar o potencial de tratamentos alternativos e inovadores para pacientes que não se adaptam aos métodos convencionais. Os resultados demonstrados nesta pesquisa precisam ser replicados em estudos maiores, e com acompanhamento mais duradouro, para avaliar a eficácia e a segurança da substância a longo prazo.
... Personality disorder-related outcomes were not examined, yet, the overall improved depressive symptoms may suggest therapeutic benefits in people with personality disorders. A secondary analysis in this trial found remission in suicidality among all individuals with BPD (n = 5) one and two days post-administration and among most individuals (n = 4) seven days post-administration ( Zeifman et al., 2019 ). ...
The therapeutic potential of the psychedelic brew ayahuasca has been investigated in preclinical and clinical studies. Currently, the most consistent evidence refers to depression. However, various studies suggest that ayahuasca may comprise therapeutic benefits in other health conditions. This narrative review provides a comprehensive, up-to-date overview of ayahuasca's therapeutic effects in diverse clinical conditions in human (clinical, cross-sectional, observational, and qualitative) and preclinical (animal and in vitro) studies. In addition to summarizing and discussing the most commonly studied conditions, such as depression, anxiety, and substance use disorders (SUD), we also examine less frequently studied psychiatric, neurological, and physical conditions. Moreover, we discuss evidence from epidemiological studies on the impact of regular, long-term ayahuasca use on health and psychosocial outcomes. Overall, evidence for depression and SUD is more consistent, with numerous and diverse studies. However, a growing body of evidence suggests that other conditions equally relevant to public health might be promising targets for ayahuasca's therapeutic effects. This includes preliminary studies indicating potential for grief, eating disorders, posttraumatic stress disorder, personality disorders, Parkinson's and Alzheimer's disease, and severe physical illnesses (e.g., cancer, chronic conditions). Moreover, preliminary evidence in long-term ayahuasca users does not suggest detrimental effects but possible benefits for individual and collective health. In light of the emerging evidence of psychedelic drugs as therapeutic agents, it is essential to further investigate in rigorous designs the therapeutic potential of ayahuasca in conditions other than depression.
... The evidence to date suggests that ayahuasca has a relatively good safety profile [(3); but also see (4,5) for potential harmful effects]. While ayahuasca and its alkaloid-containing ingredients show promise in the treatment of mental health conditions (6)(7)(8)(9), they might also aid in the treatment and prevention of movement and neurodegenerative disorders. For example, DMT binds and activates the sigma-1 receptor (10) as well as several serotonin receptors (11) which have been identified as potential therapeutic targets in certain movement and neurodegenerative disorders (12)(13)(14)(15). ...
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Background Recent research suggests that ayahuasca and its alkaloid-containing ingredients may be helpful in the treatment and prevention of certain movement and neurodegenerative disorders. However, such research is still in its infancy and more studies in normative samples seem necessary to explore effects of ayahuasca on clinically relevant brain structures, such as the corpus callosum. Aims The purpose of the present study was to investigate links between ayahuasca use and callosal structure in a normative sample. Methods Using structural imaging data from 22 ayahuasca users and 22 matched controls we compared the thickness of the corpus callosum between both groups at 100 equidistant points across the entire midsagittal surface. In addition, we investigated point-wise correlations between callosal thickness and the number of past ayahuasca sessions. Results The corpus callosum was significantly thicker within the isthmus in the ayahuasca group than in the control group. There was also a significant positive correlation between callosal thickness and the number of past ayahuasca sessions within the rostral body, albeit none of these effects survived corrections for multiple comparisons. No region was significantly thicker in the control than in the ayahuasca group, and no callosal region was negatively linked to ayahuasca use, even at uncorrected significance thresholds. Conclusion This study provides preliminary evidence of links between ayahuasca use and the corpus callosum. However, future studies need to replicate these findings, preferably using larger sample sizes and ideally also utilizing longitudinal research designs, to draw any practical conclusion and offer implications for follow-up clinical research.
... Ayahuasca has additionally robustly exhibited considerable anti-depressant effects in treatment resistant groups , including its medium-large effect sizes for reductions in suicidal ideation (Zeifman et al., 2019). Paralleling this are near-death experiences after suicide, where an almost universal response is also less desire to die and significantly lower repeat attempts -versus suicide attempts normally (without associated NDEs) being the main predictor of further attempts (Greyson, 1993). ...
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The near-death experience (NDE) is an example of an extraordinary human experience which also confers a pattern of positive psychospiritual after-effects. Both its phenomenological features and long-term changes are very comparably identified after experiences with classical psychedelic drugs, which are now surfing a new wave of intense research attention. Both experience types are overwhelmingly positive in such after-effects, yet in the minority of cases of challenging experiences they may also have deleterious outcomes. Psychedelic-assisted psychotherapy provides preparational and integrational sessions around the experience, which should be precisely mirrored for near-death experiencers, so as not only to maximise psychospiritual benefit, but minimise the potential for harm. In addition to this, the NDE is arguably a more potent inducer of transformation, and as such clinical psychedelic work could be optimised by as closely simulating the NDE as possible. This is a pre-publication version of the following article: Michael, P. (2022). Thanatotherapy: How Psychedelic-assisted Psychotherapy and the Near-death Experience can Mutually Benefit One Another. Psychotherapy Section Review, 67, 99–108.
... Hallucinogens including lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), ketamine, and N,N-dimethyltryptamine (DMT) (a natural psychoactive component in ayahuasca) have been demonstrated in clinical trials to be efficacious in managing psychological distress (Grof et al., 1973;Mitchell et al., 2021), depression (Murrough et al., 2013;Palhano-Fontes et al., 2019), and suicidality (Murrough et al., 2015;Zeifman et al., 2019) among other conditions. However, outside of clinical settings, these hallucinogens have misuse potential (Heal et al., 2018), and little is known about how use of these substances relate to psychiatric symptoms on a population level. ...
Background There is renewed interest in the clinical application of hallucinogenic substances to treat a range of psychiatric conditions. However, there is mixed evidence regarding how use of such substances outside of medical settings relates to psychological distress, depression, and suicidality. Methods We examined data from a US representative sample of noninstitutionalized adults from the 2015-2020 National Survey on Drug Use and Health (N=241,675). We evaluated whether past-year use of specific hallucinogens (i.e., LSD, DMT/AMT/Foxy, salvia divinorum, ecstasy (MDMA/Molly), ketamine) is associated with reporting past-year serious psychological distress (SPD), major depressive episode (MDE), and suicidality. Generalized linear models using Poisson and log link were used to estimate adjusted prevalence ratios (aPRs), controlling for sociodemographic characteristics and past-year use of various other illegal drugs. Results LSD use was associated with an increased likelihood of MDE (aPR=1.23, 95% CI: 1.10-1.37) and suicidal thinking (aPR=1.21, 95% CI: 1.09-1.34). Similar associations were observed between salvia divinorum use and suicidal thinking (aPR=1.41, 95% CI: 1.00-1.98) and between DMT/AMT/Foxy use and suicidal planning (aPR=1.81 95% CI: 1.17-2.81). On the other hand, ecstasy use was associated with a decreased likelihood of SPD (aPR=0.83, 95% CI: 0.77-0.89), MDE (aPR=0.91, 95% CI: 0.83-0.99), and suicidal thinking (aPR=0.86, 95% CI: 0.75-0.99). Conclusion Findings suggest there are differences among specific hallucinogens with respect to depression and suicidality. More research is warranted to understand consequences of and risk factors for hallucinogen use outside of medical settings among adults experiencing depression or suicidality.
... Other controlled trials have also confirmed the potential of ayahuasca in treating treatmentresistant depression [32,33,99], and major depressive disorder (MDD) [32,33], anxiety [69], panic-like episodes [100], and hopelessness [100]. Ayahuasca may also have potential to treat suicidality [101] as confirmed by a randomized placebo-controlled trial on patients with treatment-resistant depression. ...
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The word “psychedelic” (psyche (i.e., the mind or soul) and delos (i.e., to show)) has Greek origin and was first coined by psychiatrist Humphry Osmond in 1956, who had been conducting research on lysergic acid diethylamide (LSD) at the time. Psychedelic drugs such as N,N-DMT/DMT (N,N-dimethyltryptamine), 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine), LSD (lysergic acid diethylamide), MDMA (3,4-methylenedioxymethamphetamine) and psilocybin have had significant value as an entheogen in spiritual, religious (shamanic) and sociocultural rituals in Central and South American cultures for thousands of years. In the 1960s, the globalization of these drugs and their subsequent spread outside of their indigenous, old-world cultures, led to the subsequent implementation of strict drug control laws in many Western countries. Even today, psychedelics are still classified as Schedule I drugs, resulting in a still lingering negative stigmatization/perception, vilification, and ultimate criminalization of psychedelics. This controversy still lingers and still limits scientific research and full medical acceptance. For many years up until recently, the spiritual, religious and medicinal value of these drugs could not be explored in a scientific context. More recently, a second wave of psychedelic research is now focusing on psychedelics as neuropharmaceuticals to treat alcohol and tobacco addiction, general mood and anxiety disorders and cancer-related depression. There is now a vast array of promising evidence-based data to confirm the years of anecdotal evidence of the medicinal values of psychedelics. Natural therapeutic alternatives such as psychedelic drugs may provide a safe and efficacious alternate to conventional drugs used to treat mood and anxiety disorders. In a Western context in particular, psychedelic drugs as therapeutic agents for mood and anxiety disorders are becoming increasingly of interest amidst increasing rates of such disorders globally, changing social constructions, the implementation of government regulations and increasing investment opportunities, that ultimately allow for the scientific study to generate evidenced-based data. Alternative psychotherapeutic interventions are gaining interest also, because of their low physiological toxicity, relatively low abuse potential, safe psychological effects, and no associated persisting adverse physiological or psychological effects during and after use. On the other hand, conventional psychotic drugs and anti-depressants are becoming less favorable because of their adverse side effects. Psychedelic neuropharmaceutical interventions may with medical oversight be the solution to conventional psychiatric disorders such as depression and anxiety, and an alternative to conventional psychiatric treatment options. This paper will review the therapeutic potential of psychedelic drugs as alternative therapeutic options for mood and anxiety disorders in a controlled, clinical setting, where the chances of adverse psychological episodes occurring are mitigated.
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Ayahuasca is a psychoactive brew traditionally used in indigenous and religious rituals and ceremonies in South America for its therapeutic, psychedelic, and entheogenic effects. It is usually prepared by lengthy boiling of the leaves of the bush Psychotria viridis and the mashed stalks of the vine Banisteriopsis caapi in water. The former contains the classical psychedelic N,N-dimethyltryptamine (DMT), which is thought to be the main psychoactive alkaloid present in the brew. The latter serves as a source for β-carbolines, known for their monoamine oxidase-inhibiting (MAOI) properties. Recent preliminary research has provided encouraging results investigating ayahuasca’s therapeutic potential, especially regarding its antidepressant effects. On a molecular level, pre-clinical and clinical evidence points to a complex pharmacological profile conveyed by the brew, including modulation of serotoninergic, glutamatergic, dopaminergic, and endocannabinoid systems. Its substances also interact with the vesicular monoamine transporter (VMAT), trace amine-associated receptor 1 (TAAR1), and sigma-1 receptors. Furthermore, ayahuasca’s components also seem to modulate levels of inflammatory and neurotrophic factors beneficially. On a biological level, this translates into neuroprotective and neuroplastic effects. Here we review the current knowledge regarding these molecular interactions and how they relate to the possible antidepressant effects ayahuasca seems to produce.
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Recent trials with psychedelics in major depressive disorder and treatment-resistant depression showed remarkable improvements in depressive symptoms that can last for up to several months after even a single administration. The lack of an appropriate placebo control group—as patients are often able to discriminate the subjective effects of the drug—and an incomplete understanding of the role of the hallucinogenic and mystical experience, hampers the interpretation of these therapeutic effects. To control for these factors, we developed a translational framework based on establishing pharmacokinetic/pharmacodynamic (PK/PD) relationships in rodents and humans for hallucinogenic (i.e., discriminative stimulus effects in rodents and humans; head twitch responses in rodents; questionnaires in humans) and therapeutic effects. For the latter, we selected the pattern separation and attentional set-shifting tasks as measures for cognitive flexibility because of their high translational value. We predict that these PK/PD analyses will lead to a more objective evaluation of improvements in patients compared to relying only on the currently used self-reported questionnaires. We hypothesize that—if the role of the hallucinogenic experience is not central in the antidepressant effects of psychedelics—the ED50’s for the therapeutic effects will be significantly lower than for the hallucinogenic and mystical effects. Our framework will help to inform future studies that aim at the elucidation of the mechanism(s) of action of psychedelics in depression, and the role of the acute subjective and/or hallucinogenic experience in their effects.
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Introduction Suicidality and self-injurious behavior afflict patients with a wide variety of psychiatric illnesses. Currently, there are few pharmacologic treatments for suicidality and self-injurious behavior and none that treat these conditions emergently. Recently, ketamine has demonstrated efficacy in treating both depression and acute suicidal ideation. An increasing usage of ketamine, of a variety of formulations, has been studied for these indications. This article reviews the evidence for use of ketamine in self-injurious behavior and suicidality. Methods A review of the MEDLINE database for articles relating to ketamine, self-injurious behavior, suicidality, and self-harm was conducted. Additional articles were assessed via cross-reference. Results A total of 24 articles that included clinical trials, meta-analyses, case series, and case reports were analyzed. The majority of studies of ketamine for suicidal ideation include the intravenous route using a dose of 0.5 mg/kg over 40 minutes. These studies suggest that intravenous ketamine may be effective at reducing suicidal ideation acutely. Data on use of ketamine in the intramuscular, intranasal, and oral forms are limited and of poorer quality. Studies on these formulations contain greater variability of positive and negative results of ketamine for reducing suicidality and self-injurious behavior. The durability of the antisuicidal effects across all formulations is limited. Discussion Ketamine may be an effective option for the treatment of suicidal ideation in patients across inpatient, outpatient, or emergent settings. At this time, more research is needed on the efficacy of ketamine across all formulations being used in clinical practice.
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1 Background Depression is a risk factor for suicidal ideation. However, suicidal ideation can occur in the absence of depression and treating depression may not reduce suicidal thinking. This study tested whether trajectories of suicidal thinking are concordant with trajectories of depressive symptoms and sought to identify factors associated with these trajectories. 2 Methods Participants were community‐based Australian adults (N = 418, 77% female) enrolled in a randomized controlled trial evaluating the effectiveness of an online cognitive–behavioral intervention for suicidal ideation. Separate linear growth mixture models were estimated across 12 months of follow‐up to identify longitudinal trajectories of suicidal ideation and depression symptoms. Predictors of latent class membership were tested using logistic regression models. 3 Results Two‐class models were found to have optimal fit for both suicidal thinking and depressive symptoms. Trajectory classes of suicidal ideation were: (1) moderate severity decreasing over time; and (2) high severity remaining stable over time. Depression trajectories were: (1) moderate severity with a small decrease over time; and (2) high severity that decreased moderately over time. Lower perceived burdensomeness was associated with having a greater decrease in both suicidal thinking and depression. More severe mental health symptoms were associated with less decrease in depression symptoms but not with suicidal ideation trajectory. 4 Conclusion Class membership across the two outcomes and predictors of class membership were found to be largely independent. The lack of coupling in trajectories and predictors suggests that changes in suicidal thinking may occur independently of changes in depression.
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Background Research suggests that mindfulness-based interventions may improve mindfulness-related capacities (e.g., decentering, non-judging, and non-reacting) and emotion regulation. Previously, our group reported that ayahuasca could be a potential analogue of mindfulness practice. The main aim of the current study was to examine the effects of ayahuasca on emotional regulation and mindfulness-related capacities. Secondarily, we sought to explore the effects of ayahuasca on individuals with borderline personality disorder (BPD) traits. Method This is an observational study of 45 volunteers who participated in an ayahuasca session. The volunteers completed various self-report instruments designed to measure emotional dysregulation (Difficulties in Emotion Regulation Scale (DERS)) and mindfulness traits (Five Facet Mindfulness Questionnaire (FFMQ)–Short Form and Experiences Questionnaire (EQ)) prior to and 24 h after the ayahuasca session. The volunteers were divided into two subgroups based on their score on the McLean Screening Instrument for BPD (MSI-BPD). Twelve participants were grouped into the BPD-like traits subgroup while the rest of them were included in the non-BPD-like subgroup. We performed within-subjects and between-group analyses. Results Overall, the participants showed significant improvements on the FFMQ subscales observing, acting with awareness, non-judging, and non-reacting and also significantly improved on decentering (EQ scale) and on the DERS subscales emotional non-acceptance, emotional interference, and lack of control. The BPD-like subgroup also showed significant improvements on the DERS subscales emotional interference and lack of control but not in mindfulness capacities. Conclusions These findings suggest a potential therapeutic effect for ayahuasca in emotion regulation and mindfulness capacities (including decentering, acceptance, awareness, and sensitivity to meditation practice). Based on these results, we believe that ayahuasca therapy could be of value in clinical populations, such as individuals with BPD, affected by emotion dysregulation.
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Background/aims: Given high rates of depression and suicide among marginalized women, and increasing calls to integrate trauma-informed biomedical and community-led structural interventions, this study longitudinally examines the potential moderating effect of psychedelic use on the relationship between other illicit drug use and suicide risk. Methods: Data (2010-2017) were drawn from a community-based, prospective open cohort of marginalized women in Vancouver, Canada. Extended Cox regression analyses examined the moderating effect of psychedelic use on the association between other illicit drug use and incidence of suicidal ideation or attempt over follow-up. Results: Of 340 women without suicidal ideation or attempt at baseline, 16% ( n=53) reported a first suicidal episode during follow-up, with an incidence density of 4.63 per 100 person-years (95% confidence interval 3.53-6.07). In unadjusted analysis, psychedelic use moderated the relationship between prescription opioid use and suicide risk: among women who did not use psychedelics, prescription opioid use increased the hazard of suicide (hazard ratio 2.91; 95% confidence interval 1.40-6.03) whereas prescription opioid use was not associated with increased suicidal ideation or attempt among those who used psychedelics (hazard ratio 0.69; 95% confidence interval 0.27-1.73) (interaction term p-value: 0.016). The moderating effect of psychedelics remained significant when adjusted for confounders (interaction term p-value: 0.036). Conclusions: Psychedelic use had a protective moderating effect on the relationship between prescription opioid use and suicide risk. In the context of a severe public health crisis around prescription opioids and lack of addiction services tailored to marginalized women, this study supports calls for innovative, evidence-based and trauma-informed interventions, including further research on the potential benefits of psychedelics.
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In this review, we will discuss the safety of repeated treatments with ketamine for patients with treatment-resistant depression (TRD), a condition in which patients with major depression do not show any clinical improvements following treatments with at least two antidepressant drugs. We will discuss the effects of these treatments in both sexes at different developmental periods. Numerous small clinical studies have shown that a single, low-dose ketamine infusion can rapidly alleviate depressive symptoms and thoughts of suicidality in patients with TRD, and these effects can last for about one week. Interestingly, the antidepressant effects of ketamine can be prolonged with intermittent, repeated infusion regimens and produce more robust therapeutic effects when compared to a single infusion. The safety of such repeated treatments with ketamine has not been thoroughly investigated. Although more studies are needed, some clinical and preclinical reports indicated that repeated infusions of low doses of ketamine may have addictive properties, and suggested that adolescent and adult female subjects may be more sensitive to ketamine's addictive effects. Additionally, during ketamine infusions, many TRD patients report hallucinations and feelings of dissociation and depersonalization, and therefore the effects of repeated treatments of ketamine on cognition must be further examined. Some clinical reports indicated that, compared to women, men are more sensitive to the psychomimetic effects of ketamine. Preclinical studies extended these findings to both adolescent and adult male rodents and showed that male rodents at both developmental periods are more sensitive to ketamine's cognitive-altering effects. Accordingly, in this review we shall focus our discussion on the potential addictive and cognitive-impairing effects of repeated ketamine infusions in both sexes at two important developmental periods: adolescence and adulthood. Although more work about the safety of ketamine is warranted, we hope this review will bring some answers about the safety of treating TRD with repeated ketamine infusions.
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Introduction: Mood, anxiety, and substance use disorders are among the most prevalent psychiatric disorders in the population. Although several pharmacological treatments are available, they are not effective for a significant proportion of patients and are associated with several adverse reactions. Therefore, new treatments should be explored. Recent with serotonergic hallucinogens/psychedelics including ayahuasca, psilocybin and lysergic acid diethylamide (LSD) suggest that these drugs have anxiolytic, antidepressive, and antiaddictive effects. Areas Covered: A systematic review of systematic reviews assessing the efficacy, safety, and tolerability of serotonergic hallucinogens/psychedelic was performed using the PubMed data base until 11 April 2018. Systematic reviews with or without meta-analysis were analyzed, but only reviews that described at least one randomized controlled trial (RCT) were included. Expert Commentary: Psilocybin and LSD reduced anxiety and depression in cancer patients and symptoms of alcohol and tobacco dependence, and ayahuasca reduced depression symptoms in treatment-resistant depression. Although the results are promising, several studies were open-label and only few were RCTs, and most had small sample sizes and a short duration. Single or few doses of these drugs seem to be well tolerated, but long-term studies are lacking. New RCTs with bigger samples and longer duration are needed to replicate these findings.
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Rationale Ayahuasca is a psychotropic plant tea from South America used for religious purposes by indigenous people of the Amazon. Increasing evidence indicates that ayahuasca may have therapeutic potential in the treatment of mental health disorders and can enhance mindfulness-related capacities. Most research so far has focused on acute and sub-acute effects of ayahuasca on mental health-related parameters and less on long-term effects. Objectives The present study aimed to assess sub-acute and long-term effects of ayahuasca on well-being and cognitive thinking style. The second objective was to assess whether sub-acute and long-term effects of ayahuasca depend on the degree of ego dissolution that was experienced after consumption of ayahuasca. Results Ayahuasca ceremony attendants (N = 57) in the Netherlands and Colombia were assessed before, the day after, and 4 weeks following the ritual. Relative to baseline, ratings of depression and stress significantly decreased after the ayahuasca ceremony and these changes persisted for 4 weeks. Likewise, convergent thinking improved post-ayahuasca ceremony up until the 4 weeks follow-up. Satisfaction with life and several aspects of mindfulness increased the day after the ceremony, but these changes failed to reach significance 4 weeks after. Changes in affect, satisfaction with life, and mindfulness were significantly correlated to the level of ego dissolution experienced during the ayahuasca ceremony and were unrelated to previous experience with ayahuasca. Conclusion It is concluded that ayahuasca produces sub-acute and long-term improvements in affect and cognitive thinking style in non-pathological users. These data highlight the therapeutic potential of ayahuasca in the treatment of mental health disorders, such as depression.
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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, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. 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 placebo at all-time points. MADRS scores were significantly lower in the ayahuasca group compared 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's d = 0.84; D2: Cohen's d = 0.84; D7: Cohen's d = 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 (NCT02914769).
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Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.