Journal Pre-proof
Therapeutic use of serotoninergic hallucinogens: a review of the
evidence and of the biological and psychological mechanisms
Rafael Guimarães dos Santos, Jaime Eduardo Cecilio Hallak
PII:
S0149-7634(19)30964-9
DOI:
https://doi.org/10.1016/j.neubiorev.2019.12.001
Reference:
NBR 3614
To appear in:
Neuroscience and Biobehavioral Reviews
Received Date:
19 October 2019
Revised Date:
5 November 2019
Accepted Date:
2 December 2019
Please cite this article as: dos Santos RG, Cecilio Hallak JE, Therapeutic use of
serotoninergic hallucinogens: a review of the evidence and of the biological and psychological
mechanisms, Neuroscience and Biobehavioral Reviews (2019),
doi: https://doi.org/10.1016/j.neubiorev.2019.12.001
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© 2019 Published by Elsevier.
Therapeutic use of serotoninergic hallucinogens: a review of the evidence and of
the biological and psychological mechanisms
Rafael Guimarães dos Santos1,2,*, Jaime Eduardo Cecilio Hallak1,2
1
Department of Neurosciences and Behavior, Ribeirão Preto Medical School, University
2
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of São Paulo, Ribeirão Preto, Brazil.
National Institute for Translational Medicine (INCT-TM), CNPq, Ribeirão Preto,
Brazil.
Correspondence: Prof. Rafael Guimarães dos Santos, Ph.D. Departamento de
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*
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Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto,
Universidade de São Paulo, Hospital das Clínicas, Terceiro Andar, Av. Bandeirantes,
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Highlights
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banisteria@gmail.com.
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3900, Ribeirão Preto, São Paulo, Brazil. Tel/Fax: + 55 16 3602 2853, E-mail:
Serotoninergic hallucinogens are agonists at frontal and limbic 5-HT2A receptors

Controlled trials with these drugs report anxiolytic and antidepressive effects

Open-label trials report antiaddictive effects

Biological mechanisms include neuroplasticity and fronto-limbic activation

Psychological mechanisms include enhanced social cognition and openness to
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
experience
1
Abstract
Serotoninergic hallucinogens include drugs such as lysergic acid diethylamide (LSD),
dimethyltryptamine (DMT) and psilocybin. Recent trials with single/few doses of these
compounds show that they induce rapid and sustained antidepressive, anxiolytic, and
antiaddictive effects. These effects are also observed in religious groups using the
DMT-containing brew ayahuasca. The agonist action of these substances on 5-HT2A
receptors expressed in frontal and limbic areas increase glutamatergic transmission
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and neuroplasticity. These neurochemical effects are associated with acute alterations
on self-perception and increases in introspection and positive mood, and with
subacute and long-term decreases in psychiatric symptoms, increases in some
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personality traits such as openness, improvements in emotional processing, and
increases in empathy. These are preliminary but promising results that should be
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further explored in controlled trials with larger sample sizes, especially considering
psychiatric disorders.
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that these compounds could be beneficial in the treatment of treatment-resistant
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Keywords: hallucinogens; ayahuasca; serotonin; 5-HT2A receptor; therapeutical use.
1. Introduction
Serotoninergic psychedelics, or classical hallucinogens, are part of a group of
psychoactive drugs that include as emblematic examples the natural phenethylamine
mescaline, the natural tryptamines N,N-dimethyltryptamine (DMT) and psilocybin (4-
2
phosphoryloxy-N,N-DMT), and the semisynthetic ergoline lysergic acid diethylamide
(LSD).1 These substances are called serotoninergic drugs because they share a common
mechanism of action that consists in agonism at different serotoninergic receptors,
especially the 5-HT2A receptors.1
These drugs produce profound modifications in affect (euphoria and joy or anxiety and
terror), perceptions (synesthesia, sensory illusions, alterations in time/space perception,
blurred boundaries between self and others), and cognition (increased creativity and
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insight or confusion and disorientation).2 Subjective effects can range from blissful
mystical-type experiences with positive mood to unpleasant experiences of fear, panic,
dysphoria, and psychotic-like effects such as depersonalization/derealization and
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paranoid ideation. The nature of these effects will ultimately be influenced by drug dose
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(low/high), set (careful screening of participants; preparation for the drug session;
personality and expectations of the subject) and setting (support and monitoring by
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prepared individuals before, during, and after the drug session; adequate context of
use).2,3
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The capacity of these drugs to induce states of consciousness resembling mystical
experiences could explain their widespread ritual and religious use worldwide (except
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for LSD).4 Indeed, naturally occurring serotoninergic hallucinogens such mescaline,
DMT and psilocybin have a long history of ritual, religious, and therapeutic uses in the
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Americas. Mescaline is the main psychoactive compound in the peyote cactus, used by
indigenous groups in Northern Mexico; DMT is the main hallucinogenic substance in
ayahuasca and jurema, which are traditionally used by indigenous groups in the
Northwestern Amazon and in Northeastern Brazil, respectively; and psilocybin is found
3
in several species of hallucinogenic mushrooms used by indigenous groups in Central
Mexico.4
These substances were largely unknown by scientists until the late 1800s and early
1900s. Indeed, mescaline was isolated in the late 1890s, LSD was first synthetized in
1938, and psilocybin was isolated and synthetized in the late 1950s.2,5,6 Between 1950
and 1970, several studies investigated the potential therapeutic use of psilocybin and
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LSD in the treatment of neurosis, obsessive–compulsive disorder (OCD), substance
dependence, and existential anxiety and depression in the terminally ill, with promising
results.2,6 Experimental studies with healthy volunteers and clinical studies with
psychiatric patients performed in that period suggest that these drugs have a good safety
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profile and a low incidence of serious adverse reactions (such as prolonged psychotic
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reactions).2,6
Nevertheless, these studies were interrupted in the late 1960s/early 1970s. Motives
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included increases in recreational use and legislation changes demanding the inclusion
of placebo and control groups in the investigation of new therapeutic drugs, which were
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lacking in many studies with hallucinigens.2,3,6
Human hallucinogen research resumed more than two decades later in the early 1990s
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with studies in healthy volunteers using mescaline in Germany7 and DMT in the United
States.8,9 Since then, the number of human studies involving the administration of
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serotoninergic psychedelics such as LSD, psilocybin and ayahuasca/DMT to both
healthy volunteers and clinical populations is continually increasing. The first clinical
trials of this second wave of psychedelic research were performed in the early 2000s.
The number of studies currently being performed continues to increase, including
studies on the antidepressive and anxiolytic effects of these drugs, as well as on their
4
beneficial effects for treating substance-related disorders. The results of these studies
are promising. Furthermore, since the resumption of clinical research with these
compounds in the early 1990s, there have been no reports of serious adverse
reactions.2,6,10
Thus, the objective of this work is to summarize disparate reviews on the therapeutic
uses of serotoninergic hallucinogens on anxiety, mood, and substance use disorders,
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with an emphasis on the studies performed by the Universidade de São Paulo (USP) and
the Universidade Federal do Rio Grande do Norte (UFRN) regarding the therapeutic
properties of ayahuasca/DMT. Moreover, the biological and psychological aspects
involved in these effects will also be discussed.
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2. Therapeutic potentials of LSD and psilocybin
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2.1. Anxiety and depression related to cancer and other life-threatening diseases
This was one of the first and most promising indications for the use of psychedelic
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drugs in the 1960s, and still is one of the areas of research where the evidence is more
robust.2,11,12 Between 1964 and 2016, 11 clinical trials were performed assessing the
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effects of serotoninergic hallucinogens in a total of 445 participants with symptoms of
depression and anxiety associated with life threatening diseases. Five open-label studies
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using LSD or dipropyltryptamine (DPT) (also a serotoninergic hallucinogen) were
published between 1960–2000, while four randomized, double-blind, placebo-
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controlled, cross-over trials using LSD or psilocybin were published between 2000–
2017.2,11,12
In the four more recent and controlled trials, involving samples of 12–51 patients, single
doses of LSD (one study, 200 μg dose) or psilocybin (three studies, dose range 14–30
mg/70kg) associated with psychological support significantly reduced anxiety and
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depression and increased quality of life, life meaning, death acceptance, and optimism,
and these effects endured from some weeks to six months after drug intake. Moreover,
both psychedelics were well tolerated, with most adverse reactions including transitory
symptoms of anxiety and distress, sensorial illusions and psychotic-like symptoms,
headache, nausea and vomiting, and mild increases in blood pressure and heart rate.11-16
Despite the small sample sizes of these trials and their crossover designs, their results
are promising. In fact, these results led to the proposal of phase III trials in the United
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States.12 These substances should be further investigated in patients with other life-
threatening diseases, and they also should be compared to other interventions, including
(but not limited to) other serotoninergic hallucinogens, such as ayahuasca/DMT.
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2.2. Depression
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A recent systematic review on the effects of serotoninergic psychedelics in the treatment
of unipolar mood disorders reviewed 21 studies conducted from 1949 to 1973 involving
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the administration of LSD or mescaline (but not psilocybin) to a total of 423 patients
and reported a high (almost 80%) rate of clinician-judged improvements.17 However,
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these early studies shared important methodological limitations and varied levels of risk
of bias, which seriously limit their results, including open-label designs (only 1 of the
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21 studies was a controlled study), lack of control groups, small sample sizes, and high
heterogenicity of diagnoses, therapeutic interventions, and drug dosage.17,18
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A recent open-label feasibility trial with 12 volunteers with treatment-resistant major
depression disorder (MDD) reported that two oral doses of psilocybin (10 mg and 25
mg, 7 days apart) administered with psychological support produced rapid and sustained
(one week and three months after the second dose, respectively) decreases in depression
6
and anxiety symptoms, and the treatment was well tolerated with transient effects such
as increased anxiety, confusion, nausea, and headache.19
In October 2018 the investigation of psilocybin as a possible treatment for treatmentresistant MDD received the Breakthrough Therapy designation by the United States
Food and Drug Administration (FDA).20 This designation is given when a treatment
shows preliminary (but substantial) evidence of improvement, and the FDA give
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support for the clinical development of the treatment. Large-scale, multicenter,
controlled trials of psilocybin for treatment-resistant MDD are planned to take place in
the next year in several research centers in Europe and North America
(ClinicalTrials.gov Identifier: NCT03181529, NCT03380442, NCT03429075).
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2.3. Substance use disorders
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Another early and promising field of investigation in the 1960s involved the
administration of serotoninergic hallucinogens to patients with opioid and, especially,
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alcohol dependence.2,6,18 For instance, a recent meta-analysis of six controlled trials
conducted from 1966 to 1970 involving single high-dose (210–800 μg) LSD sessions to
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536 alcoholic patients reported significant decreases in alcohol misuse and increases in
alcohol abstinence from one to 12 months after drug intake, and LSD was well
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tolerated.21 Nevertheless, these studies share the same limitations with other studies
from the same period, including small sample sizes and significant heterogenicity of
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diagnostics and therapeutic interventions.2,6,18,21
More recently, two open-label, proof-of-concept studies showed evidence of significant
improvements in abstinence and craving for alcohol22 and nicotine23 use in dependent
individuals after psilocybin intake (doses of 20–30 mg/70 kg) associated with
psychotherapy (motivational enhancement therapy and cognitive behavioral therapy,
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respectively). Significant reductions in alcohol and nicotine use were observed after
psilocybin administration, and these effects remained significant after six months in
both studies. These results are promising, but the open-label design and small sample
size of these trials (10–15 patients) are important limitations that should be overcome by
the performance of controlled studies with more patients. Indeed, based on these
promising results, these and other research groups are currently developing other trials
(NCT0194399), and cocaine (NCT02037126) dependence.
2.4. Other therapeutic potentials
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to try to replicate these preliminary results for alcohol (NCT02061293), nicotine
Another promising area of the early investigations with serotoninergic hallucinogens in
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the 1960s involved cancer-related pain and other difficult-to-treat pain syndromes.2,11,24
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Preliminary open-label studies and case series reported that LSD administration
decreased pain perception acutely and up to two-to-three weeks after dosing in patients
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with cancer-related pain, and LSD also improved other outcomes including sleep,
mood, and quality of life.2,11,24 However, studies had small sample sizes and were
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noncontrolled trials or case series. This is an interesting area of research that deserves to
be better investigated with controlled trials, especially if we consider that the above-
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mentioned data were derived from studies with cancer-related pain, a condition that
often co-occurs with depressive and anxiety symptoms that seem to respond to
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serotoninergic hallucinogens (as discussed above).
The first and only clinical trial of a serotoninergic hallucinogen in the treatment of
symptoms of OCD was performed in 2006 with nine patients and involved four
ascending doses of psilocybin (0.025–0.3 mg/kg) administered at least one week apart.25
Although there was no significant effect of dose, psilocybin significantly reduced
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compulsive symptoms for 24 hours after drug intake, and the treatment was well
tolerated. Considering these promising but preliminary results, further trials should be
performed with different doses of psilocybin and other serotoninergic hallucinogens.
Some observational and clinical studies also suggest that acute administration of
serotoninergic psychedelics such as LSD and psilocybin is associated with positive
effects in some personality measures.26 Experimental studies in healthy volunteers with
LSD and psilocybin reported increases in openness and optimism, but the evidence is
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mixed and inconsistent.26-30 The original open-label trial with psilocybin for treatmentresistant MDD with 12 volunteers19 was expanded to 20 subjects and reported
significant decreases in neuroticism and increases in extraversion and openness three
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months after psilocybin treatment.31 Thus, future controlled trials should try to replicate
effects of serotonergic hallucinogens.
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these results and further investigate the role of personality changes on the therapeutic
LSD and psilocybin.
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Table 1 shows the therapeutic indications with the most robust evidence of efficacy for
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[insert Table 1 here]
3. Therapeutic potentials of ayahuasca
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3.1. Historical overview
Since the 1960s and 1970s, LSD and psilocybin (and to a lesser extent mescaline) have
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been used recreationally and have been extensively associated with the countercultural
and hippie movements of that decades. Currently, these drugs are still used mainly for
recreational purposes, especially LSD and psilocybin, while the ritual and religious uses
of mescaline (in the peyote cactus) and psilocybin (in hallucinogenic mushrooms)
continues, but in very specific areas of Mexico.4
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The trajectory of ayahuasca is somewhat different. Ayahuasca (from the Quechua “vine
of the soul”) is a botanical hallucinogenic beverage traditionally used for ritual and
therapeutic purposes by several indigenous groups from the Northwestern Amazon.4
Indigenous groups from countries such as Brazil, Colombia, Peru and Ecuador have
been using ayahuasca for centuries, and the rural and urban populations of these
countries have been using ayahuasca for ritual and therapeutic purposes for
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decades.4,32,33 In fact, ayahuasca is just the name that has been established in the
scientific literature, but in the indigenous and mestizo contexts it has many other
names.4,32,33
In Brazil and Peru, ayahuasca is usually prepared by boiling the stems of the liana
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Banisteriopsis caapi with the leaves of the shrub Psychotria viridis, but in Colombia,
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and Ecuador the plant Diplopterys cabrerana is often used instead of P. viridis, and
several other plants may be added to ayahuasca, especially in the indigenous and
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mestizo contexts (Figure 1).4,33
[insert Figure 1 here]
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The B. caapi vine contains β-carboline alkaloids such as harmine, tetrahydroharmine
(THH), and harmaline, while P. viridis and D. cabrerana contain N,N-
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dimethyltryptamine (DMT), an hallucinogenic tryptamine that act as partial agonist at
cortical 5-HT1A/2A/2C receptors (in a similar way to LSD, psilocybin, and mescaline)
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(Figure 2).34
[insert Figure 2 here]
Interestingly, pure DMT is not orally psychoactive due to peripheral metabolism by
gastrointestinal and hepatic monoamine oxidase A (MAO-A), but the indigenous groups
somehow discovered that mixing the β-carboline-rich liana to the DMT-rich leaves of P.
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viridis and D. cabrerana makes ayahuasca psychoactive. Preclinical and human studies
have now shown that the psychoactivity of ayahuasca involves the reversible inhibition
of peripheral MAO-A by the β-carbolines (especially harmine), which allow DMT to
reach the systemic circulation and the brain.34-36
The identification of B. caapi was made by the English botanical explorer Richard
Spruce in 1852 in Brazil, but the observation that the vine was used in combination with
another plant that made ayahuasca psychedelic was made only in the 1950s by the
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beatnik poet William Burroughs, who described his personal experiences with “yagé”
(as ayahuasca is called in Colombia and Ecuador) in Colombia and Peru in
correspondences with the other beatnik poet Allen Ginsberg.37,38 Burroughs collected a
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specimen of P. viridis (without botanical identification at that time) in 1954 and send it
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to the ethnobotanist Richard Evans Schultes for identification, but Schultes labelled the
specimen as another plant, and described the first use of P. viridis in 1967,
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acknowledging the earlier herbarium collection by Burroughs. The specimen collected
by Burroughs was correctly identified as P. viridis only in 1973.37,38 The letters between
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Burroughs and Ginsberg were published as the book The Yage Letters in 1964, and this
book is one of the first descriptions of the effects of ayahuasca to be more available to
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the public.37
Unlike LSD and psilocybin, that were already being used at that time (1960-1970s) as
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recreational drugs, ayahuasca remained restricted to the indigenous and mestizo
Amazonian cultures until the late 1970s, when the first Brazilian ayahuasca religions
arrived in Southeastern Brazilian cities.32,33 These Brazilian religions, including the
Santo Daime, Barquinha, and União do Vegetal (UDV), originated in the 1930-1960s in
Northern Brazil and were originally formed by communities of rubber tappers that
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learned about ayahuasca from indigenous and mestizo populations in the near cities in
the Brazilian border with Peru, Colombia and Bolivia.32,33 The ritual and religious use
of ayahuasca by these and other organizations is allowed in Brazil since the late 1980s,
and these groups are currently present in all Brazilian states. Moreover, since the early
1990s, some of these religious groups expanded their activities to Europe and North
America, and currently some estimate that there are around 20.000 regular ritual
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ayahuasca users in 23 countries.32,33 By “ritual user” we are referring to the fact that
most people that use ayahuasca do it in a ritual, religious, or therapeutic context, usually
in group and with the presence of people with more experience in the use of ayahuasca
(shamans, religious leaders, guides).32,33 LSD and psilocybin can also be used in a
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similar way, but they are more often used as recreational drugs, and that use usually do
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not have the historical and spiritual background and culture attached to the ritual use of
ayahuasca.32,33
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Another difference between the paths of LSD/psilocybin and ayahuasca is related to
pharmacological research on these compounds. Over 1000 scientific articles were
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published from the early 1950s to the mid-1960s reporting results on the treatment of
over 40.000 patients with classic hallucinogens,39 while the first human research with
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ayahuasca (a study involving a mental health assessment of long-term ritual ayahuasca
users in Brazil) was published in 1996.40 This study was the first to report that the ritual
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ayahuasca use was not associated with psychiatric or cognitive deficits, and was in fact
associated with remission of psychopathologies including depression, anxiety, and
substance use disorders. In the last two decades, other observational studies assessing
the mental health of ritual ayahuasca users failed to find associations between ayahuasca
use and increases in psychopathology. Instead, these studies reported that ayahuasca
12
users had better scores on psychiatric, personality, and cognitive measures.26,40-42
However, rare cases of psychotic disorders have been reported in ritual contexts, but are
apparently related to individual predisposition to psychosis and concomitant use of
other psychoactive drugs including other hallucinogens and cannabis.42,43
Furthermore, several uncontrolled and controlled studies in healthy volunteers were
performed since the early 2000s.42 These studies reported that acute administration of
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single ayahuasca doses in controlled experimental contexts was well tolerated, inducing
moderate and transitory (<24h) autonomic and neuroendocrine modifications including
moderate increases in blood pressure and heart rate, mydriasis, elevations on cortisol,
prolactin and growth hormone levels, reductions on CD4 and CD3 cells percentage and
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increases in natural killer cells.35,42,44 There are no reports of prolonged psychotic
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reaction in experimental settings involving the administration of ayahuasca, which is
probably related to the strict inclusion and exclusion criteria used in these trials.42,43
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These studies also reported that acute ayahuasca intake induces typical psychedelic
effects including increased introspection and positive mood, and altered perceptions and
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cognition, and these effects were apparently mediated by increased activation of frontal
and paralimbic regions.35,42,44,45 Moreover, the first double-blind, placebo-controlled
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study reporting antidepressive and anxiolytic properties of a single dose of ayahuasca in
nine healthy experienced ritual ayahuasca users was published in 2007.46
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A timeline describing some of the most relevant historical developments in the
scientific ayahuasca research in the last 15 years is shown on Figure 3.
[insert Figure 3 here]
3.2. Depression and anxiety
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The evidence from observational and controlled studies suggesting safety and
antidepressive and anxiolytic potentials for ayahuasca use motivated our group to
investigate these therapeutic properties.
Few data are available on the subjective effects of the β-carbolines from ayahuasca.
Self-experiments from the 1990s suggest that oral or sublingual harmine (120–300 mg)
could induce relaxation, but to the best of our knowledge there is no human study
assessing the antidepressive or anxiolytic effects of harmine or other β-carbolines from
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ayahuasca.47,48 The first evidences from animal models showing that the β-carbolines in
ayahuasca had anxiolytic and antidepressive properties were published in the early- and
mid-2000s. The first study showing that harmaline induced anxiolytic effects in animals
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(mice) was published in 2005.49 The first study reporting that harmine had
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antidepressive effects (also in mice) was published in 2006.50
Since 2009, our research group at the Ribeirão Preto Medical School from the
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Universidade de São Paulo (FMRP-USP), in collaboration with the Universidade do
Extremo Sul Catarinense in Criciúma, has published several rodent studies describing
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the antidepressive properties of harmine.51-54 These studies showed that harmine (5-15
mg/kg) induced behavioral (reduced immobility time and increases in climbing and
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swimming) and neurochemical (increases in hippocampal levels of brain-derived
neurotrophic factor (BDNF)) antidepressant effects after acute and prolonged (7-14
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days) administration.
Regarding DMT, to the best of our knowledge the first evidence that this tryptamine
could have anxiolytic-like effects came from an open-label trial published in 1974
involving the intramuscular administration of 0.7 mg/kg DMT to healthy volunteers,
were 93% of the sample reported feelings of relaxation.55 This effect was also observed
14
in a placebo-controlled study performed 50 years later involving the administration of
four doses of intravenous DMT (0.04–0.4 mg/kg) to healthy volunteers, where the nonhallucinogenic DMT dose (0.05 mg/kg) produced relaxation in some participants.8 The
first preclinical evidence of the antidepressive and anxiolytic effects of DMT was
recently reported in a study showing that chronic and intermittent administration of
microdoses (low, subhallucinogenic) of DMT dose (1 mg/kg) induced improvements in
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mood and anxiety measures in rodents.56 Like the literature on harmine, we are not
aware of any human study assessing the antidepressive or anxiolytic effects of pure
DMT.
Brazilian scientists were the first to report evidence that ayahuasca (5-9 mg/kg DMT)
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also has antidepressive effects in rodents.57,58 More recently, researchers from our group
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collaborated with scientists from the Universidade Federal do Rio Grande do Norte
(UFRN, Brazil) in the first study showing that a single dose of ayahuasca (1.67 mL/300
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g) produced rapid (24 h) and persistent (14 days) significant physiological and
behavioral improvements in a juvenile non-human primate model of depression (social
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isolation).59 This is the first study reporting antidepressive effects of serotoninergic
hallucinogens in general, and of ayahuasca/DMT in particular, in non-human primates.
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Moreover, it is also the first study reporting these effects in a juvenile/adolescent model.
The antidepressant effects observed were rapid and sustained, which corroborates the
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results observed with treatment-resistant MDD patients (improvements lasting 7-21
days, as will be described below).
The first open-label trial to assess the antidepressant effects of a single ayahuasca dose
in patients with treatment-resistant MDD was performed at the FMRP-USP, in
collaboration with the UFRN.60,61 The preliminary results with six patients were
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published in January 2015,60 while the results with the final sample of 17 patients
(including the initial six patients) were published in February 2016.61 Thus, this study
was the first clinical trial assessing the effects of serotoninergic hallucinogens in
patients with MDD (the study with psilocybin and MDD patients was published on May
201619). In the ayahuasca study, a single dose of 2.2 mL/kg oral ayahuasca (0.8 mg/mL
DMT) was administered to depressed patients in a supportive environment in an
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inpatient psychiatric unit. Significant reductions in depressive and anxiolytic symptoms
were observed after the first hours of ayahuasca administration and remained significant
for three weeks. No serious adverse effects were observed, and vomiting was the only
adverse effect recorded, being reported by 47% of the patients. None of the patients
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described full-blown psychedelics effects, suggesting that lower ayahuasca doses, below
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the psychedelic threshold, could have antidepressive and anxiolytic effects.
Furthermore, blood perfusion was assessed eight hours after ayahuasca intake using
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single photon emission tomography (SPECT), and ayahuasca administration was
associated with significant increases in blood perfusion in the left nucleus accumbens,
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right insula and left subgenual area.
These preliminary but promising results were recently replicated in a placebo-controlled
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trial performed this time in the UFRN, in collaboration with our group in the FMRPUSP.62 In this trial, 29 patients with treatment-resistant MDD received a single dose of
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ayahuasca (1 mL/kg, 0.36 mg/kg DMT) or placebo in a supportive hospital context.
Compared to placebo, ayahuasca produced significant reductions in depressive and
anxiety symptoms from the first hours after ayahuasca intake until seven days
afterwards. As in the open-label trial, ayahuasca intake was well tolerated, with no
serious adverse reactions. The only adverse reactions reported that were statistically
16
different from placebo and more common with ayahuasca were transient nausea (71%)
and vomiting (57%).
Taken together, the above-mentioned results show translational evidence of the
antidepressant and anxiolytic effects of single ayahuasca doses, including evidence from
preclinical (rodents, non-human primates), experimental/healthy volunteers (Phase I),
and clinical/patients (Phase II) studies.
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3.3 Substance use disorders
Another potential therapeutic effect commonly described in observational studies of
ayahuasca ritual/religious users and therapeutic communities (or retreats and healing
centers) is the apparent recovery of substance-related disorders, including reductions in
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use of alcohol, tobacco, psychostimulants, cannabis, and opiates.40,42,63 A recent
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systematic review of preclinical and human studies assessing the effects of ayahuasca
and its alkaloids in substance-related outcomes found five animal studies (one used
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harmaline, three used harmine, and another one used ayahuasca) and five observational
studies of ritual ayahuasca users.63 Results showed improvement of biochemical and
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behavioral parameters related to drug-use disorders in all animal studies, and reductions
of dependence symptoms or substance use in four of the five human studies.63
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After the publication of that review, other preclinical studies in rodents64,65 and
observational studies among religious ayahuasca users and therapeutic communities66-71
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were published, all reporting evidence of the antiaddictive properties of ayahuasca.
However, despite the positive results from preclinical and observational studies, there
are no controlled trials that have assessed the antiaddictive effects of ayahuasca.
Considering that substance-related problems are a major public health issue worldwide
and the preliminary but promising results from clinical trials with LSD and
17
psilocybin,22,23 controlled trials should be performed to further explore the potential of
ayahuasca in the treatment of substance use disorders.
3.4. Other therapeutic potentials
Observational studies performed among ritual ayahuasca users showed evidence of
beneficial changes in some personality traits including reductions in impulsivity and
shyness, and increases in confidence, agreeableness, optimism, openness, and
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spirituality.26,40,41,66 Ritual ayahuasca intake was also associated with significant
increases in mindfulness-related capacities, including decentering (the capacity to
observe thoughts and feelings in a detached manner), acceptance (to be non-judgmental
and non-reactive), positive self (spontaneity and flexibility), and attention and
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awareness.72-77 There is also evidence suggesting improvements in emotion
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dysregulation in people with borderline personality traits.77 Other observational studies
suggest that ritual ayahuasca use could improve neuropsychological functions40-42,78 and
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be beneficial for treating eating disorders79 and grieving processes.80 Moreover, a recent
naturalist study performed among Spanish ritualistic ayahuasca users reported that the
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sample had higher levels of general, mental, and positive health when compared with
the general Spanish population.81
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Although these studies report promising results, it is not possible to infer causality due
to their observational nature, and that is also true for safety and tolerability outcomes.
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Moreover, the participants of most studies were self-selected healthy individuals, which
limits the interpretation of the results regarding their translation to clinical samples.
Another limitation of these studies is the fact that it is not possible to separate the
possible effects of ayahuasca from the effects of ritual and religious aspects. However,
naturalistic studies are complementary to clinical trials since they reflect the use of
18
ayahuasca in more realistic contexts. Thus, these positive potentials observed in
naturalistic/observational studies should be complemented by controlled trials.
Table 2 shows the therapeutic indications with the most robust evidence of efficacy for
ayahuasca/DMT.
[insert Table 2 here]
4. Mechanisms of action
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4.1 Biological mechanisms
The mechanisms of action of serotoninergic hallucinogens are still poorly understood.
From a biological perspective, preclinical and human studies have provided evidence
that the mind-altering effects of these drugs are due to their agonist action on cortical 5-
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HT2A receptors.1,82-87 Activation of the 5-HT2A receptor produces glutamate release and
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activation of alpha-amino-3-hydroxy-methyl-5-4-isoxazolpropionic (AMPA)
glutamatergic receptors, thus increasing cortical electrical activity and information
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processing.76,85-87 These drugs increase neuroplasticity by stimulating c-fos expression
in the medial prefrontal (mPFC) and anterior cingulate (ACC) cortices and by
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increasing BDNF expression in the PFC.1,85-87
Recent studies have shown that, like ketamine, classic psychedelics such as LSD and
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DMT rapidly (24 hours) increase neuritogenesis, spinogenesis, and synaptogenesis in
prefrontal cortical neurons in vitro and in vivo.87,88 These effects were mediated through
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agonism of cortical 5-HT2A receptors and activation of BDNF’s high-affinity receptor
(tyrosine kinase B receptor, TrkB) and of the mammalian target of rapamycin (mTOR).
Because of their neuroplastic effects, these researchers labeled this group of drugs
“psychoplastogens”.87,88
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This enhanced neuroplasticity induced by serotoninergic hallucinogens and ketamine
could be one of the mechanisms involved in the antidepressive and anxiolytic effects of
these drugs. For instance, in the case of ayahuasca, preclinical studies have shown that
the β-carboline harmine produces antidepressant activity through increases in
hippocampal BDNF levels,51,52,54,90 and there is evidence that this alkaloid also
stimulates the proliferation of human neural progenitors and adult neurogenesis.91,92
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Preclinical studies have also shown that harmine93 and DMT94 have neuroprotective
effects related to modifications on glutamatergic (harmine) and sigma-1 (DMT)
receptors. These neuroprotective effects could be related not only to their antidepressant
properties, but also to some of the improvements in cognition observed among long-
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term ritual ayahuasca users.40-42
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Furthermore, the MAO-inhibiting properties of harmine, harmaline and THH (which
also acts as a serotonin reuptake inhibitor) could also be involved in the antidepressant
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effects of continuous (but not acute) ayahuasca intake.34,35 However, traditional MAOinhibiting antidepressants do not show rapid and persistent antidepressant effects with
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single doses. Thus, the effects of ayahuasca are probably not mediated by this
mechanism. Instead, these effects are observed with other serotoninergic hallucinogens
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and with ketamine.87,88
Ketamine and serotoninergic hallucinogens induce antidepressive effects by increasing
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glutamatergic transmission, neurogenesis and synaptic plasticity, but by different
mechanisms. Ketamine acts as an antagonist of the N-methyl-D-aspartate receptor, while
serotoninergic hallucinogens act as agonists/partial agonists of the 5-HT2A receptor. The
glutamatergic system seems to play a crucial role in the therapeutic effects of
ayahuasca. Reductions in posterior cingulate cortex (PCC) glutamate–glutamine levels
20
were positively correlated with increases in mindfulness-related capacities acutely (24
hours) and two months after ayahuasca intake.73
Another evidence of the relationship between glutamatergic neurotransmission,
depression, ketamine, and serotoninergic hallucinogens comes from our recently
completed controlled trial showing that, compared to placebo, administration of
ayahuasca to patients with treatment-resistant MDD induced significant increases in
BDNF levels 48 hours later, which was negatively correlated with the antidepressive
modulated by acute increases of cortisol levels.44,96
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effects of ayahausca.95 These effects of ayahuasca on BDNF levels were apparently
Neuroimaging studies have shown consistent evidence that agonism at cortical 5-HT2A
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receptors is crucial for the generation of the effects produced by serotoninergic
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hallucinogens, since administration of 5-HT2A receptor antagonists reduces or blocks
both their subjective and neurophysiological effects.82,84,85,97 5-HT2A receptors
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modulated by drugs such as ayahuasca/DMT, LSD and psilocybin are expressed in
brain regions involved in emotion regulation, cognition, memory, introspection, and
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self-awareness, such as the PFC, ACC, PCC and amygdala.45,85 The subjective effects
of psychedelics are associated with excitatory effects in frontolateral/frontomedial
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cortex, medial temporal lobe, and occipital cortex.45,82,84,85 The drugs also decrease
functional connectivity in key hubs of the default mode network (DMN)85,98-100 and
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reduce amygdala reactivity to threat.85,101,102
The ACC and the PCC (a key DMN hub) are especially relevant for the effects
produced by serotoninergic psychedelics. Indeed, neurophysiological studies show that
these drugs induce a suppression of the inhibitory alpha rhythm in the parieto-occipital
cortex, including the PCC,85,97,98,103 and functional neuroimaging studies showed
21
reduced connectivity in the PCC after administration of psychedelics.85,99 Radiotracer
data shows increased blood flow in the ACC and other areas (such as the insula,
amygdala, and hippocampus),45,82,85 while functional studies show decreased activity in
this area.85,98
Neurometabolic reductions in the PCC and increased functional connectivity between
the ACC and the PCC and between the ACC and the medial temporal lobe were
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correlated with mindfulness-related capacities after ayahuasca intake.73 Moreover, longterm ritual ayahuasca use was associated with increased cortical thickness of the ACC
and cortical thinning of the PCC. Effects on the PCC were inversely correlated to age of
onset, intensity of prior ayahuasca use, and self-transcendence, a personality trait
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closely related to openness.78 Modulation of the amygdala, ACC and PCC could also be
the emotional expression of pain.11,24
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involved in the effects of serotoninergic hallucinogens on pain perception by modifying
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The global effects of serotoninergic psychedelics on brain function seem to involve
disruptions of neural hierarchies by reducing top-down control and increasing bottom-
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up information transfer, which is reflected in alterations of self-perception and increases
in functional connectivity between normally distinct brain networks.104,98 These effects
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are often correlated with “ego dissolutive” and mystical experiences, which appear to
mediate the therapeutic effects of these compounds.10,82,85,105
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Finally, it is important to consider the possibility that other serotoninergic receptors
could also mediate the therapeutic effects of psychedelics. For instance, 5HT7 receptors
are involved in the modulation of synaptogenesis or neuritogenesis,106 although they are
not consistently involved in the effects of psychedelics.1 There is more consistent
evidence suggesting the involvement of the 5-HT1A and 5HT2C receptors.1,83,107 5-HT1A
22
receptors are colocalized with 5-HT2A receptors on cortical pyramidal cells, with the
highest density found in the cortex and hippocampus.1 These receptors are involved
both in mood and anxiety regulation and in the therapeutic effects of anxiolytic and
antidepressive drugs.108 Regarding the 5-HT2C receptor, most psychedelics are agonists
at both the 5-HT2A and 5-HT2C receptors.1,83 Preclinical studies show that agonists of
this receptor counteract the effects of addictive drugs by modulating the activity of
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dopamine neurons in the ventral tegmental area and nucleus accumbens. This effect
could be involved both in the low dependence potential of psychedelic and in their
antiaddictive effects.109 Table 3 summarizes the possible effects of LSD, psilocybin and
ayahuasca alkaloids (DMT and β-carbolines) on serotoninergic receptors and other
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targets.
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[insert Table 3 here]
4.2. Psychological mechanisms and the role of psychotherapy
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In the early research with classic hallucinogens in the 1960-70s, these drugs were
commonly administered in combination with psychotherapy before, during, and after
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drug intake. Nevertheless, these studies often used different theoretical models and
psychotherapeutic approaches, such as the psycholytic model using low to moderate
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doses on multiple occasions using psychoanalytic principles, the psychedelic model
using higher doses administered on a single or few occasions with the objective of
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inducing a peak or mystical experience, and many other hybrid models.2,3,6 These
variety of non-standardized methods, together with the lack of placebo, adequate control
groups, and standardized criteria for therapeutic outcome, are important limitations of
the studies of that period.2,3,6
23
Recent studies with classic hallucinogens have improved some of these limitations by
including placebo, control groups, and standardized instruments to measure and assess
therapeutic outcomes. Moreover, the biological mechanisms of these compounds have
been (and still are) extensively investigated in preclinical and human studies. However,
standardization of psychotherapeutic techniques used in these trials and evaluation of
the psychological variables that can improve therapeutic outcomes are still poorly
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investigated.
In the last years, some studies reported that the intensity and quality of the experience,
personality traits, social cognition, mindfulness-related capacities, and mystical
experiences are among some of the most prominent psychological processes behind the
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therapeutic effects of serotoninergic psychedelics. For instance, personality traits such
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as absorption and neuroticism can predict the intensity and quality of the effects of
psychedelics,10,26 and observational studies among ritual ayahuasca users26,40,41,66 and
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experimental studies in healthy volunteers with LSD and psilocybin26-30 reported
increases in openness (although the evidence is mixed and inconsistent). Ritual
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ayahuasca use is also associated with increases in mindfulness-related capacities such as
decentering and acceptance, but these observational data need to be replicated by
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controlled studies.72-77
Recent studies reported positive correlations between the intensity of mystical
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experiences induced by psychedelics and improvements in quality of life, personality,
and symptom reduction.15,16,22,23,26 These experiences are characterized by the sense of
oneness, transcendence, sacredness, and positive mood. They also involve a process of
“letting go” and self-surrender. However, these results are derived from open-label trials
and were only partially replicated in the controlled trial of ayahuasca and MDD.62 Thus,
24
their role as a possible mechanism of the therapeutic effects of psychedelics should be
observed with caution.
Recent studies also have shown that classic psychedelics may improve emotion
processing and social cognition by reducing the recognition of negative emotions and
by increasing empathy,110-112 and the open-label trial with psilocybin and MDD reported
a positive correlation between reduced reaction time in face recognition (positive and
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negative emotions) and reduced anhedonia.113 However, this last result should be
interpreted with caution due to its open-label design and small sample size.
Other less studied psychological processes that could explain the therapeutic effects of
serotoninergic hallucinogens include increases in self-acceptance and psychosocial
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bonds,41 psychological flexibility and creativity,114 and experiences of catharsis,
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forgiveness, and self-compassion.115,116
Regarding psychotherapeutic interventions, the term “psychedelic-assisted
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psychotherapy” has often been used to describe the combined use of serotoninergic
hallucinogens with psychotherapy, although the psychotherapeutic interventions both in
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early and modern trials is highly heterogeneous. For instance, some of the interventions
used in recent trials include motivational enhancement therapy,22 cognitive behavioral
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therapy,23 and a combination of existential psychotherapy, psychoanalytic therapy, and
transpersonal psychology (a combination rooted in the psycholytic and psychedelic
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models of the 1960-1970s2,3).13-16,19,113 In general terms, these interventions adopt a nondirective, supportive approach, and include preparation sessions with therapists,
instructions to increase the likelihood of positive and mystic-like experiences (including
the use of eyeshades, a preselected music program, and instruction to focus on inner
25
experiences), and integration sessions after the experience where the volunteers describe
their subjective experiences.
As psychedelic-assisted therapy is still in early development as a clinical practice, it is
still not known neither if the therapeutic effects of these drugs are truly increased by the
inclusion of psychotherapy, nor which psychotherapeutic approach would be the most
effective. Moreover, some of the above-mentioned studies are open-label trials lacking a
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control arm,19,22,23,113 so it is not possible to distinguish drug effects from the effects of
the psychological intervention. Therefore, it is important to perform studies that keep
psychological interventions to a minimum, so that drug effects can be distinguished
from those of the intervention. Moreover, from a practical and economical point of
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view, if the psychotherapeutic interventions used is simple, practical, and unexpansive
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(and of course effective), this is an advantage when planning replication and training of
the protocol, both in research and clinical settings.
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For instance, in our open-label and controlled trials with ayahuasca and MDD, which
reported rapid and sustained improvements in depression and anxiety scores, no specific
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psychotherapeutic intervention was used before, during, or after the experiments.60-62
Our protocols included general principles described in the psycholytic and psychedelic
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models of the 1960-1970s and in recent guidelines for safety in human hallucinogen
research.3 They included the creation of trust with the volunteers before the experiment,
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the use of a non-directive, supportive approach during drug sessions, and follow-up
encounters from some days to several weeks after the session. However, the studies
were not conducted by psychiatrists or psychologists trained in psychedelic-assisted
psychotherapy. Before the trial, volunteers were screened and informed about the details
of the trial and the effects of ayahuasca, and during the experiments simple instructions
26
were given to the volunteers to “remain quiet, with their eyes closed, while focusing on
their body, thoughts, and emotions”. Volunteers were followed for days to weeks after
the drug session, when they could freely describe their experiences, but no specific
integration technique was used. Moreover, in the open-label trial60,61 there was no
music, while in the controlled trial there was a predefined music playlist.62
More studies should be performed comparing different therapeutic interventions in
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human hallucinogen research. Moreover, the influence of the social, religious and
spiritual context in which these substances are used should also be further investigated,
since these factors could influence the subjective effects and therapeutic properties of
these substances. This is especially relevant in the case of ayahuasca, which is often
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used in ritual contexts. Maybe the use of ayahuasca in religious or therapeutic
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communities can have distinct therapeutic potentials compared to the use of the brew in
experimental contexts.
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5. Conclusions
Evidence from carefully designed and performed open and controlled trials involving
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the administration of single or few doses of serotoninergic hallucinogens suggests that
these compounds have antidepressive, anxiolytic, and antiaddictive properties that
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should be further investigated in controlled trials with larger samples sizes. Importantly,
the incidence of severe adverse reactions such as psychotic episodes in these trials is
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extremely low or nonexistent, which is based on careful screening, preparation of the
subject and of the experimental context, and monitoring during drug effects.
Furthermore, evidence from observational studies on the physical and mental health of
ritual ayahuasca users suggest a low toxicity profile for this practice, and even suggests
benefits on mood, anxiety, a substance use disorders.
27
In 2018 the investigation of psilocybin as a possible treatment for treatment-resistant
MDD received the Breakthrough Therapy designation by the FDA, and similar trials are
planned to occur in Europe.20 If these trials show positive results, the carefully
controlled use of psilocybin can become available for treating MDD in the US and
Europe, which could later expand to the off-label and compassionate use of psilocybin
in cancer-related depression and anxiety and maybe in other medical conditions
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characterized by mood and anxiety symptoms. The therapeutic use of LSD should
follow the same steps as those of psilocybin.
In the case of ayahuasca, indigenous and mestizo communities of the Northwestern
Amazon and Brazilian syncretic religions have been using it ritually and therapeutically
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for generations, and these practices are continuously evolving into new forms and
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expanding to new territories. If the clinical trials with ayahuasca continue to show
positive results, regulatory agencies worldwide (including in Brazil) may be faced with
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the challenge of regulating a plant-based hallucinogen/psychedelic.
It should also be considered that a synthetic equivalent of ayahuasca could be developed
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(for example by combing harmine with DMT), which could bypass the complexities of
a plant-based preparation. Chemical changes in the DMT molecule could allow its oral
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absorption. While the use of synthetic equivalents may be unacceptable to some people
involved in the religious ayahuasca practices, it may be a more practical way to have the
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medicine become approved for use in patients. However, legislations regarding the use
of purified DMT are very restrict. Thus, the use of a plant-based preparation that is
already allowed in some countries could be the fastest and cheapest way to make the
medicine reach the population. Moreover, the ritual users of ayahuasca developed over
the generations techniques to use ayahuasca in a safe manner. This could also facilitate
28
the incorporation of ayahuasca as a medicine, at least in countries were these religious
groups are present.
Mood, anxiety, and substance use disorders are among the most important contributors
to global disability. Available medications are ineffective for many patients, induce
significant adverse reactions, and need weeks of daily intake before therapeutic effects
appear. Therefore, new drugs with rapid onset of action and sustained effects after
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single or few doses could be beneficial for many patients.
Moreover, although ketamine (which also has hallucinogenic/psychedelic effects and
has been recently approved by the FDA to treat MDD) has a rapid onset of action and
enduring effects, its use may be associated with tolerance, potential for dependence and
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diversion, and urinary adverse events.117,118 None of these problems have been observed
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in trials with serotoninergic hallucinogen, but long-term studies are lacking. Further
clinical trials using different doses of serotoninergic hallucinogens and larger samples
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are necessary to evaluate the long-term efficacy and safety of these drugs, as well as
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naturalistic studies of large populations of ritual ayahuasca regular users.
Declaration of Conflicting Interests and Source of Funding
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RGS is Fellow of the Brazilian National Post-Doctorate Program (PNPD/CAPES).
JECH receives a CNPq (Brazil) Productivity Fellowship Award. None of the authors
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received any specific funding for writing this manuscript. The authors have no conflict
of interests to disclose.
Acknowledgments
29
RGS is Fellow of the Brazilian National Post-Doctorate Program (PNPD/CAPES).
JECH receive a CNPq (Brazil) Productivity Fellowship Award. None of the authors
received any specific funding for writing this manuscript. The authors have no conflict
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of interests to disclose.
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Figure legends
Figure 1. In Brazil and Peru, ayahuasca is usually prepared with the stalks of the
Banisteriopsis caapi vine (upper left) and with the leaves of the Psychotria viridis bush
(lower left). The prolonged decoction of the plants (center) creates a brownish and bitter
brew that can vary in alkaloid content and visual appearance depending on the
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preparation method (right). Photographs by Giordano Novak Rossi.
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Figure 2. Chemical structures of the main ayahuasca alkaloids. DMT, N,Ndimethyltryptamine; THH, tetrahydroharmine.
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Figure 3. Timeline of the most relevant historical developments in the scientific
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N,N-dimethyltryptamine.
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research of ayahuasca in the last 15 years (see text for details and references). DMT,
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Tables
Table 1. Main therapeutic properties of LSD and psilocybin and level of evidence1
Anxiolytic
Justification
Moderate
Limited preclinical evidence; evidence
from few, small Phase II RCTs in patients
with advanced-stage cancer and nonmalignant life-threatening diseases (LSD,
psilocybin) and with treatment-resistant
MDD (psilocybin)
Moderate
Limited preclinical evidence; evidence
from few, small open-label trials and Phase
II RCTs in patients with advanced-stage
cancer and non-malignant life-threatening
diseases (LSD, psilocybin) and with
treatment-resistant MDD (psilocybin)
Low/Moderate
Limited preclinical evidence; evidence
from few, small open-label trials
(psilocybin for tobacco and alcohol
dependence) and Phase II RCTs (LSD for
alcohol dependence)
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Antiaddictive
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Antidepressive
Level of evidence
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Therapeutic effect
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Other effects
Low
Personality: limited and mixed evidence
from Phase I RCTs (LSD, psilocybin) and
from a small open-label trial with
depressed patients (psilocybin)
OCD: limited preclinical evidence;
evidence from a Phase II RCT with OCD
patients (psilocybin)
Analgesic: limited preclinical evidence;
evidence from few, small open-label trials
and case series in patients with cancerrelated pain
1
Adapted from Dos Santos et al. 2018.18
LSD: lysergic acid diethylamide; MDD: major depressive disorder; OCD: obsessivecompulsive disorder; RCT: randomized controlled trial.
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Table 2. Main therapeutic properties of ayahuasca and its alkaloids and level of
evidence1
Antiaddictive
Low/Moderate
Limited preclinical evidence (DMT);
evidence from observational studies
(ayahuasca), Phase I (ayahuasca) and
Phase II (ayahuasca for anxiety
symptoms in patients with treatmentresistant MDD) RCTs
Moderate
Preclinical evidence (harmine,
ayahuasca); evidence from observational
studies (ayahuasca), Phase I (ayahuasca)
and Phase II (ayahuasca for depressive
symptoms in patients with treatmentresistant MDD) RCTs
Low/Moderate
Preclinical evidence (harmine,
ayahuasca); evidence from observational
studies (ayahuasca)
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Antidepressive
Justification
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Anxiolytic
Level of evidence
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Therapeutic effect
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Other effects:
Evidence from naturalistic/observational
studies (ayahuasca)
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Personality,
cognition, eating
Low/Moderate
disorders, grieving,
mindfulness-related
capacities, general
health
Adapted from Dos Santos et al. 2018.18
MDD: major depressive disorder; RCT: randomized controlled trial.
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Table 3. Main serotoninergic and non-serotoninergic targets for LSD, psilocybin
and ayahuasca alkaloids (DMT and β-carbolines)
Drug
Targets (possible effects)
5HT1A (anxiolytic, antidepressive)
5HT2A (anxiolytic, antidepressive, neuroplasticity)82,84,97,103
5HT2C (antiaddictive)
5HT7 (neuroplasticity)
GLU (antidepressive, neuroplasticity)73
Psilocybin
BDNF (antidepressive, neuroplasticity)95
DMT
AMPA (neuroplasticity)
mTOR (neuroplasticity)
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sigma-1 (DMT; anxiolytic, antidepressive, neuroprotection)
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Cortisol (ayahuasca; antidepressive)96
RIMAs (antidepressive)35
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SRI (THH; antidepressive)
BDNF (antidepressive, neuroplasticity)
GLT-1 (harmine; neuroprotection)
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β-carbolines
(harmine, THH,
harmaline)
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Neurogenesis (antidepressive, neuroplasticity)
Glia/astrocytes (harmine; antidepressive, neuroplasticity)
Targets marked in bold have been implicated in the effects of psychedelics in humans
(references in the table; for the other targets see references in the text).
AMPA: alpha-amino-3-hydroxy-methyl-5-4-isoxazolpropionic glutamatergic receptor;
GLT-1: glutamate transporter 1; GLU: glutamate; mTOR: mammalian target of
rapamycin; RIMAs: reversible inhibitors of monoamine oxidase type A; SRI: serotonin
reuptake inhibitor; THH: tetrahydroharmine; TrkB: tyrosine kinase B receptor.
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