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Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report

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  • Ribeirão Preto Medical School, University of São Paulo, Brazil

Abstract and Figures

Ayahuasca (AYA), a natural psychedelic brew prepared from Amazonian plants and rich in dimethyltryptamine (DMT) and harmine, causes effects of subjective well-being and may therefore have antidepressant actions. This study sought to evaluate the effects of a single dose of AYA in six volunteers with a current depressive episode. Open-label trial conducted in an inpatient psychiatric unit. Statistically significant reductions of up to 82% in depressive scores were observed between baseline and 1, 7, and 21 days after AYA administration, as measured on the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Anxious-Depression subscale of the Brief Psychiatric Rating Scale (BPRS). AYA administration resulted in nonsignificant changes in Young Mania Rating Scale (YMRS) scores and in the thinking disorder subscale of the BPRS, suggesting that AYA does not induce episodes of mania and/or hypomania in patients with mood disorders and that modifications in thought content, which could indicate psychedelic effects, are not essential for mood improvement. These results suggest that AYA has fast-acting anxiolytic and antidepressant effects in patients with a depressive disorder.
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ORIGINAL ARTICLE
Antidepressant effects of a single dose of ayahuasca in
patients with recurrent depression: a preliminary report
Fla´via de L. Oso´rio,
1,2
Rafael F. Sanches,
1,3
Ligia R. Macedo,
1
Rafael G. dos Santos,
1
Joa˜ o P. Maia-de-Oliveira,
4
Lauro Wichert-Ana,
1
Draulio B. de Araujo,
5,6
Jordi Riba,
3,7,8,9
Jose´ A. Crippa,
1,2
Jaime E. Hallak
1,2
1
Department of Neurosciences and Behavior, Ribeira˜ o Preto Medical School, Universidade de Sa˜o Paulo (USP), Ribeira˜o Preto, SP, Brazil.
2
National Science and Technology Institute for Translational Medicine (INCT-TM), Brazil.
3
Centre d’Investigacio´ de Medicaments, Servei de
Farmacologia Clı´nica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
4
Department of Clinical Medicine, Universidade Federal do Rio
Grande do Norte (UFRN), Natal, RN, Brazil.
5
Hospital Universita´ rio Onofre Lopes, UFRN, Natal, RN, Brazil.
6
Brain Institute, UFRN, Natal, RN,
Brazil.
7
Human Experimental Neuropsychopharmacology, Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
8
Department of Pharmacology and Treatment, Universitat Auto`noma de Barcelona, Spain.
9
Centro de Investigacio´ n Biome´ dica en Red de
Salud Mental, CIBERSAM, Barcelona, Spain.
Objectives: Ayahuasca (AYA), a natural psychedelic brew prepared from Amazonian plants and rich
in dimethyltryptamine (DMT) and harmine, causes effects of subjective well-being and may therefore
have antidepressant actions. This study sought to evaluate the effects of a single dose of AYA in six
volunteers with a current depressive episode.
Methods: Open-label trial conducted in an inpatient psychiatric unit.
Results: Statistically significant reductions of up to 82% in depressive scores were observed between
baseline and 1, 7, and 21 days after AYA administration, as measured on the Hamilton Rating Scale
for Depression (HAM-D), the Montgomery-A
˚sberg Depression Rating Scale (MADRS), and the
Anxious-Depression subscale of the Brief Psychiatric Rating Scale (BPRS). AYA administration
resulted in nonsignificant changes in Young Mania Rating Scale (YMRS) scores and in the thinking
disorder subscale of the BPRS, suggesting that AYA does not induce episodes of mania and/or
hypomania in patients with mood disorders and that modifications in thought content, which could
indicate psychedelic effects, are not essential for mood improvement.
Conclusions: These results suggest that AYA has fast-acting anxiolytic and antidepressant effects in
patients with a depressive disorder.
Keywords: Psychedelic agents; dimethyltryptamine; harmine; monoamine oxidase inhibitors;
therapeutic use
Introduction
Depression is a highly prevalent disorder andis associated
with intense personal suffering, increased mortality, and
high morbidity.
1,2
Although its etiology is unknown, some
theories suggest that biological factors may be implicated.
3
One such theory is the monoamine hypothesis, which
suggests that an imbalance in cerebral monoamines such
as dopamine, norepinephrine, and, especially, serotonin is
responsible for depressive symptomatology.
3
The mono-
amine hypothesis is the theory on which the leading
commercially available antidepressants are based.
3
Currently available treatments have limitations that can
lead to low therapeutic effectiveness, especially related to
low response rates, as well as adverse effects and
latency to onset of therapeutic action.
3
Thus, new
interventions, particularly those that with the potential
for acute effect, would have a huge impact on the
treatment of depression. The N-methyl-D-aspartate
(NMDA) receptor antagonist ketamine, for example, has
rapid and potent antidepressant effects in treatment-
resistant major depressive disorder (MDD) and bipolar
depression, and its use is considered one of the most
exciting areas in contemporary psychiatric research.
4,5
Ayahuasca (AYA), a botanical hallucinogen tradition-
ally used by indigenous groups of the Northwest Amazon
region for ritual and medicinal purposes,
6,7
is a potential
candidate for this new generation of antidepressant
research focusing on new pharmacological treatments
that produce immediate and more pronounced effects.
AYA is prepared by prolonged decoction of the bark of the
vine Banisteriopsis caapi with the leaves of the shrub
Psychotria viridis.
6,7
B. caapi contains the b-carboline
alkaloids harmine, tetrahydroharmine (THH), and harma-
line, which act as monoamine oxidase A inhibitors
Correspondence: Jaime E. C. Hallak, Departamento de Neurocieˆncias
e Cieˆ ncias do Comportamento, Faculdade de Medicina de Ribeira˜o
Preto, Universidade de Sa˜ o Paulo, Hospital das Clı´nicas, 36andar,
Av. Bandeirantes, 3900, Ribeira˜o Preto, SP, Brazil.
E-mail: jhallak@fmrp.usp.br
Submitted Jun 20 2014, accepted Aug 08 2014.
Revista Brasileira de Psiquiatria. 2015;37:13–20
ß2015 Associac¸a˜ o Brasileira de Psiquiatria
doi:10.1590/1516-4446-2014-1496
(MAOI), while P. viridis is rich in the psychedelic
tryptamine N, N-dimethyltryptamine (DMT).
6,8-11
The psychoactive effects of AYA are produced by a
combined action of peripheral (gastrointestinal and liver)
monoamine oxidase A (MAO-A) inhibition by harmine and
central 5-HT
1A/2A/2C
agonist action of DMT on frontal and
paralimbic brain areas.
8,9,12
Studies conducted among
long-term (i.e., years or decades) members of religious
groups that use AYA ritually suggest that this population
does not present evidence of psychological, neuropsy-
chological, or psychiatric harm caused by AYA.
13-15
In
fact, there are several reports describing reduced mental
health problems in AYA users.
13-15
Nevertheless, given
the small number of studies, most with a limited number
of participants, there is insufficient information to allow a
definitive conclusion on this topic, and more studies on
the potential long-term toxicity of AYA are required.
An increasing number of studies report antidepressive
potential for AYA alkaloids in animals.
16-24
Furthermore,
a double-blind, placebo-controlled animal study reported
reduced hopelessness and panic-related signs after
acute AYA administration,
25
and preliminary data in
humans also support an antidepressive action for AYA.
26
The agonist action of AYA alkaloids on serotonergic
receptors and its inhibitory effects on MAO-A, associated
with field and laboratory evidence suggesting that AYA
causes a sensation of well-being, led to the hypothesis
that this substance could be useful in the treatment of
depression in humans. Thus, the objective of the present
preliminary, open-label study was to evaluate the acute
effects of a single dose of AYA in patients diagnosed with
depression and to test whether AYA administration could
produce an acute antidepressant effect.
Methods
Volunteers
Six volunteers (two men and four women, mean age
44.16613.55 years) with a diagnosis of recurrent MDD
participated in the study. Within this group, two volunteers
were experiencing a current mild depressive episode,
three were experiencing a moderate episode, and one
was experiencing a severe depressive episode. None of
the volunteers were experiencing depressive episodes
with psychotic symptoms.
Participants were recruited through local advertise-
ments and by referrals from private psychiatric clinics.
Volunteers were not taking any psychopharmaceuticals
at the time of recruitment; they were patients that did not
exhibit a significant therapeutic response to their latest
medication and were in the process of switching to a new
agent. Patients participated in the study before the
introduction of the new medication.
None of the participants had ever used illicit drugs or
AYA, as assessed by a medical interview, and had no
evidence of current clinical conditions or pregnancy, as
assessed by medical interview, physical examination,
and laboratory tests. A diagnosis of bipolar disorder and
a previous history of mania or hypomania induced by
antidepressants/substance use were considered exclu-
sion criteria.
The study was conducted in accordance with the
Declarations of Helsinki and Tokyo concerning human
subject research and approved by the Research Ethics
Committee of Hospital das Clı´nicas da Faculdade de
Medicina de Ribeira˜ o Preto da Universidade de Sa˜o
Paulo, Ribeira˜ o Preto, state of Sa˜ o Paulo, Brazil (HC-RP
process no. 2484/2008). The volunteers received detailed
information on the nature of AYA, the general psycholo-
gical effects of hallucinogens, and its possible adverse
effects, as reported in the psychiatric literature. All volunteers
gave their written informed consent to participate.
Drug
We obtained a standard sample of AYA prepared by
members of the Santo Daime community, consisting of the
stalks of B. caapi (rich in harmine, THH, and harmaline)
combined with the washed leaves of P. viridis (rich in
DMT), boiled and concentrated for several hours. The
resulting brew was stored in plastic bottles at room
temperature at the Santo Daime community and sub-
sequently in a refrigerator in the Department of
Neurosciences and Behavior, Ribeira˜ o Preto Medical
School, Universidade de Sa˜o Paulo, Ribeira˜ o Preto,
Brazil. AYA was stored under refrigeration until the day
of the experimental session. All AYA used in the present
study was from this original batch.
Each subject drank 120-200 mL of AYA (2.2 mL/kg
body weight). The AYA batch used in the experiment
contained 0.8 mg/mL DMT, 0.21 mg/mL harmine, and no
harmaline at the chromatography detection threshold of
0.02 mg/mL. To quantify the content of each alkaloid, a
1-mL sample of AYA was homogenized with sodium
acetate buffer solution (pH = 9), extracted with 5 mL
diethyl ether in a shaker (20 min), and centrifuged at
3,000 rpm for 15 min. The organic phase was collected
and evaporated under a nitrogen stream. The residue
was dissolved in 1 mL methanol and 1 mL of the resulting
solution was analyzed by gas chromatography/mass
spectrometry (GC/MS), performed using a Varian
CP3800 gas chromatograph coupled to a Varian Saturn
2000 ion trap mass spectrometer (Varian Inc.). A capillary
column (DB-5MS, 30 m 60.25 mm i.d. 60.25 mm film
thickness; Agilent) was used. The chromatographic
conditions were as follows: injector temperature 2506C
in splitless mode and oven temperature program 806C for
1 min, ramped at 56C/min to 2206C and held for 10 min,
and then to 3006C for 5 min. Helium at a flow rate of 0.8
mL/min was used as carrier gas.
Medical interview and laboratory tests
A general clinical examination; a laboratory workup
consisting of a complete blood cell count; evaluation of
blood glucose levels; measurement of plasma sodium
and potassium, urea, creatinine, urinary beta-HCG (in
women of childbearing age), bilirubin, and liver enzymes;
and an electrocardiogram were performed.
FL Oso´rio et al.14
Rev Bras Psiquiatr. 2015;37(1)
Psychometric instruments
Structured Clinical Interview for DSM-IV (SCID-IV)
This interview was used to assess whether potential
patients met the inclusion and exclusion criteria.
27,28
Brief Psychiatric Rating Scale (BPRS)
This clinician-administered scale was used to evaluate
four symptom dimensions: 1) Withdrawal-Retardation;
2) Thinking Disorder; 3) Anxious-Depression; and
4) Activation.
29,30
Young Mania Rating Scale (YMRS)
This clinician-administered scale was used to assess
manic symptoms.
31,32
Hamilton Rating Scale for Depression (HAM-D)
This clinician-administered scale was used to assess and
quantify depressive symptoms in patients with a previous
diagnosis of mood disorder.
33,34
Montgomery-A
˚sberg Depression Rating Scale (MADRS)
This clinician-administered scale was used to assess the
severity of depressive symptoms.
34,35
Assessment of tolerability
Systolic blood pressure (SBP) and diastolic blood
pressure (DBP) were measured at the following time
points: 10 minutes (-10) before AYA administration
(baseline) and 40 min (+40), 80 min (+80), 140 min
(+140), and 180 min (+180) after AYA administration.
Blood pressure was measured using a mercury sphyg-
momanometer (Becton Dickinson, Brazil).
Adverse effects were not systematically assessed.
Dysphoric effects were recorded by means of sponta-
neous verbal reports.
Experimental procedure
Volunteers were admitted to an inpatient psychiatric unit
for 2 weeks prior to AYA administration as part of an
open-label trial. During this time, volunteers were not
under the influence of any psychiatric medication or
recreational drugs. The experimental session, which was
performed individually, lasted on average 4 h and
consisted of AYA intake followed by administration of
the scales. During measurements, volunteers remained
seated in a comfortable recliner in a quiet, dimly lit room.
After the end of the session, patients remained under
observation for 24 h; if no complications were observed,
they were discharged.
The BPRS, YMRS, HAM-D and MADRS scales were
completed by a psychiatrist with clinical experience and
training in the use of these scales, at the following time
points: 10 minutes (-10) before AYA administration
(baseline); 40 min (+40), 80 min (+80), 140 min (+140),
and 180 min (+180) after AYA administration; and on
days 1 (D1), 7 (D7), 14 (D14), and 21 (D21) after AYA
administration.
Data analysis
After verification of data distribution, descriptive statistics
and repeated-measures analysis of variance (ANOVA)
were used for statistical analysis. Significance was set at
p,0.05.
Results
The clinical and demographic characteristics of the study
participants are presented in Table 1.
Regarding depressive symptoms, the average baseline
HAM-D score of the volunteers was 17.5667.73, which
was classified according to the scale guidelines as a
moderate level of depression. At D1, there was a 62%
decrease in the mean score, which was statistically
significant (p = 0.01) (Figures 1 and 2). This decrease
was even more pronounced by D7 (72%, p = 0.01).
However, on D14, the level of symptoms increased, and
although the symptom score remained 45% below base-
line, this difference was not statistically significant (p =
0.11). On D21, there was a further significant decrease in
depressive symptoms (p = 0.01). The greatest score
changes were observed for items related to depressed
mood, feelings of guilt, suicidal ideation, and difficulties at
work/activities, i.e., those associated with typical depres-
sive symptoms.
Regarding MADRS scores, results were similar to
those observed for the HAM-D scale. The average
baseline score of the volunteers was 23.5611.14 points.
At +180, there was a significant decrease in MADRS
scores (38%, p = 0.01) (Figures 1 and 3). On D1, a more
robust decrease was observed (p = 0.003), and the
average score on D7 was 82% below baseline (p =
0.009). On D14, a significant increase in symptoms was
observed (p = 0.001), although a subsequent significant
decrease occurred on D21 (p = 0.002). As observed with
the HAM-D scale, the most significant score changes
were observed for items related to apparent and
Table 1 Clinical and demographic characteristics of patients with recurrent major depressive disorder (n=6)
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
Age (years)/sex 47/female 61/female 28/female 58/male 31/female 36/male
Severity of current depressive episode Moderate Mild Severe Mild Moderate Moderate
HAM-D score 16 11 29 7 20 20
MADRS score 18 16 39 9 27 32
HAM-D = Hamilton Rating Scale for Depression; MADRS = Montgomery-A
˚sberg Depression Rating Scale.
Antidepressant effects of ayahuasca 15
Rev Bras Psiquiatr. 2015;37(1)
expressed sadness, pessimistic thinking, suicidal idea-
tion, and difficulty concentrating.
Regarding the BPRS scale, volunteers were generally
asymptomatic on the withdrawal-retardation (BPRS-WR),
thinking disorder (BPRS-TD), and activation (BPRS-A)
subscales at baseline (Figure 4). AYA administration
produced nonsignificant increases in the scores of these
subscales, with effect peaking at 80 min. After this time
point, scores decreased and returned to baseline at 180
min. Generally, the symptoms expressed referred to
disorientation/confusion, conceptual disorganization, psy-
chomotor retardation, and emotional withdrawal. Although
nonsignificant, the increase in the scores of these sub-
scales at 80 min after AYA administration suggests that
AYA produced mild psychoactive effects.
On the Anxious-Depression BPRS subscale (BPRS-
AD), volunteers demonstrated higher scores at baseline,
likely due to the presence of depressed mood, feelings of
guilt, and psychic anxiety, which are typical symptoms of
the underlying psychopathology. Throughout the experi-
ment, the presence of these symptoms varied, but values
remained lower as compared to baseline. At +140, these
symptoms were significantly reduced (p = 0.02) and
remained so (72% below baseline) until D7, when they
began to increase but still remained significantly lower
than baseline values (Figure 4).
Regarding the YMRS scale, volunteers exhibited no
significant changes in symptoms throughout the experi-
ment (Figure 1). However, irritability and decreased
capacity for insight and sleep were more prevalent during
the first 80 minutes following AYA administration, which
was likely associated with the peak period of the sub-
jective effects of AYA.
AYA was well tolerated by all patients. With the
exception of vomiting, volunteers did not spontaneously
report any other adverse effect. Volunteers considered the
effects of AYA on thought content and sensory perception
mild and short-lived, and none reported dysphoric mani-
festations associated with the psychoactive effects of AYA.
Blood pressure increased moderately and nonsignificantly
(Table 2).
Vomiting was reported by 50% of the volunteers.
However, patients were informed before the experimental
session that AYA could induce vomiting, and this emetic
Figure 1 Temporal distribution of scores (means from six volunteers) on the Hamilton Rating Scale for Depression (HAM-D),
Montgomery-A
˚sberg Depression Rating Scale (MADRS), and Young Mania Rating Scale (YMRS). HAM-D: *p,0.05;
MADRS:
{
p,0.05,
{
p,0.01. Error bars denote one standard error of the mean.
Figure 2 Temporal distribution of individual scores on the Hamilton Rating Scale for Depression (HAM-D) (n=6).
FL Oso´rio et al.16
Rev Bras Psiquiatr. 2015;37(1)
effect was considered by patients as an integral part of
the effects produced by AYA. Patients did not consider
vomiting as causing severe discomfort.
Discussion
The results of the present investigation demonstrate that
AYA has significant and quite impressive acute antide-
pressive effects. Score reductions were observed in both
the HAM-D and MADRS scales on D1 and D7, and these
effects lasted for several days. It is noteworthy that these
changes showed a profile that was very similar across
volunteers, regardless of the prior level of depression, i.e.,
the severity of the current depressive episode. The
antidepressant potential of AYA was previously demon-
strated in a study that reported a decrease in hope-
lessness symptoms after acute AYA intake.
25
The average time necessary for the onset of therapeu-
tic action of commercially available antidepressants is
2 weeks.
3
Considering currently available medications,
the fast antidepressant action of AYA is promising, as it
may provide faster reductions in depressive symptoms.
Moreover, the antidepressant effects of AYA alkaloids
may inspire a new area of depression research.
Interestingly, symptoms increased on D14 as measured
by the HAM-D and MADRS scales, although a subsequent
significant decrease occurred on D21 in both scales.
Although increased, HAM-D scores still remained 45%
below baseline values, but this difference was nonsignifi-
cant. On the other hand, MADRS scores on D14 were
significantly increased.
The decreases and increases in depressive symptoms
after AYA administration could reflect complex intracellular
events that remain active after the acute effects of AYA
have subsided. The acute antidepressive effects of keta-
mine, for instance, may be sustained for weeks to months
and are associated with increased synaptogenesis and
spine formation, which seem to be related with increases in
brain-derived neurotrophic factor (BDNF) protein levels.
4,5
Studies conducted in rodents by our group and by others
using doses of 10-15 mg/kg harmine have demonstrated
antidepressive effects for this compound, which were
associated with increases in BDNF levels.
17,19,21
Furthermore, harmine, THH, and harmaline are potent
natural, selective, reversible, and competitive inhibitors of
Figure 3 Temporal distribution of individual scores on the Montgomery-A
˚sberg Depression Rating Scale (MADRS) (n=6).
Figure 4 Temporal distribution of scores (means from six volunteers) on the Brief Psychiatric Rating Scale (BPRS) subscales
(WR = Withdrawal-Retardation; TD = Thinking Disorder; AD = Anxious-Depression; and A = Activation). *p,0.05. Error bars
denote one standard error of the mean.
Antidepressant effects of ayahuasca 17
Rev Bras Psiquiatr. 2015;37(1)
the MAO enzyme, especially of the MAO-A subtype.
9,36
THH acts as a selective serotonin reuptake inhibitor as
well as an MAOI.
9,37
Inhibition of both systems –
MAO
and serotonin reuptake –
may result in elevated levels of
brain serotonin and other monoamines, producing anti-
depressant effects.
9,25,38
The statistically significant reductions in BPRS-AD
scores from D1 to D21 suggest that AYA produced anti-
depressive and anxiolytic effects. A previous study
reported decreased panic-related signs after acute AYA
intake.
25
AYA administration did not produce statistically sig-
nificant sensory, cognitive, or affective modifications as
assessed by the BPRS and YMRS scales. Although
nonsignificant, in the present study these effects were
observed during a period ranging from 80 to 140 min after
AYA administration, which is the time point when the
subjective effects of AYA are peaking, as are DMT
plasma levels.
8-12
The absence of statistically significant effects on
BPRS-TD scores could be explained by the DMT con-
centration found in our AYA batch (0.08 mg/mL), which is
lower than DMT doses used in previous studies that
reported significant psychotropic effects of AYA (0.53 mg/
mL DMT).
9,12
The nonsignificant effects of AYA on the
BPRS-TD subscale suggest that changes in sensory
perception and thought content may not be essential for
therapeutic effects.
AYA was well tolerated by all patients, suggesting that
it can be safely administered to depressed patients. This
result corroborates previous studies reporting a good
tolerability profile for AYA administration to healthy
volunteers.
8-12,15,25,39
In the present study, the psychoac-
tive effects of AYA were considered by participants as
mild and short-lived, corroborating the nonsignificant
effect of AYA on the BPRS-TD subscale. The nonsigni-
ficant increases in blood pressure replicate previous
findings in human studies suggesting that AYA produces
moderate cardiovascular effects.
8-12,15,25,39
Early academic research on classical hallucinogens
was designed considering the powerful influences of set
(psychological state) and setting (environment) on the
effects of this class of substances.
40
Considering this
background, in the present study volunteers were kept as
comfortable as possible, remaining seated in a recliner
in a quiet, dimly lit room throughout the experimental
session. Investigator interference was minimal, allowing
patients to concentrate on the effects of AYA. This safe
environment may have reduced the probability of
dysphoric reactions.
40
Vomiting was the only adverse effect reported by
volunteers (50%). Patients were informed before the
experimental session that vomiting was a possible effect
of AYA, as nausea and vomiting are the most frequently
reported adverse effects in clinical trials of acute AYA
administration.
8-12,15,39
In the present study, vomiting
apparently did not have a significant influence on the
antidepressive effects of AYA. Patients did not consider
this emetic effect to be a severe discomfort, a result that
is in line with previous studies of acute AYA administra-
tion to healthy volunteers, which reported that most
participants regarded their AYA experience as pleasant
despite the occurrence of vomiting.
8-12,15,39
In future studies, it would be interesting to try to reduce
the emetic effect of AYA by premedicating with an
antiemetic. However, this possibility should be explored
with caution, considering that AYA alkaloids could interact
with antiemetic drugs. Another possibility could be to
administer AYA in different formulations. Freeze-dried
AYA appears to produce less vomiting than oral
AYA.
8,11,15,39
Interestingly, variable degrees of nausea,
vomiting, and, occasionally, simultaneous diarrhea are
common in AYA rituals. In these contexts, however, these
purgative effects are considered positive and cleansing.
7
Important limitations of the present open-label study
include the small sample size, the absence of a
systematic inquiry about side effects, and the lack of
placebo and control groups. Although patients did not
spontaneously report adverse effects other than vomiting,
the lack of a systematic assessment of adverse effects
may have reduced the likelihood of registering more
subtle effects, such as impacts on cognition. Future
studies should assess the possible adverse effects of
AYA in clinical populations by using other subjective
measures, such as visual analogue scales and other
scales that measure hallucinogenic effects, and by
exploring other variables that could be modified by AYA
administration as reported in previous studies, such as
neuropsychological, neurophysiological, autonomic, neu-
roendocrine, and immunological parameters.
8,10,11,14,15
Ideally, future studies involving AYA and depressed
patients or other clinical populations should also be
designed to include a control group. This group could
receive a placebo, a comparator drug with an established
therapeutic indication, or AYA preceded by pretreatment
with a 5-HT
2A
receptor antagonist to investigate possible
Table 2 Systolic/diastolic blood pressure measurements in patients with recurrent major depressive disorder (n=5)*
Mean 6SD Median Minimum Maximum
SBP (baseline) 118614.83 120 100 140
SBP (140 min) 119623.02 120 85 150
DBP (baseline) 79.469.31 80 70 90
DBP (140 min) 76.4613.74 80 60 90
HR (baseline) 78611.48 78 68 96
HR (140 min) 72.267.69 70 64 84
DBP = diastolic blood pressure; HR = heart rate; SBP = systolic blood pressure; SD = standard deviation.
*Data missing for one patient.
The 140-min time point was chosen because the subjective effects of AYA peak around this time, as do DMT plasma levels.
8-12
All blood
pressure values expressed in mmHg. HR values expressed in beats per minute.
FL Oso´rio et al.18
Rev Bras Psiquiatr. 2015;37(1)
mechanisms of action. Regarding the small number of
patients, additional studies with larger sample sizes and
using neuroimaging techniques (single photon emission
tomography, SPECT) are underway in our laboratory.
The aforementioned limitations should be considered
taking into account the novelty of this research and
its preliminary nature. To our knowledge, the use of AYA
in a controlled clinical setting in patients with current
depression –
or in any other clinical population –
has
never been investigated. Moreover, the results of the
present study, although preliminary, are corroborated
by mounting research showing antidepressive potentials
for AYA alkaloids in nonhuman animals
16-24
and in
humans.
13,25,26
Finally, the reported results may prompt novel research
into substances with faster therapeutic actions than
currently available pharmacological resources, thus mak-
ing antidepressive treatment more effective.
The findings of this preliminary study demonstrate the
potential antidepressant and anxiolytic effects of AYA,
effects that, importantly, have an earlier onset of action
when compared to traditional antidepressants. These
findings suggest that AYA may represent a powerful new
substance for the treatment of depressive and anxiety
symptoms. However, these results deserve careful
analysis, given the inherent limitations of an uncontrolled,
open-label study with a small sample size. Other studies
are needed to replicate these preliminary observations
and to test, for example, the most effective dose (or
doses) of AYA and the safety, tolerability, and effective-
ness of AYA administration over a longer period of time.
Acknowledgements
This study was conducted at the Department of
Neurosciences and Behavior, Ribeira˜ o Preto Medical
School, Universidade de Sa˜ o Paulo, Ribeira˜ o Preto,
Brazil. RFS is a Fellow of the Science without Borders
Program, Brazil (process no. 245447/2012-1).
Disclosure
The authors report no conflicts of interest.
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20
Rev Bras Psiquiatr. 2015;37(1)
... A decades-long hiatus on clinical trial research with psychedelic ended in 2006 (Moreno et al., 2006). Since then, supportive evidence for psychedelicassisted therapy has begun to accrue promising results, particularly in the treatment of depressive and anxiety symptoms and disorders (Barbosa et al., 2016;Carhart-Harris et al., 2017Davis et al., 2021a;Gasser et al., 2014;Griffiths et al., 2016;Grob et al., 2011;Moreno et al., 2006;Osório et al., 2015;Palhano-Fontes et al., 2019;Ross et al., 2016;Sanches et al., 2016). Notably, improvements in symptom severity have been observed several months after just one or two isolated doses of the drug Davis et al., 2021a;Gasser et al., 2014;Griffiths et al., 2016;Grob et al., 2011). ...
... These trials were of a period prior to the establishment of validated measures and quantitative response criteria, but more recent experimental and cross-sectional studies have lent support to the merits of psychedelic therapy for depression, with two notable recent controlled trials finding response rates exceeding 70% (Carhart-Harris et al., 2021a;Davis et al., 2021a). These trials supplement a number of lab-based experimental studies conducted in the last 10 years that have found consistent positive results in favour of the therapeutic potential of psychedelic therapy for treating symptoms of depression and anxiety (Carhart-Harris et al., 2016a, 2017Davis, Barrett and May, 2021;Gasser et al., 2014;Grob et al., 2011;Griffiths et al., 2016;Osório et al., 2015;Ross et al., 2016;Sanches et al., 2016;Watts et al., 2017). Specifically, controlled trials involving both inert and active comparators, such as first-line standard of care (an SSRI course) plus psychological support in one recent trial (Carhart-Harris et al., 2021a), serve to highlight the robust and reliable antidepressant and anxiolytic effects of psychedelic therapy. ...
Article
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Background Over the last two decades, a number of studies have highlighted the potential of psychedelic therapy. However, questions remain to what extend these results translate to naturalistic samples, and how contextual factors and the acute psychedelic experience relate to improvements in affective symptoms following psychedelic experiences outside labs/clinics. The present study sought to address this knowledge gap. Aim Here, we aimed to investigate changes in anxiety and depression scores before versus after psychedelic experiences in naturalistic contexts, and how various pharmacological, extrapharmacological and experience factors related to outcomes. Method Individuals who planned to undergo a psychedelic experience were enrolled in this online survey study. Depressive symptoms were assessed at baseline and 2 and 4 weeks post-psychedelic experience, with self-rated Quick Inventory of Depressive Symptomatology (QIDS-SR-16) as the primary outcome. To facilitate clinical translation, only participants with depressive symptoms at baseline were included. Sample sizes for the four time points were N = 302, N = 182, N = 155 and N = 109, respectively. Results Relative to baseline, reductions in depressive symptoms were observed at 2 and 4 weeks. A medicinal motive, previous psychedelic use, drug dose and the type of acute psychedelic experience (i.e. specifically, having an emotional breakthrough) were all significantly associated with changes in self-rated QIDS-SR-16. Conclusion These results lend support to therapeutic potential of psychedelics and highlight the influence of pharmacological and non-pharmacological factors in determining response. Mindful of a potential sample and attrition bias, further controlled and observational longitudinal studies are needed to test the replicability of these findings.
... AYA (or saline solution) was administered via gavage at a dose of 4 mL/kg [13]. The beverage used is composed of 0.10 mg/mL of HRL, 2.43 mg/mL of HRM, 1.43 mg/mL of THH, and 1.40 mg/mL of DMT. ...
... Besides, groups that received ayahuasca have reduced immobility time, demonstrating the antidepressant potential of the substance. These results reinforce other studies that also demonstrated acute antidepressant effects of AYA, both in animals and in humans, even in the case of treatment-resistant depression [13,26]. Some compounds present in tea, when isolated, also have antidepressant effects, such as the case of harmine, which decreased the immobility time in the forced swimming test in mice through an inverse agonist mechanism located in benzodiazepine receptors [27]. ...
Article
The objective of this study was to evaluate the behavioral response of ayahuasca in rats submitted to neuroinflammation through the intraperitoneal application of lipopolysaccharide (0.63 mg/kg/mL). Eighty animals, male, about 90 days old, were divided into control and LPS groups and later into prevention and treatment subgroups. The prevention subgroup was administered ayahuasca or saline solution, via gavage, at a dose of 4 mL/kg one hour before applying LPS or saline, while the treatment subgroup received the same dose of the respective substances 24 hours after intraperitoneal applications. Behavioral parameters were evaluated using open field (anxiety-like) and forced swimming (depressive-like) tests. A decrease in LPS/AYA rats in the prevention and treatment subgroups regarding anxiety-like behavior was observed. As for the depressive-like behavior, there was a decrease in the group induced to the disease model, both in the prevention subgroup (when compared to the SAL/SAL, SAL/AYA, and LPS/AYA with LPS/SAL groups) and in the treatment (when comparing SAL/SAL and LPS/AYA with LPS/SAL). This study concludes the anxiolytic and antidepressant potential of ayahuasca in an animal model of neuroinflammation, possibly due to the antineuroinflammatory effects already reported of the compound.
... Rich in the alkaloid N,N-dimethyltryptamine (DMT), and β-carbolines β-carboline-independent antidepressantlike effect of the standardized extract of the barks of Mimosa tenuiflora (Willd) Poir. occurs via 5-HT 2A/2C receptors in mice (mainly harmine), this tea-like beverage, in addition to producing visionary effects and changes in perception and senses, has a rapid antidepressant effect, demonstrated through clinical studies in humans (Osório et al., 2015;Sanches et al., 2016). The psychedelic effects of ayahuasca are possible due to the concerted activity between the β-carbolines (enzyme inhibitors-monoamine oxidases A and B-MAO-A and MAO-B) and the DMT. ...
... Furthermore, unlike ayahuasca, which is prepared by cooking its ingredients (Banisteriopsis caapi and Psychotria viridis) (Labate and Araújo, 2002), jurema wine is a cold-prepared tisane (Ott, 2002). These and other observations made about jurema wine and ayahuasca lead us to believe that there are fundamental pharmacological characteristics not shared between these two beverages, despite DMT being present in both (Amariz et al., 2020;Osório et al., 2015). ...
Article
Background Depression is a psychiatric disorder with limited therapy options. Psychedelics are new antidepressant candidates, being the ayahuasca one of the most promising ones. A synergistic combination of N,N-dimethyltryptamine (DMT) and β-carbolines allows ayahuasca antidepressant properties. Another psychedelic and DMT-containing beverage is the jurema wine used religiously by indigenous people from Northeastern Brazil. Aims To evaluate the antidepressant-like effect of standardized extract of Mimosa tenuiflora (SEMT), associated or not with harmine (β-carboline), in behavioral models of depression. Methods The SEMT was submitted to (+) ESI-IT-LC/MS analysis for DMT quantification. To assess the antidepressant-like effect of SEMT, the open field (OFT), tail suspension (TST), and forced swim (FST) tests were performed. To verify the participation of serotonergic systems, the 5-hydroxytryptophan (5-HTP)-induced head twitch test was performed. Results The content of DMT found in SEMT was 24.74 ± 0.8 mg/g. Yuremamine was also identified. SEMT presented an antidepressant-like effect in mice submitted to the TST and FST, independent from harmine, with no significant alterations on the OFT. The sub-dose interaction between SEMT and ketamine also produced an anti-immobility effect in the TST, with no changes in the OFT. SEMT potentiated the head twitch behavior induced by 5-HTP and ketanserin prevented its antidepressant-like effect in the TST ( p < 0.05). Conclusions SEMT presented a harmine-independent antidepressant-like effect in mice submitted to the TST and FST. This effect occurs possibly via activation of serotonergic systems, particularly the 5-HT 2A/2C receptors.
... Remarkably, the sustained positive effects of psychedelics are also observed in clinical populations, particularly in mood disorders. Recent clinical trials testing the effects of the DMT-containing ayahuasca brew or psilocybin for treatmentresistant depression have consistently shown rapid and long-lasting antidepressant effects, typically starting one day after dosing and lasting for at least one week Davis et al., 2020;Osório et al., 2015;Palhano-Fontes et al., 2018;Sanches et al., 2016). ...
... Altogether, our results may help to explain the antidepressant and anxiolytic effects of serotonergic psychedelics Davis et al., 2020;Osório et al., 2015;Palhano-Fontes et al., 2018;Sanches et al., 2016;Winne et al., 2020), which seem to stem at least in part from a boost in synaptogenesis, improving both local and long-range connectivity. The synaptogenesis-stimulating mechanisms triggered by LSD make it one of the most significant promises as a cognitive enhancer (Aday et al., 2020), side by side with delta-9-tetrahydrocannabinol, which also induces synaptic plasticity in the elderly (Bilkei-Gorzo et al., 2017). ...
Article
The therapeutic use of classical psychedelic substances such as d-lysergic acid diethylamide (LSD) surged in recent years. Studies in rodents suggest that these effects are produced by increased neural plasticity, including stimulation of the mTOR pathway, a key regulator of metabolism, plasticity, and aging. Could psychedelic-induced neural plasticity be harnessed to enhance cognition? Here we show that LSD treatment enhanced performance in a novel object recognition task in rats, and in a visuo-spatial memory task in humans. A proteomic analysis of human brain organoids showed that LSD affected metabolic pathways associated with neural plasticity, including mTOR. To gain insight into the relation of neural plasticity, aging and LSD-induced cognitive gains, we emulated the experiments in rats and humans with a neural network model of a cortico-hippocampal circuit. Using the baseline strength of plasticity as a proxy for age and assuming an increase in plasticity strength related to LSD dose, the simulations provided a good fit for the experimental data. Altogether, the results suggest that LSD has nootropic effects.
... 19 Moreover, single-dose ayahuasca administrations have shown a rapid reduction in depressive symptoms in patients with recurrent depression. 21 Recent evidence has pointed to disrupted functional connectivity (FC) within and between higher-order intrinsic connectivity networks (ICNs) in depression. 22 Neuroimaging research has suggested that MDD is characterized by functionally deviant coupling within the central executive network (CEN), default mode network (DMN), and salience network (SN). ...
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Preliminary evidence supports the use of psychedelics for major depressive disorder (MDD). However, less attention has been given to the neural mechanisms behind their effects. We conducted a systematic review examining the neuroimaging correlates of antidepressant response following psychedelic interventions for MDD. Through MEDLINE, Embase, and APA PsycINFO, 187 records were identified and 42 articles were screened. Six published studies and one conference abstract were included. Five ongoing trials were included from subjective outcomesTrials.gov. Our search covered several psychedelics, though included studies were specific to psilocybin, ayahuasca, and lysergic acid diethylamide. Three psilocybin studies noted amygdala activity and functional connectivity (FC) alterations that correlated with treatment response. Two psilocybin studies reported that FC changes in the medial and ventromedial prefrontal cortices correlated with treatment response. Two trials from a single study reported global decreases in brain network modularity which correlated with antidepressant response. One ayahuasca study reported increased activity in the limbic regions following treatment. Preliminary evidence suggests that the default mode and limbic networks may be a target for future research on the neural mechanisms of psychedelics. More data is required to corroborate these initial findings as the evidence summarized in this review is based on four datasets.
... There is also evidence a single dose of LSD produces lasting reductions in anxiety in healthy volunteers (Schmid and Liechti 2018) and increases feelings of trust and closeness (Dolder et al. 2016), effects likely to benefit individuals with PTSD. In open-label and placebo-controlled trials in depressed participants, ayahuasca significantly reduced depression severity (Osório et al. 2015;Palhano-Fontes et al. 2019). These findings provide preliminary evidence that classic psychedelics can reduce anxiety, improve mood, and facilitate trauma processing. ...
Chapter
Posttraumatic stress disorder (PTSD) is a debilitating, chronic disorder and efficacy rates of current PTSD treatments are underwhelming. There is a critical need for innovative approaches. We provide an overview of trauma and PTSD and cite literature providing converging evidence of the therapeutic potential of psilocybin for PTSD. No study to date has investigated psilocybin or psilocybin-assisted psychotherapy (PAP) as treatments for PTSD. An open-label study in traumatized AIDS survivors found that PAP reduced PTSD symptoms, attachment anxiety, and demoralization. Several PAP trials show preliminary efficacy in facilitating confronting traumatic memories, decreasing emotional avoidance, depression, anxiety, pessimism, and disconnection from others, and increasing acceptance, self-compassion, and forgiveness of abusers, all of which are relevant to PTSD recovery. There is also early evidence that other classic psychedelics may produce large reductions in PTSD symptoms in combat veterans. However, this body of literature is small, mechanisms are not yet well understood, and the risks of using psychedelic compounds for trauma-related disorders need further study. In sum, evidence supports further investigation of PAP as a radically new approach for treating PTSD.
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Anxiety disorders are the most common type of psychiatric disorders among Western countries. Evidence-based treatment modalities including pharmacological and cognitive-behavioral therapy result in deficient treatment responses. Historical and recent research suggests psychedelic drugs may be efficacious in alleviating anxiety-related symptoms among healthy and clinical populations. The main aim of the present study was investigation of the effects of psilocybin-containing truffles, when taken in a supportive group setting, on ratings of state and trait anxiety across self-reported healthy volunteers. Attendees of psilocybin ceremonies were asked to complete a test battery at three separate occasions: before the ceremony (baseline), the morning after, and 1 week after the ceremony. The test battery included questionnaires assessing state and trait anxiety (State-Trait Anxiety Inventory), mindfulness capacities (Five Facet Mindfulness Questionnaire), and personality (Big Five Inventory). Additionally, the psychedelic experience was quantified with the Persisting Effects Questionnaire and the Ego Dissolution Inventory. The total amount of psilocybin-containing truffles consumed by each participant was recorded, and a sample of the truffles was analyzed to determine psilocin concentrations. Fifty-two attendees (males = 25; females = 25; others = 2) completed parts of the baseline assessment, 46 (males = 21; females = 24; others = 1) completed assessments the morning after the ceremony, and 23 (males = 10; females = 13) completed assessments at the 1-week follow-up. Average psilocin consumption across individuals was 27.1 mg. The morning after the ceremony, we observed medium reductions in anxiety measures (both state and trait) compared to baseline (d¯ = 6.4; p < 0.001 and d¯ = 6; p = 0.014, respectively), which persisted over a 1-week period post-ceremony (d¯ = 6.7; p = 0.001 and d¯ = 8.6; p = 0.004, respectively). At 1 week post-ceremony, the non-judging facet of the mindfulness scale was increased (d¯ = 1.5; p = 0.03), while the personality trait neuroticism decreased (d¯ = 5.2; p = 0.005), when compared to baseline. Additionally, we found ratings of ego dissolution (mean: 59.7, SD: 28.3) and changes in neuroticism to be the strongest predictors of reductions in state and trait anxiety, respectively. In sum, results suggest rapid and persisting (up to 1 week) anxiolytic effects in individuals with sub-clinical anxiety symptoms, which are related to the acute experience of ego dissolution, as well as lasting changes in trait neuroticism. Results also add support to the feasibility and potential efficacy of group sessions with psychedelics. To understand whether these effects extend to wider populations suffering from heightened anxiety, and the mechanisms involved, further experimental research is needed.
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This is a narrative review about the role of classic and two atypical psychedelics in the treatment of unipolar and bipolar depression. Since the 1990s, psychedelics experience a renaissance in biomedical research. The so-called classic psychedelics include lysergic acid diethylamide (LSD), psilocybin, mescaline and ayahuasca. Characteristic effects like alterations in sensory perception, as well as emotion- and self-processing are induced by stimulation of serotonin 2A receptors in cortical areas. The new paradigm of psychedelic-assisted psychotherapy suggests a therapeutic framework in which a safely conducted psychedelic experience is integrated into a continuous psychotherapeutic process. First randomized, controlled trials with psilocybin show promising efficacy, tolerability, and adherence in the treatment of unipolar depression. On the other hand, classic psychedelics seem to be associated with the induction of mania, which is an important issue to consider for the design of research and clinical protocols. So called atypical psychedelics are a heterogeneous group with overlapping subjective effects but different neurobiological mechanisms. Two examples of therapeutic value in psychiatry are 3,4-methyl enedioxy methamphetamine (MDMA) and ketamine. Since 2020 the ketamine enantiomer esketamine has been granted international approval for treatment-resistant unipolar depression, and also first evidence exists for the therapeutic efficacy of ketamine in bipolar depression. Whether psychedelics will fulfil current expectations and find their way into broader clinical use will depend on future rigorous clinical trials with larger sample sizes. A well-considered therapeutic and legal framework will be crucial for these substances to create new treatment settings and a potential paradigm shift.
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Classical psychedelics represent a family of psychoactive substances with structural similarities to serotonin and affinity for serotonin receptors. A growing number of studies have found that psychedelics can be effective in treating various psychiatric conditions, including post-traumatic stress disorder, major depressive disorder, anxiety, and substance use disorders. Mental health disorders are extremely prevalent in the general population constituting a major problem for the public health. There are a wide variety of interventions for mental health disorders, including pharmacological therapies and psychotherapies, however, treatment resistance still remains a particular challenge in this field, and relapse rates are also quite high. In recent years, psychedelics have become one of the promising new tools for the treatment of mental health disorders. In this review, we will discuss the three classic serotonergic naturally occurring psychedelics, psilocybin, ibogaine, and N, N-dimethyltryptamine, focusing on their pharmacological properties and clinical potential. The purpose of this article is to provide a focused review of the most relevant research into the therapeutic potential of these substances and their possible integration as alternative or adjuvant options to existing pharmacological and psychological therapies.
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While anecdotal reports claim that psychedelic microdosing reduces anxiety and mood symptoms, evidence supporting these claims is scarce. This cross-sectional study investigated the association between microdosing and trait anxiety. Furthermore, it was investigated if trait mindfulness mediated this association. Participants completed anonymous online questionnaires and were divided into three groups: current microdosers (n = 186), former microdosers (n = 77) and microdosing-naïve controls (n = 234). Trait anxiety and trait mindfulness were measured using the State-Trait Anxiety Inventory - Trait subscale (STAI-T) and the 15-item Five-Facet Mindfulness Questionnaire (FFMQ-15) respectively. Current and former microdosers reported lower STAI-T scores compared to microdosing-naïve controls. Furthermore, associations of current and former microdosing with trait anxiety were mediated by trait mindfulness, with small effects of FFMQ-15 Total, Non-judging and Non-reactivity scores. However, in an exploratory analysis, all associations between microdosing and STAI-T scores became non-significant when participants with previous macrodose experience (n = 386) were excluded. Our findings suggest that RCT<apos;>s are warranted to test causal hypotheses concerning the effects of microdosing and the role of trait mindfulness in the effects of microdosing, while controlling for previous macrodose experience.
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Ayahuasca is an Amazonian psychoactive plant beverage containing the serotonergic 5-HT 2A agonist N,N-dimethyltryp-tamine (DMT) and monoamine oxidase-inhibiting alkaloids (harmine, harmaline and tetrahydroharmine) that render it orally active. Ayahuasca ingestion is a central feature in several Brazilian syncretic churches that have expanded their activities to urban Brazil, Europe and North America. Members of these groups typically ingest ayahuasca at least twice per month. Prior research has shown that acute ayahuasca increases blood flow in prefrontal and temporal brain regions and that it elicits intense modifications in thought processes, perception and emotion. However, regular ayahuasca use does not seem to induce the pattern of addiction-related problems that characterize drugs of abuse. To study the impact of repeated ayahuasca use on general psychological well-being, mental health and cognition, here we assessed personality, psychopathology, life attitudes and neuropsychological performance in regular ayahuasca users (n = 127) and controls (n = 115) at baseline and 1 year later. Controls were actively participating in non-ayahuasca religions. Users showed higher Reward Dependence and Self-Transcendence and lower Harm Avoidance and Self-Directedness. They scored significantly lower on all psychopathology measures, showed better performance on the Stroop test, the Wisconsin Card Sorting Test and the Letter-Number Sequencing task from the WAIS-III, and better scores on the Frontal Systems Behavior Scale. Analysis of life attitudes showed higher scores on the Spiritual Orientation Inventory, the Purpose in Life Test and the Psychosocial Well-Being test. Despite the lower number of participants available at follow-up, overall differences with controls were maintained one year later. In conclusion, we found no evidence of psychological maladjustment, mental health deterioration or cognitive impairment in the ayahuasca-using group.
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Major depressive disorder (MDD) is generally classified as a mood dis-order with a profound effect on the individual's behavior and quality of life. According to the World Health Organization, in about 20 years, depression will be the disorder with the most significant repercussions, both socially and economically. Despite the substantial progress in the development of new antidepressants, their effectiveness remains low, with remission of about 50 % after a single regime of treatment. The most common form of pharmacological treatment of MDD is based F. Palhano-Fontes Á D. B.
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