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published: 02 March 2016
doi: 10.3389/fphar.2016.00035
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Reviewed by:
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Eduardo Ekman Schenberg,
Instituto Plantando Consciência, Brazil
*Correspondence:
Ede Frecska
efrecska@hotmail.com
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Published: 02 March 2016
Citation:
Frecska E, Bokor P and Winkelman M
(2016) The Therapeutic Potentials
of Ayahuasca: Possible Effects
against Various Diseases
of Civilization. Front. Pharmacol. 7:35.
doi: 10.3389/fphar.2016.00035
The Therapeutic Potentials of
Ayahuasca: Possible Effects against
Various Diseases of Civilization
Ede Frecska1*, Petra Bokor2and Michael Winkelman3
1Department of Psychiatry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary, 2Doctoral School of
Psychology, University of Pécs, Pécs, Hungary, 3School of Human Evolution and Social Change, Arizona State University,
Tempe, AZ, USA
Ayahuasca is an Amazonian psychoactive brew of two main components. Its active
agents are β-carboline and tryptamine derivatives. As a sacrament, ayahuasca is still
a central element of many healing ceremonies in the Amazon Basin and its ritual
consumption has become common among the mestizo populations of South America.
Ayahuasca use amongst the indigenous people of the Amazon is a form of traditional
medicine and cultural psychiatry. During the last two decades, the substance has
become increasingly known among both scientists and laymen, and currently its use
is spreading all over in the Western world. In the present paper we describe the
chief characteristics of ayahuasca, discuss important questions raised about its use,
and provide an overview of the scientific research supporting its potential therapeutic
benefits. A growing number of studies indicate that the psychotherapeutic potential of
ayahuasca is based mostly on the strong serotonergic effects, whereas the sigma-1
receptor (Sig-1R) agonist effect of its active ingredient dimethyltryptamine raises the
possibility that the ethnomedical observations on the diversity of treated conditions
can be scientifically verified. Moreover, in the right therapeutic or ritual setting with
proper preparation and mindset of the user, followed by subsequent integration of the
experience, ayahuasca has proven effective in the treatment of substance dependence.
This article has two important take-home messages: (1) the therapeutic effects of
ayahuasca are best understood from a bio-psycho-socio-spiritual model, and (2) on the
biological level ayahuasca may act against chronic low grade inflammation and oxidative
stress via the Sig-1R which can explain its widespread therapeutic indications.
Keywords: addiction medicine, ayahuasca, diseases of civilization, dimethyltryptamine, oxidative stress
INTRODUCTION
Ayahuasca, a psychoactive Amazonian sacrament, has raised increased scientific and lay interest
during the last two decades. Traditionally ayahuasca has been used in Ecuador, Columbia,
Peru, and Brazil, where it is also known as natema,hoasca,daime,yagé, or yajé. The
decoction is prepared by simultaneously boiling two admixture plants, the Banisteriopsis caapi
Abbreviations: DMT, dimethyltryptamine; ER, endoplasmic reticulum; LGI, low-grade inflammation; MAM,
mitochondrion-associated membrane; MDP, mesolimbic dopamine pathways; PTSD, post-traumatic stress disorder;
Sig-1R, sigma-1 receptor; UPR, unfolded-protein response.
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Frecska et al. Therapeutic Potentials of Ayahuasca
(Malpighiaceae) containing β-carboline type alkaloids such as
harmine and tetrahydroharmine; and most commonly Psychotria
viridis (Rubiaceae), which provides the psychoactive alkaloid
DMT (McKenna, 2004;Szára, 2007). Sometimes Psychotria
viridis is substituted by other DMT containing plants such
as Diplopterys cabrerana (formerly B. rusbyana) of the family
Malpighiaceae. The name ayahuasca is a compound word
in Quechua language, where aya means soul, ancestors or
dead persons and wasca (huasca) means vine or rope (Luna,
2011). Therefore, the most prevalent translation of the word
is “vine of the soul”. Skeptics may prefer the other linguistic
alternative: “rope of death”, but this paper will provide
arguments favoring the former interpretation above the latter
one.
Ayahuasca has been used as a central element of religious,
magical, curative, initiation, and other tribal rituals for millennia
(Naranjo, 1986), originally by the indigenous groups and later
by the mestizo populations of the region, who respect the
brew as a sacrament and value it as a powerful medicine. The
indigenous and mestizo communities regularly use ayahuasca to
treat physical ailments, mental problems and frequently handle
their social issues, spiritual crises with the help of the brew.
A Peruvian tradition called vegetalismo regards ayahuasca as one
of the teacher plants that convey knowledge to humans (Luna,
1986), and considers the experience induced by its ingestion
trabajo (work). In addition to its traditional and mestizo uses,
ayahuasca also forms a central component of the rituals of three
Brazilian syncretic churches: the Santo Daime, the União do
Vegetal and the Barquinha. The history of these churches dates
back to the first half of the 20th century, and by now they are
present in 23 countries (de Rios and Rumrrill, 2008;Liester and
Prickett, 2012). Obviously there is a striking discrepancy between
the indigenous South American and official Western view1on
ayahuasca use, which calls for scientific explanation and a healthy
resolution.
Due to the growing popularity of the sacrament, masses
of people from all parts of the world travel to the Amazon
to participate in ayahuasca rituals. This unique phenomenon
characterized by some as “drug tourism” (de Rios, 1994) is
not as frivolous pursuit as it sounds (Grunwell, 1998), since
a significant number of travelers searches for spiritual and
therapeutic opportunities. The principal motivations can be
characterized as: seeking improved insight, personal growth;
emotional healing; and contact with a sacred nature, deities,
spirits and natural energies produced by the ayahuasca
(Winkelman, 2005). The trend of popularization—known as
the “globalization of ayahuasca”—flows both ways, as this
Amazonian tradition spreads beyond its native habitat and
gets adopted into non-indigenous circles of the Western world
1The purpose of traditional ayahuasca use has been to heal both physical and
spiritual ailments. Mestizo curanderos consider ayahuasca as a plant teacher Luna
(1984). DMT has been scheduled worldwide as an illicit drug with no medical
use. Due to their DMT and/or β-carboline content ayahuasca constituent plants
are included as controlled substances in several countries (i.e., Australia, Bulgaria,
Canada, France, Lithuania, Poland, Switzerland, and Ukraine). Ayahuasca’s
classification in France as stupéfiant illustrates well the discrepancy with Mestizo
views.
(Tupper, 2008) either within or outside of the context of syncretic
churches.
During the last couple of years several publications have
been written with the goal to summarize our knowledge
about ayahuasca from various perspectives (see in Labate
and Cavnar, 2014). The primary aim of this article is to
give an overview about the facts and hypotheses related to
the possible therapeutic mechanisms of the brew in light
of recent advances of the field; with the secondary aim
of addressing its known adverse effects. By adhering to a
biopsychosociospiritual model (Bishop, 2009) the authors
will explore every level in the following order: starting
with biochemistry, neuropharmacology, physiology, brain
imaging, then moving to the psychological effects, social
ramifications, and finally addressing spiritual implications.
Efforts are taken to keep a balance among the biomedical,
psycho-social and spiritual aspects of healing since “Madre
Ayahuasca, la sagrada medicina (Mother Ayahuasca, the
sacred medicine)” is best understood within this quadrilateral
framework.
THE NEUROBIOLOGICAL
BACKGROUND OF AYAHUASCA
From a pharmacological perspective the main ingredients of
ayahuasca are DMT and the β-carboline derivative alkaloid
harmine, harmaline, and tetrahydroharmine (Callaway et al.,
1996). The harmine, tetrahydroharmine, and harmaline work
as reversible inhibitors of the A-type isoenzyme of the
monoamine oxidase (MAO), while tetrahydroharmine also
exerts selective serotonin reuptake inhibitor (SSRI) effects
(dos Santos, 2010). The hallucinogenic component DMT is
abundant in the plant kingdom (Khan et al., 2012) and it is
also present in mammalian organism; studies have detected it
in human blood, brain, cerebrospinal fluid (Wallach, 2009),
and the pineal gland of rats (Barker et al., 2013). While
DMT is classified as an endogenous hallucinogen, together
with bufotenin and 5-methoxy-DMT (Christian et al., 1977;
Hollister, 1977), its exact function is yet unclear (Barker et al.,
2012).
More than 50 years of research has proven to be insufficient
to provide a proper neurobiological description of the role of
endogenous hallucinogens. This is in part due to a paradigm
problem in which these natural substances with many biological
functions have been primarily studied in terms of being
“hallucinogens,” producing false perceptions. It is obvious
that these substances play a role in producing alterations of
consciousness such as dreaming, psychosis, and near death
experience (Strassman, 2001). These effects presumably reflect
action on serotonin (5-HT) receptors (5-HT1A, -2A and -2C)
as well as the trace amine associated receptors (supposedly
TAAR6) (Wallach, 2009). While the scientific knowledge about
trace amine associated receptors is rapidly increasing, it is
still deficient. However, the Sig-1R action of DMT may turn
out to be more revealing about its physiological function (see
below).
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Dimethyltryptamine exerts anxiolytic effects through 5-HT1A
receptor agonism (Jacob and Presti, 2005), and its psychedelic
effect is connected to its 5-HT2A receptor-activating capacity
(Nichols, 2004). However, simple 5-HT receptor mediated
actions are not sufficient to explain drug-induced hallucinations
since 5-HT itself, and some 5-HT2A agonists (i.e., lisuride)
are not hallucinogenic. Over the past two decades, it became
clear that different agonists having similar binding affinities
for the same sites, could elicit distinct signaling pathways
within the cell. These observations are interpreted on the
basis of receptor–receptor and ligand–receptor interactions
such as “receptor oligomerization,” “receptor trafficking,” or
“biased agonism” (Moreno et al., 2011;Borroto-Escuela et al.,
2014) which activate different G proteins resulting in divergent
intracellular cascades. Figure 1 schematically illustrates the
mechanism of receptor dimerization wherein metabotropic
glutamate (mGlu2) receptors belonging to an entirely separate
receptor family form a complex with the 5-HT receptor
and trigger an intracellular pathway for hallucinogenic action.
This may explain why lisuride which has a similar receptor
binding profile to the chemically similar ergoloid lysergic
acid diethylamide (LSD), lacks the psychedelic effects of its
sister compound (Rogawski and Aghajanian, 1979). In case of
DMT, a recent study (Carbonaro et al., 2015) concluded that
while 5-HT2A receptors play a major role in mediating its
effects, mGluR2 receptors likely modulate the action. Unlike
the related tryptamine derivative psilocybin, DMT does not
precipitate tolerance upon repeated use (Strassman et al., 1996);
this produces further complications for simple receptor-based
interpretations.
The latest identified target for DMT’s action is the Sig-
1R. Sigma receptors were originally misclassified as opioid
receptors but later turned out to be non-opioid receptors of
FIGURE 1 | Cross-talk between receptors by dimerization. The 5-HT2A
receptor mediated hallucinogen-specific intracellular pathway requires the
dimerization of the 5-HT2A receptor with the mGlu2 receptor. This unique (G
protein-coupled) pathway is associated only with the dimer and not activated
by either receptor alone. Serotonin lacks the mGlu2 receptor binding feature
and the psychotropic effects of hallucinogens are abolished by the elimination
of the mGlu2 receptor. The 5-HT2A-mGlu2 dimer is the prime target of some
serotonergic hallucinogens (Moreno et al., 2011).
their own type. The Sig-1R subclass has been demonstrated to
consist of chaperone molecules concentrated in normal cells
of the brain, retina, liver, lung, heart, immune system, but
also in many tumor lines (Maurice and Su, 2009). Chaperones
are proteins that assist the correct folding of other protein
clients. The Sig-1R chaperon has many unique features with
an amino acid sequence distant from mammalian proteins and
homologous to fungal sterol isomerases (Moebius et al., 1997).
Sig-1R sites are concentrated in the human brain with the
highest densities in the cerebellum, nucleus accumbens, and
cerebral cortex (Weissman et al., 1988). Inside the cell Sig-1R is
located mainly at the ER–mitochondrion interface—referred to
as the MAM—and regulates cellular bioenergetics, particularly
under stressful conditions (Su et al., 2010;Mori et al., 2013;
Hayashi, 2015). There is another mode of Sig-1R action at the
plasma membrane where it translocates under stimulation by
agonists.
As an intracellular receptor localized at the MAM, Sig-1R
integrates many signaling pathways and serves as a “tunnel”
for lipid transport and Ca2+-signaling between the ER and
mitochondria (Hayashi and Su, 2007). Its involvement is critically
in ion channel activities and neuronal differentiation. The wide
scope and effect of ligand binding to Sig-1R indicate that Sig-
1Rs are intracellular signal transduction amplifiers (Su and
Hayashi, 2003). The ER-mitochondrion interface at the MAM
serves as an important subcellular entity in the regulation of
cellular survival via Sig-1R by enhancing the stress–response
signaling (Mori et al., 2013). Sig-1R also protects the cells against
reactive oxygen species and activates the antioxidant response
elements (Pal et al., 2012), therefore Sig-1R agonists such as
DMT may function as indirect antioxidants. More interestingly
the induction of Sig-1R can repress cell death signaling: up-
regulation of Sig-1R suppresses the apoptosis caused by ER
stress (Omi et al., 2014). Tryptaminergic trace amines as well
as neurosteroids (e.g., dehydroepiandrosterone, pregnenolon) are
endogenous ligands that activate the Sig-1R (Fontanilla et al.,
2009).
The Sig-1R ER chaperone function is essential for the
metabotropic receptor signaling and for the survival against
cellular, particularly ER stress. Dysfunctional chaperones are
responsible for numerous diseases (Tsai et al., 2009). Altogether,
no other receptor has ever been associated with so many
different diseases as the Sig-1R. It has so far been implicated
in illnesses like Alzheimer’s disease, Parkinson’s disease, cancer,
cardiomyopathy, retinal dysfunction, perinatal and traumatic
brain injury, frontal motor neuron degeneration, amyotrophic
lateral sclerosis, HIV-related dementia, major depression, and
psychostimulant addiction (Su, 2015). How those two modes
of actions of the Sig-1R may relate to this plethora of diseases
remain to be clarified but its protective influence has been
verified on various aspects of cellular processes, such as calcium
signaling, mitochondrial functions, ER stress, survival and
apoptotic pathways (to be discussed later), and tumor cell
proliferation (Tsai et al., 2014). As Sig-1Rs are expressed in
the immune system, immunomodulatory functions have also
been reported in the literature (Szabo et al., 2014;Dong et al.,
2015).
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THE POSSIBLE ROLE OF DMT IN
TISSUE PROTECTION AND
NEUROREGENERATION
Dimethyltryptamine is considered as a natural ligand, an
endogenous agonist of the Sig-1R (Fontanilla et al., 2009). It
is assumed that the Sig-1R might be involved in the DMT-
induced psychedelic effects (Su et al., 2009); however, this is
somewhat counterintuitive since many drugs—including non-
hallucinogens—bind promiscuously to the Sig-1R with higher
affinity than DMT. The results of a recent surge in Sig-1R
research are pointing toward a different horizon by outlining a
physiological role of DMT instead of the long-held pathological
view. If the Sig-1R promotes cellular (neuronal) survival against
oxidative stress (Pal et al., 2012) and regulates immune processes
(Jarrott and Williams, 2015), one may attribute the same
physiological role to its endogenous ligands, like DMT (Frecska
et al., 2013). Since the Sig-1R is also known to regulate
morphogenesis of neuronal cells, such as neurite outgrowth,
synaptogenesis, and myelination (Ruscher and Wieloch, 2015);
neurorestorative effects are reasonably expected from DMT. In
a previous paper (Frecska et al., 2013) we concluded that the
function of DMT may extend central nervous activity and involve
a more universal role in cellular protective mechanisms. We
provided converging evidence that while DMT is a substance
which produces powerful psychedelic experiences, it is better
understood not as a hallucinogenic drug of abuse, but rather an
agent of significant adaptive mechanisms like neuroprotection,
neuroregeneration, and immunity.
Nevertheless, immunoregulation by DMT is a bidirectional
process. Sig-1Rs are expressed together with 5-HT receptors
in immune cells conveying both inflammatory and anti-
inflammatory signals (Szabo, 2015). These receptors are essential
in the “fine-tuning” of innate and adaptive immune responses.
Human clinical studies showed that ayahuasca can alter the
number and distribution of blood immune cells in a way that
can increase the antiviral and anti-tumor immunity of the
consumer (reviewed in Frecska et al., 2013). Ayahuasca also
influences the distribution of lymphocyte subpopulation: CD4
lymphocytes decrease and the number of natural killer cells
increase significantly with time (dos Santos et al., 2012). The
possible anti-cancer activity of the decoction makes it a promising
candidate for further researches in novel pharmacotherapies
(Schenberg, 2013). Furthermore, DMT may also be an adaptogen
increasing the survival rate of neurons or other cell types during
acute hypoxia or under chronic oxidative stress.
MECHANISMS PROPOSED AS A BASIS
FOR AYAHUASCA’s EFFECTS ON
SYSTEMIC AND DEGENERATIVE
ILLNESSES
Chronic LGI is becoming widely accepted as a common basis
for many diseases of civilization (Ruiz-Núñez et al., 2013;
Table 1). Repeated psychological stress, constant environmental
pollution, and smoking behavior are associated with chronic LGI,
which is one of the main causes of insulin resistance that is
the pathological foundation of metabolic diseases (Aseervatham
et al., 2013). Moreover, chronic LGI is involved in all stages of the
atherosclerotic process and is being increasingly recognized as a
universal mechanism in various chronic degenerative diseases,
such as autoimmune diseases, certain cancers, neuropsychiatric
diseases (e.g., Alzheimer’s disease, Parkinson’s disease, major
depression), and osteoporosis. Dysbiosis of the gut microbiota
with increased intestinal permeability (“leaky gut”) are all
possible root causes of LGI (Carrera-Bastos et al., 2011).2
Chronic LGI is closely related to oxidative stress and ER
stress, and together they form a molecular web, a network
interwoven with loops exacerbating each other (Chaudhari et al.,
2014). Regulation of protein folding homeostasis (proteostasis)
is essential for the execution of fundamental cellular functions.
ER is the cellular organelle responsible for this role. Disturbance
in protein folding is central to a large diversity of illnesses
and growing evidences suggest ER stress as being a cardinal
component in the development of a pathological condition (Díaz-
Villanueva et al., 2015;Srivastava and Kumar, 2015). The cause of
diseases may be various, but ER stress resulting from chronic LGI
or oxidative stress may contribute to the severity and the poor
prognosis of the diseased state. ER function can be altered and
made dysfunctional by hypoxia, hyperglycemia, hyperlipidemia,
viral infections, disturbances in cellular calcium levels, redox
regulation, or by endogenous reactive oxygen species production
(Chaudhari et al., 2014). These so-called stress signals exhaust the
ER machinery and result in accumulation of unfolded proteins.
An adaptive process called UPR is triggered with an aim to restore
ER homeostasis. However, if the stress signal is severe and/or
prolonged cell death pathways are elicited in form of apoptotic
and pro-inflammatory reactions (Hiramatsu et al., 2015).
ER stress with UPR is thought to play a key role in
neuropsychiatric illnesses such as Alzheimer’s disease,
Parkinson’s disease, amyotrophic lateral sclerosis, bipolar
disorder, and in other illnesses of civilization such as
atherosclerosis, diabetes, cancer, autoimmune, and cardiovas
cular disorders (Chaudhari et al., 2014). All of these disorders
may have common mechanism: failure of protein homeostasis.
Deficits in ER-proteostasis lead to the formation of misfolded
proteins characteristic of neurodegenerative diseases (Hetz and
Mollereau, 2014;Plácido et al., 2014). Originally UPR has a cell
protective effect: it prevents overload of ER lumen with newly
synthesized proteins and activates degradation of misfolded
proteins. However, misfolded proteins directly enter from ER
into mitochondria and after prolonged UPR activation they
2Based on more and more converging evidence, it is tempting to speculate that
the “Grand Unification Theory” (GUT) of medicine can be based on the gut.
According to this unifying concept, a “leaky gut” lets some gut contents (e.g.,
bacterial endotoxins) to enter circulation and shifts the anti-inflammatory ↔pro-
inflammatory cytokine balance to pro-inflammatory direction. A long-standing
pro-inflammatory condition with the simultaneous oxidative, mitochondrion, and
ER stress (see in the text) can change the permeability of other membranes in
the body (e.g., blood-brain barrier, synovial stratum, endothel, bronchial mucosa,
and/or alveolar wall). This way the permeability problem of the gut extends to other
barriers, and a universal membrane deficiency may serve as a common ground of
many illnesses of civilization.
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TABLE 1 | Common diseases of civilization.
•Metabolic syndrome •Neurodegenerative diseases
•Cardiovascular diseases •Alzheimer’s dementia
•Cancer •Autism
•Osteoarthrosis, osteoporosis •Depression
•Autoimmune disorders •Schizophrenia
•Chronic obstructive pulmonary disease •Attention deficit hyperactivity disorder
•Macular degeneration •Chronic pain syndrome
The table lists those illnesses which—due to different diet, lifestyle, and
environmental factors—are more prevalent in advanced agricultural and industrial
societies as compared to hunter-gatherers, traditional pastoralists and horticultural
communities, or have poorer outcome in the urban environment (after; Carrera-
Bastos et al., 2011;Aseervatham et al., 2013;Ruiz-Núñez et al., 2013;Srivastava
and Kumar, 2015).
cause dysfunction in energy production (Schon and Area-
Gomez, 2013;Volgyi et al., 2015). Targeting Sig-1R by agonists
may regulate ER stress and UPR, manage ER perturbations,
regulate the formation of toxic misfolded proteins, and prevent
the cell-killing apoptotic pathways (Rivas et al., 2015). Similar
effects are expected from the endogenous Sig-1R ligand DMT.
Tracing Alzheimer’s disease, Parkinson’s disease, or major
depression to inflammatory processes (chronic LGI), “leaky
gut”, ER stress, protein folding deficit, glutamate excitotoxicity,
mitochondrial dysfunction, calcium overload, death receptor
pathways, and Sig-1R involvement means following the loops
of the same web of interactions since all are different aspects of
the same core phenomenon. The Sig-1R located at the MAM
is an excellent candidate for interfering with the conversion
of environmental stress in general and psychological stress in
particular into cellular stress response by its regulatory effect on
signaling between the ER and mitochondrion (Hayashi, 2015).
This is the point where DMT and ayahuasca take their place in
this puzzle via Sig-1R action. It seems to us that the ingenuity
of South American people discovered a broad-spectrum remedy,
which hits the dead center of the discussed vicious circle of
the malfunctioning molecular web involved in oxidative stress
(Figure 2).
There is more to ayahuasca’s therapeutic potentials besides
its DMT content and above the neurobiological level. The
psychological aspects will be discussed later. Here we address
the other important active agents of ayahuasca, the β-carboline
alkaloids, which act as selective, reversible MAO-A inhibitors
(McKenna and Towers, 1984;dos Santos, 2010) with almost
no effect on MAO-B (Herraiz et al., 2010). MAO inhibition is
crucial as without the β-carbolines the DMT content of orally
ingested ayahuasca would be broken down before crossing the
blood-brain barrier. Moreover, the fact that MAO is located
inside cells bound to the outer membrane of mitochondria in
proximity of the Sig-1R raises the possibility that the synergy
between the active compounds of ayahuasca happens not only
at the periphery, but also inside neurons and glial cells. Without
this intraneuronal MAO inhibition less DMT would reach the
Sig-1R at the MAM. Furthermore, there are indications that
the β-carboline alkaloids themselves have medicinal properties,
such as anthelmintic (Hassan, 1967), antimicrobial (Ahmad et al.,
1992), and vasorelaxant (Shi et al., 2001) effects, in addition
FIGURE 2 | The polygon of self-destructive forces. Every angle of this
octagon represents a pathophysiological process closely related to almost all
of the others, and each pathological process is known to be involved in
several illnesses of civilization (see Table 1) with extensive overlap (e.g.,
Alzheimer’s disease has chronic low grade inflammation, increased nitric oxide
signaling, calcium dyshomeostasis, apoptosis, mitochondrial dysfunction,
oxidative, and endoplasmic reticulum stress in its etiopathology). The central
position of the Sig-1R illustrates its significant influence in mitigating these
pathological processes. The number of angles is rather arbitrary: one may add
others like insulin resistance, glutamate release, plasma membrane deficiency,
etc.
to ethnopsychiatric (Shepard, 1998), sociopsychotherapeutic
(Andritzky, 1989), and rehabilitative functions (Mabit et al.,
1995). Harmala alkaloids have demonstrated strong psychoactive
properties (Naranjo, 1967), and they act as stimulants on
the central nervous system (Venault and Chapouthier, 2007).
Osório’s team (Osório et al., 2011) attributed an observed
antidepressant effect of ayahuasca (Osório et al., 2015) to
these alkaloids, which is in line with ethnographic observations
suggesting that many native users of ayahuasca ascribe
sacramental respect to the B. caapi and not the DMT containing
plant constituents.
From a biological standpoint the extent to which DMT
and harmine play a role in ayahuasca effects is difficult
to judge since the brew contains a significant amount of
bioactive substances in addition to the indole and β-carboline
alkaloids. An important example of such compounds is the
group of antioxidant polyphenols, which can also be linked
to the observed immunomodulatory effects (Szabo et al.,
2014). Antioxidants are known for their capacity of reducing
inflammatory processes or even stopping them (Grimble, 1994;
Geronikaki and Gavalas, 2006). Malignant transformation is
also inhibited by polynucleotides through providing protection
against oxidative stress for other cellular compounds (Marquardt,
1984). In addition to the immunomodulatory effects, ayahuasca
may also exhibit neuroprotective and neurorestorative qualities.
Hence, it has been suggested that ayahuasca can be applied
therapeutically in Parkinson’s and other neurodegenerative
diseases (Samoylenko et al., 2010). Ayahuasca’s high content of
bioactive materials points toward a combined mechanism of the
various effect and calls for further clinical research to reveal the
detailed pharmacology of the constituents.
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VEGETATIVE AND ADVERSE EFFECTS
OF AYAHUASCA
Serotonin stimulation is known to affect the whole organism
not just the brain. It causes vegetative changes such as increase
in systolic and diastolic blood pressure, pulse rate, provokes
nausea, vomiting, and pupil dilation (Boyer and Shannon, 2005).
Ayahuasca was found to significantly raise the systolic and
diastolic blood pressure by 35 Hgmm and the pulse rate by
26 bpm in a 2 min time interval while the rate of increase declines
upon repeated intake (Riba et al., 2001). Besides actions on
the vegetative nervous system ayahuasca also induces endocrine
response. Elevation in prolactin, cortisone, and growth hormone
levels has been reported (dos Santos et al., 2011;dos Santos et al.,
2012).
While the intravenously injected DMT can cause considerable
cardiac stress, it is less burdensome for humans if taken orally.
Based on animal research Gable (Gable, 2007) developed a
model calculation that determined the median lethal dose of
DMT in 8 mg/kg for oral ingestion in human subjects. The
average ceremonial dose of DMT in ayahuasca preparations
is about 27 mg; therefore, the safety margin for ayahuasca is
approximately 20 (Gable, 2007). Scientific sources mention only
one fatal case of ayahuasca consumption (Sklerov et al., 2005).
The toxicological judgment based on uncontrolled street abuse is
largely influenced by cases when extra ingredients other than the
two basic components (e.g., datura or tobacco) are mixed into the
decoction since the intoxicating effects of these extra ingredients
can in turn be attributed to ayahuasca by the toxicological reports.
The MAO-A inhibition induced by the β-carboline alkaloids
presumably results in an increased level of serotonin in the
neural pathways, which theoretically can lead to serotonin
syndrome in extreme cases (Callaway and Grob, 1998).
However, the competitive, reversible nature of the inhibition
may explain the lack of well documented serotonin syndrome
cases despite the globalization of ayahuasca and probable
inclusion of a large number of session participants taking
SSRIs. What makes the issue more complicated is that at
the time of onset, ayahuasca’s vegetative effects represent
some sort of mild or moderate serotonin syndrome.
Nevertheless, materials which may negatively interact
with ayahuasca and capable to induce hyperserotonemia
include ginseng (Panax ginseng), St John’s-wort (Hypericum
perforatum), dextromethorphan, 3,4-methylenedioxy-N-
methylamphetamine, SSRIs or MAO inhibitors (Callaway
and Grob, 1998). Furthermore, cardiovascular or endocrine
problems, abnormal lipid metabolism, glaucoma, fever, and
pregnancy are contraindications for ayahuasca consumption
(Gable, 2007).
A tendency for psychosis or family history of mental illness
predispose ayahuasca for triggering a psychotic episode or long-
term depersonalization syndrome. dos Santos and Strassman
(2011) reported a case where a young male individual with
prior experience in the use of psychedelic substances and having
previous positive experience with ayahuasca fell repeatedly into
psychosis after two Santo Daime ceremonies. Even without
proper screening the statistical probability of such cases seems to
be low. The majority of the encountered problems originate from
the unpreparedness of the participants, the inadequate setting
(the parameters of the circumstances in which the ingestion of
ayahuasca takes place), the lack of socio-cultural-cosmological
embeddedness of the experiences or the lack of their integration
afterward.
There is not yet any scientific evidence—or even personal
reports—indicating that ayahuasca use elicits substance
dependence. The ritual use of ayahuasca shows considerable
differences to the traditional psychosocial harms of drug
consumption (Fábregas et al., 2010). As with other psychedelic
experiences an elevated emotional state may remain for a few
days or weeks after ayahuasca consumption. In such cases life
seems more beautiful and joyful, filled with a deeper meaning
than before the experience. Therefore a feeling of emptiness or
grayness can arise after the experience fades away but this is not
generally the case.
CENTRAL NERVOUS SYSTEM EFFECTS
OF AYAHUASCA
Riba’s group (Riba et al., 2006) conducted single-photon emission
computed tomography to reveal the brain areas affected by
ayahuasca ingestion. Increased activity was recorded bilaterally
in the anterior insula, in the fronto-medial cortical anterior
cingulate of the right hemisphere and the left amygdala. The
latter two play a role in the regulation of emotional arousal and
the information processing of emotions. Moreover the anterior
cingulate is involved in somatic attention and the experience of
subjective feeling states (Bouso and Riba, 2011). By analyzing
the binocular rivalry under the effect of the brew, conclusions
were drawn that ayahuasca influences hemispheric dominance
(Frecska et al., 2003) and gamma oscillations (Frecska et al.,
2004).
Using functional magnetic resonance imaging technique de
Araujo et al. (2012) found that ayahuasca induces a robust
activation of occipital, temporal, and frontal areas during a
closed-eyes imagery task. The consumption of the brew activated
an extended network in the brain (that has previously been
correlated to visual perception, memory and intention) in which
the Brodmann areas BA10, BA17, BA30, and BA37 play a
central role. The ayahuasca-produced stimulation of the primary
visual cortex was comparable to the effect of natural images
with the eyes open. Moreover, this effect correlated significantly
with the occurrence of perceptual changes measured by rating
scales. These authors concluded that by boosting the intensity of
imagination to the same level of sensory perception ayahuasca
lends a status of reality to inner experiences.
Several studies have employed electroencephalographic
methods to record brain oscillatory activity after ayahuasca
intake. Results indicated significant power increase in the slow
gamma (36–44 Hz) band at left occipito-temporo-parietal
electrodes, with tendencies to power decreases in theta and
delta bands (Don et al., 1998). Another study revealed alpha
power decrease at left temporal and centro-parietal sites peaking
90 min after ingestion, while decreases were found for delta
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and theta waves in the parietal areas (Riba et al., 2002). The
analysis of Alonso’s group (Alonso et al., 2015) showed that
ayahuasca preparation significantly changed the coupling of
brain oscillations between anterior and posterior recording
sites in the following pattern. Frontal structures decreased
their influence over posterior (central, parietal, and occipital)
sites which correlated with the intensity of subjective effects.
On the other hand, posterior areas increased their influence
over signals measured at anterior locations in parallel with the
degree of incapacitation experienced (Alonso et al., 2015). These
effects reflect the general action of psychedelics hypothesized by
Winkelman (2007) in the proposed concept of psychointegrator,
where the normal domination of cognition by frontal brain
activity is replaced by intense discharges from the lower areas of
the brain that are imposed on the frontal cortex.
Another recent project addressing the time course of
ayahuasca effects on the electroencephalogram revealed a
biphasic feature (Schenberg et al., 2015). After 50 min from
ingestion of the brew there was observed a reduced alpha
band activation over the left parieto-occipital cortex, followed
by increased slow- and fast-gamma power (30–50 and 50–
100 Hz, respectively) between 75 and 125 min. The slow-
gamma power increase was located at the left centro-parieto-
occipital, left fronto-temporal, and right frontal cortices while
fast-gamma increases were significant at left centro-parieto-
occipital, left fronto-temporal, right frontal, and right parieto-
occipital areas. These effects correlated significantly with the
circulating levels of ayahuasca’s main ingredients, such as DMT,
harmine, tetrahydroharmine, and some of their metabolites.
The significance of gamma power in the broader context
of consciousness involves its role in binding of information
across diverse regions of the brain and in driving theta wave
responses.
Based on the conceptual framework of integrated information
theory Gallimore (Gallimore, 2015) supposed that the promotion
of gamma oscillations is responsible for the perceptual effects
of psychedelic drugs and surmised that the psychedelic state
might be characterized by an increase in integration compared
to a normal waking state. Gallimore referenced a small study
which employed quantitative electroencephalography to measure
changes in gamma oscillatory power and coherence following
ayahuasca ingestion and reported a highly integrated brain
state (Stuckey et al., 2005). This finding is in accordance with
an earlier study showing an increase of the gamma band
power in ayahuasca users (Don et al., 1998). However, contrary
to these results, other studies found generalized decreases in
power across all frequency bands (Riba et al., 2002, 2004).
While the neuropsychological correlates and clinical relevance
of these electroencephalogram patterns remain to be elucidated,
Gallimore’s work underscores the necessity of a comprehensive
approach to ayahuasca’s pharmacology and the mechanisms of its
cognitive, affective, and emotional effects.
The central nervous system effects of ayahuasca are distinct
from our normal resting mental states sustained by the Default
Mode Network as defined by specific brain areas which are
activated when the person is at rest and/or not engaged in
specific mental tasks. This Default Mode Network is usually
active in meta-cognition, day-dreaming, reflecting on memories,
but is apparently disabled by psychedelics (Carhart-Harris et al.,
2014). Psychedelics alter this relaxed brain function by reducing
cerebral blood flow and the oscillatory power in brain areas
of the Default Mode Network that are typically synchronized
and functionally connected. Ayahuasca decreases the functional
connectivity within the prefrontal cortex and in connections with
other areas of the brain that are involved in a wide range of
ordinary cognitive processes (Palhano-Fontes et al., 2015).
This decoupling phenomenon results in increased flexibility
of high-level networks involving a more open communication
among them. It permits a freer operation of the medial temporal
lobe structures, which are associated with the release of cognitive
states closely related to emotions and fears. The outcome
is a complex mental condition characterized by increased
somatic awareness and subjective feelings, but lacking the
metacognitive ability for self-reflection on personal behavior and
one’s mentalization provided by the frontal cortex. This so-called
primary cognition produces a state of heightened suggestibility
because of the suspension of the frontal networks that are
typically used to maintain control over mental processes and
perceptions of the outside environment.
Bouso and Riba (2014) suggested that these varied effects of
ayahuasca may also result from its ability to increase activity in
various areas of the right hemisphere (anterior insula, anterior
cingulate/fronto-medial cortex). These areas are implicated in
somatic awareness, emotional arousal, feelings, and processing
of emotional information. Ayahuasca also appears to increase
activity in the left hemisphere’s amygdala/parahippocampal gyrus
structures that play a role in emotional arousal and memory,
enabling ayahuasca to make repressed memories conscious
and to re-experience emotions associated with them. Such
apperception enables one to reprocess these memories in more
constructive ways and with a potential for processing traumatic
pasts in novel ways.
NEUROCHEMICAL AND
PSYCHOPHYSIOLOGICAL MECHANISMS
PROPOSED AS A BASIS FOR
AYAHUASCA’S EFFECTS ON ADDICTION
There are a variety of biochemical and physiological mechanisms
through which ayahuasca can effectively address addictions
(Prickett and Liester, 2014). The inclusion of two plant species
in ayahuasca provides a variety of mechanisms for direct and
indirect actions on both dopaminergic and serotonergic systems.
Since the effects of DMT appear to reflect the general effects of
tryptamines (e.g., DMT, LSD, bufotenin, psilocin, and psilocybin)
some of therapeutic mechanisms would also be shared with these
related substances. The effects of the harmine alkaloids, however,
would be unique to ayahuasca. Separate studies with each of these
chemical classes will be necessary to distinguish their different
contributions.
Liester and Prickett (2012) proposed that “ayahuasca exerts
anti-addictive properties via its direct and indirect actions
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on dopaminergic and serotonergic neurons in the mesolimbic
pathway. Ayahuasca raises global 5-HT levels attenuating
withdrawal effects and mitigating against potential dopaminergic
excess when utilizing dopamine (DA) agonists. Ayahuasca
balances DA in the MDP between the low levels associated
with withdrawal and the elevated levels associated with initiation
and reinforcement of addictive behavior” (Prickett and Liester,
2014). Therefore, the resolution of addiction through ayahuasca’s
therapeutic potentials may act on four levels: (1) reducing brain
DA level in the MDP through effects on the 5-HT receptors,
which in turn (2) interferes with the synaptic plasticity. This
neurochemical mechanism is supported by (3) psychological
insights and processing of repressed traumas, enhancing decision
making capabilities, which allowing the person to (4) examine
first person transcendental experiences.
Additional neurophysiologic mechanisms for ayahuasca’s
therapeutic effects involve neuroplasticity, the ability of neurons
to alter their synaptic connections. Constituents of ayahuasca
may affect brain derived neurotropic factor release through
effects on the GABAergic and glutamatergic systems. These are
involved in producing neuroplastic changes through triggering
changes in gene expression which affect the architecture and
communication between neurons. These exert effects on the
existing neural circuits which mediate maladaptive addictive
habits in stimulating the production of new circuits supporting
new behaviors, with ayahuasca facilitating a neurological rewiring
of the brain’s reward pathways. This model is supported
by animal experiments (Oliveira-Lima et al., 2015) which
demonstrated that ayahuasca not only inhibits early behaviors
associated with the initiation and development of alcohol
addiction, but also has long-term effects in preventing the
reinstatement of ethanol-induced behavioral sensitization.
PSYCHOLOGICAL AND PSYCHOSOCIAL
EFFECTS OF AYAHUASCA
After an approximately 35 to 40-min latency period, the
consumption of ayahuasca induces an intense modified state of
consciousness that lasts approximately 4 h (McKenna, 2004).
Perception, spatiotemporal orientation, beliefs about reality
and the self, cognitive and emotional processes can all alter
significantly during the experience. Visions of beautiful visual
scenery are commonly reported together with some typical
elements of the “ayahuasca world”: ayahuasca beings, power
animals, spirit guides, tropical motifs, vibrant, and varying
geometric patterns known from the literature of the cultural
anthropology of shamanism. The neurological background of the
strong visual effects has been revealed by functional magnetic
resonance imaging studies as it was discussed above (de Araujo
et al., 2012).
Considering the psychological therapeutic benefits, the
emphasis is on the induction of an introspective dream-
like experience characterized by visions, autobiographic and
emotional memories which increase mindfulness capacities
(Soler et al., 2015), as well as on the intellectual and spiritual
insights gained during the encounters with ayahuasca. Ayahuasca
experiences are a constant flow of mental contents, during which
knowledge is gained by intuition rather than logic. They also
show a high level of overall coherence. The level of self-reflection,
reminiscence, ethical sensation, prosocial behavior (Frecska,
2008), creative thinking (Frecska et al., 2012), and redemption
(de Rios et al., 2002) can be increased or elicited during
the experiences. Various psychological blockages and denials
may enter awareness and become illuminated from multiple
perspectives allowing the participants to gain insight into their
maladaptive behavioral, emotional and/or cognitive patterns.
These psychodynamic contents are often accompanied by an
enhanced internal moral attitude that forces the participants to
face their deep thoughts and emotions that confront them with
earlier wrongdoings, self-deceptions, and lies (Frecska, 2011).
Repressed memories can surface causing emotional catharsis
and opening the way to abreaction, relief, and remission.
The strong serotonergic effect of ayahuasca and the internal
phenomenon of being held or guided by an intelligent power
can be considered responsible for the observation found in many
personal reports that indicate that the retraumatization by the
experience is avoided by reaching a certain flip-point, a “slew-
round” to a previously inaccessible, corrective positive aspect
of the emotional pattern. In such cases post traumatic growth
becomes possible.
The emotional charge of ayahuasca experiences often follows
a sine wave. Kjellgren et al. (2009) described an initial “contractile
frightening state” during which participants frequently confront
their innermost fears: fear of insanity, fear of death, paranoid
thoughts or the despair of cosmic loneliness and outcast.
Distressful somatic symptoms such as dizziness, diarrhea, nausea,
and vomiting may also arise and become essential part of the
process, carrying the subjective experience of purge and relief.
If the subject is able to surrender, this unpleasant initial phase
is usually followed by a sudden transformation of the experience
into transcendental experiences, reflections, changed worldview
and/or new orientation to life.
It is frequently reported—especially in what Metzner
(Metzner, 1998) called hybrid shamanic and psychotherapeutic
ritual setting—that participants arrive at ayahuasca ceremonies
with a predefined personal intention such as asking for healing,
guidance, teaching or a solution to a personal problem. These
intentions seem to support the experience by two means. They
seem to provide a basic structure to the unconscious materials
that arise during the experience as well as a narrative frame for
the interpretation and integration of the experience.
Scientific interest toward ayahuasca has grown rapidly over
the last decades and so the most pregnant directions of its
possible therapeutic use have begun to be outlined. However, the
illicit legal status of the brew that ensues from its DMT content
imposes heavy impediments to its scientific understanding. Many
findings therefore come from investigations carried out among
the members of the Brazilian syncretic churches, where the
legal use of ayahuasca primarily serves religious aims instead of
therapeutic ones.
The Hoasca Project was first to provide scientific findings
regarding the psychopharmacological and psychological effects
of ayahuasca (Grob et al., 1996). The study involved 15 members
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of the União do Vegetal and suggested that the long-term use of
ayahuasca resulted in positive behavioral and lifestyle changes in
the participants’ lives. An unexpected finding was the possible
anti-addictive effect of the brew as revealed from the reports of
several participants of the study who had struggled with alcohol
and substances abuse before having joined the União do Vegetal.
Two decades later a similar study involving 32 members of Santo
Daime arrived at the same conclusions (Halpern et al., 2008).
Barbosa’s team (Barbosa et al., 2005) concluded that the use of
ayahuasca increased assertiveness, joy of life and liveliness among
the members of the Brazilian syncretic churches, while da Silveira
and others (da Silveira et al., 2005) found that adolescents who
regularly consume ayahuasca show less signs of anxiety, are more
optimistic, self-confident, insistent, and emotionally mature than
their peers. Similarly, results of psychometric tests applied by
dos Santos’ group (dos Santos et al., 2007) revealed that after
ayahuasca use, individuals respond with less anxiety to states
that involve hopelessness and resemble panic, while measures of
state- or trait-anxiety remain unaffected. Recently Barbosa’s team
(Barbosa et al., 2012) performed a meta-analysis on publications
listed on PubMed with the aim to summarize current knowledge
about the effect of ayahuasca on health. It concludes that the
consumption of ayahuasca is safe and under certain conditions
may even be beneficial. Results of a longitudinal prospective
study on a large population of regular users showed no signs of
cognitive impairment and the decoction had no negative effect
on coping strategies or the general mental health (Bouso et al.,
2012). While there are occasional reports of ayahuasca users
dying during the episode, they typically reflect underlying health
conditions or prolonged neglect of participants during rituals.
The prolonged social contact among participants that is
typical of ayahuasca based treatments provides the opportunity
for developing the social support that is crucial to recovery
from many mental illnesses including addiction. The ceremonial
context enhances bonding among participants that can facilitate
therapeutic processes, especially through the provision of social
support and the enforcement of social norms that encourage
an abstinent lifestyle. The participants in ayahuasca ceremonies
of the churches provides social support for managing stress
and gives a sense of belonging that motivates lasting behavioral
changes.
Since DMT is known to be a very potent 5-HT agonist, it
can decrease impulsive behavior and facilitate social interactions
(Frecska, 2008). A rapid 5-HT receptor action can explain the
traditional indication of ayahuasca use in crisis prevention and
occasioning redemption (de Rios et al., 2002). The prosocial,
cohesive action effect of ayahuasca is reflected in the quality of the
elicited subjective experience, which commonly involves ethical
lessons (Shanon, 2002). Ayahuasca is highly revered by mestizo
curanderos as a stern moral teacher (Luna, 1986).
PSYCHOTHERAPEUTIC AND SPIRITUAL
EFFECTS OF AYAHUASCA
Ayahuasca experiences often reflect psychodynamic effects that
contribute important therapeutic outcomes through providing
a connection with significant aspects of the person’s past,
elevating repressed memories into consciousness where they
can play a role in psychological healing through restructuring.
A frequent theme mentioned by victims of abuse and
recovered addicts is that the ayahuasca-induced visions helped
them to recover long-forgotten memories of traumatic events
that they were then able to work through, providing a
basis for restructuring their personal life (Loizaga-Velder
and Verres, 2014). Ayahuasca-induced insights facilitate self-
reflection, producing changes in self perspectives that can trigger
psychodynamics insights which provide solutions to personal
problems that underlie maladaptive lifestyles. Ayahuasca helps
resolve personal conflicts by providing conscious insights into
patterns of psychological functioning that underlie pathological
behaviors such as substance abuse and dependence. Participants
of ayahuasca rituals often report insights that enable acceptance
of previously denied problems and dysfunctional patterns. The
visionary state of consciousness produced by ayahuasca can also
provoke reflections on personal relationships which provided
the motivation for making the changes necessary to resolve
interpersonal problems.
Hence, ayahuasca’s effects appear to evoke psychodynamic
mechanisms and psycholytic effects that can augment access
to pre-conscious and unconscious memories. This release
of repressed emotions can catalyze healing processes by
contributing to the resolution of traumas by releasing the person
from dysfunctional habits that underlie the dynamics of addiction
and many other behavioral problems. Psycholytic processes
engendered by ayahuasca also promote an awareness of the
likely future outcomes and personal consequences of maladaptive
behaviors, providing a motivation for change. Personal accounts
of addicts reveal that the ayahuasca experiences led many of
them to perceive that their drug use was leading them down a
path of self-destruction that would lead to their death. Ayahuasca
might produce death experiences, sometime a sense that one was
dying, or a vision of oneself as dead as a consequence of drug
use. These experiences led to realizations that helped them to
make radical changes in their behavior by providing additional
motivation to make necessary changes in personal behavior and
lifestyle (Loizaga-Velder and Verres, 2014). A basic effect of
ayahuasca on psychological process involves a confrontation
with oneself, forcing a greater personal awareness that facilitates
a reconstruction or restructuring of the nature of oneself
(Fernández and Fábregas, 2014). A reassessment of the past
provides the basis for an experience of cleansing from the past
events and the basis for new perspectives into one’s patterns of
behavior.
Speculating on the psychotherapeutic effects of ayahuasca,
Naranjo (1979) suggested that its effects are similar to that of
an intense psychotherapy. He attributed the prime therapeutic
effect of ayahuasca to its harmaline content instead of DMT.
Trichter (2010) claimed that the therapeutic effect reported in
personal anecdotes results from the psychological work being
carried out at a much deeper level than in the case of traditional
psychotherapeutic methods. Mabit (2007) listed eleven factors
that contribute to the brew’s therapeutic effect, one of which is its
ability to lower defenses and to reveal ego defense mechanisms.
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This in turn allows repressed unconscious materials to enter
consciousness and extinguish the emotional charge of past
traumatic experiences, helping the participants to temporarily
experience thus far unknown emotional states and cognitive
patterns; and through them they better understand the means and
directions of adjustments needed in their lives.
Maté (2014) proposed that ayahuasca is capable of treating
many conditions because both physical and psychological
conditions can be based in unconscious psychological
conditions. Psychedelics assist by bringing these dynamics
into consciousness, initiating a process of liberating the person
from these influences. Maté (2014) also suggested that while
deep psychological dynamics may emerge into awareness during
ayahuasca ceremonies, their therapeutic potential depends on
trained guidance to bring these potentials to fruition. Successful
treatment with ayahuasca requires an experienced person to
provide structure and guidance to effectively orient to the
visions, the therapeutic purpose, and the development of the
experience across sessions. Lacking qualified assistance in
achieving their full integration, important experiences may
not produce benefits. Nonetheless, he emphasizes that in the
right supportive circumstances, ayahuasca can help provide
the insights and personal meanings that can help resolve the
underlying dynamics of addiction by triggering visions of the
emotional states and traumatic imprints.
Frecska (2011) supposes that the experience consists of
repeated sequences of deconditioning and reintegration. This
can be conceived as a “secure” form of regression, which
makes the correction of maladaptive cognitive and emotional
structures (personal network of concepts, maladaptive patterns,
etc.) possible. Echenhofer (2012) endeavored to draw parallels
with experiences from other spiritual traditions and divides the
process of deconditioning and reintegration into three subphases:
(1) form dismantling and healing, (2) form creation, and (3) form
expression.
Ayahuasca also produces transcendent and mystical
experiences, the “peak experiences” that led to the “psychedelic”
paradigm of LSD treatment that was based in recognition that
these substances provide an effective treatment for alcoholism
by changing the individual’s personal awareness, self-perceptions
and worldview. A significant dimension of the spiritual
experience was a transformation of personal consciousness
in ways that eliminated the craving for drugs. Mystical or
spiritual experiences reported during the ayahuasca sessions are
frequently said to have a life changing effect on those bearing
them, sometimes setting them off on a path of spiritual mission
(Krippner and Sulla, 2000).3Although subjective accounts have
limitations as they are vulnerable to memory distortion and self-
defense mechanisms, the high rate of such reports is remarkable.
Furthermore, these early observations are in line with the
experimental findings of Griffiths’ team at the Johns Hopkins
University (Griffiths et al., 2011) using psilocybin. By analyzing
the reports of many 100s of ayahuasca experiences Shanon
(Shanon, 2002) came to the conclusion that the experiences can
3This was exactly the way every Brazilian syncretic church União do Vegetal,Santo
Daime, and Barquina got started!
sometimes have such a deep effect that the individuals may feel
they are no longer the same person.
The psychotherapeutic effect, however, does not only depend
on the experience and its phenomenal content or depth. In
addition, it depends on how much the insights gained during
the experiences become integrated into the everyday life of
the participants afterward. Without adequate integration any
experience loses its therapeutic potential in time. House (2007)
warned that psychedelic experiences can carry the feeling that
the desired psychological change happened during the experience
itself. Such feelings are, however, illusionary and by diverting the
participants from real integration they may cause more harm
than benefit.
Another possible pitfall emphasized by Trichter (2010) is
the phenomenon of spiritual bypassing, which occurs when
individuals escape into repeated spiritual practice in order to
avoid their psychological blockages. As a result an unhealthy
relationship may be developed with the given spiritual tradition
and techniques, which disguises the real psychological problems.
The integration of the experiences can best be supported by
psychotherapy carried out by an expert. Given the uncertain
legal status of ayahuasca in many countries, however, this is
only possible afterward, separate from the ritual (Jungaberle
et al., 2008;Oak et al., 2015). Such professional assistance
for the integration is, however, not at all straight forward
since the number of therapists who are familiar with handling
such unusual experiences is generally very low. Considering
that the number of people seeking out ayahuasca ceremonies
keeps growing every year, the rate of related scientific research
and professional education has become crucial and requires
attention.
USE OF AYAHUASCA IN THE
TREATMENT OF ADDICTIONS
The potentials of ayahuasca administration in substance
use disorders illustrate the necessity of an integrative view
spanning from the biological to spiritual levels. In recent
years there has been a growing scientific interest in the
possible therapeutic use of ayahuasca in the treatment of
addictions. Various forms of clinical research have attempted to
reveal the mechanisms that lie under the commonly reported
anti-addictive effects of ayahuasca (see Winkelman, 2014 for
review). Loizaga-Velder and Pazzi (2014) revealed the bases
of ayahuasca therapies with an empirical study of therapists
who used ayahuasca professionally in addictions treatment
and addicts who participated in ayahuasca treatment programs
based on indigenous shamanistic approaches. These authors
noted that most patients reported therapeutic effects involving:
“augmenting body awareness, reducing drug-craving, triggering
different types of emotional processes (catharsis, perception of
previously suppressed emotions, generating inner resources for
coping with emotions or urges to use), supporting introspection
(self-analysis, eliciting awareness of addiction, and its adverse
effects on oneself and others), and enhancing self-efficacy
(becoming aware of positive aspects of oneself, thus improving
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self-esteem and confidence to stay sober)” (Loizaga-Velder and
Pazzi, 2014).
Successful treatment of addictions involves a range of
physical effects of ayahuasca, including the purgative and
emetic effects, bodily sensations, the evoked visions and the
recall of significant past memories. The physical experiences
produced are interpreted within the ritual context, one’s personal
circumstances and with respect to the recovery processes.
Ayahuasca activates a body-oriented dynamics that provides
relief from stress, as well as a detoxification experience derived
from the emetic effects which may produce an attenuation
of craving. Within the shamanistic traditions, the vomiting
or purge is seen as a part of the process of detoxification
of the body, not only the elimination of toxins, but also the
expulsion of morbid emotional and mental conditions. Loizaga-
Velder and Pazzi (2014) noted that many report that the emetic
effect experienced through vomiting is seen as providing an
elimination of troublesome emotions as well as provoking diverse
emotional dynamics that trigger psychological and spiritual
reactions.
One important institution where ayahuasca is applied
therapeutically is the Takiwasi Center for Rehabilitation of Drug
Addicts and for Research on Traditional Medicines in Tarapoto,
Peru (Mabit, 2007). The program integrates traditional ayahuasca
rituals with physical, psychological, and spiritual activities
into treatments that address a range of factors contributory
to addiction. Founded in 1992 by Jaques Mabit, a French
medical doctor, the Takiwasi uses a mixed approach of Western
psychotherapy and traditional Amazonian medicine based on
local herbs. The success is attributed not to the ayahuasca alone,
but the use of other plants, the ritual setting, the community
life and the interactions with therapists. Within the Takiwasi
program the traditional medicines and rituals are combined with
transpersonal psychology and modern social techniques to guide
the personal transformation of addicts, using the ayahuasca ritual
to produce profound alterations of mind that change addicts’
outlook on life, on their spiritual strength and faith.
The Institute of Applied Amazonian Ethnopsychology (see
Fernández and Fábregas, 2014) is another group which has
applied shamanistic perspectives to the treatment of addictions
with ayahuasca. The approach is based on a minimalist
model, without extensive focus on ritual healing processes,
but nonetheless integrates influences from the Brazilian Santo
Daime religion, shamanism, Eastern meditative disciplines
and transpersonal psychology. The approach also includes
other healing techniques outside of the ayahuasca sessions
such as: “individual psychotherapy; workshops on emotions,
breathing techniques, psychodrama, and bibliotherapy; and
family constellation therapy [and] . . . other practices such
as massage, colonic irrigation, shiatsu, and naturopathy”
(Fernández and Fábregas, 2014). While the community context
is used to counter the extreme self-centeredness of the addict,
the treatment also involved solitary periods during ayahuasca
sessions when the participants would retreat to their own cabins
for periods of introspection, self-reflection and engaging their
own healing processes based on self-regeneration from within the
person.
Some centers have developed structured studies for
monitoring their therapeutic outcome. In an observational study
Thomas’ group (Thomas et al., 2013) followed 12 members of a
Canadian First Nations community, a subpopulation especially
prone to addictions due to a mixture of social and psychological
factors including transgenerational historic traumas and
cultural dislocation. These authors found that participation
in ayahuasca retreats correlated with enhanced mindfulness,
personal empowerment, hopefulness, improvements in quality
of life, and increased subjective feelings of connection with self,
others, spirit and nature as rated with the Difficulty in Emotion
Regulation Scale, Hope Scale, Philadelphia Mindfulness Scale,
and the McGill Quality of Life questionnaires. In addition,
the four Week Substance Use Survey also suggested that this
form of ayahuasca-assisted group therapy might be associated
with reductions in substance use, particularly reductions in
problematic cocaine use.
Cross-sectional and longitudinal case-control studies showed
that ritual and religious ayahuasca users present fewer alcohol-
related problems than control groups and that illicit drug use
diminished after joining ayahuasca churches (Grob et al., 1996;
Doering-Silveira et al., 2005;Halpern et al., 2008;Fábregas
et al., 2010). It is an open question whether ayahuasca
has anti-addictive properties per se or if the social factors
(e.g., religious social reinforcement) are the primary factor in
producing these results. However, known neurochemical and
psychophysiological actions of ayahuasca constituents provide
evidence that pharmacological factors are a significant feature of
ayahuasca’s anti-addiction effects.
DISCUSSION
Evaluating the health benefits and risks of a remedy of plant
origin is more difficult than that of assessing synthetized
compound. In the case of ayahuasca such an evaluation is also
complicated by the admixture nature of the brew, the strong
psychoactive effects, the setting of its typical administration,
and by the legal and financial impediments. As far as the plant
components of the brew are concerned, significant differences
in health potentials may stem not only from the particular
species of the DMT plant being used (Psychotria viridis or
Diplopterys cabrerana), but from the variety of the B. caapi (e.g.,
cielo,trueno, black, or red, etc.) in the mixture. A range of
interactions may emerge between the plant alkaloids. Among
those the most important occurs between the β-carbolines
MAO inhibitor effect and the DMT content. MAO activity may
vary considerably between individuals and across sessions (for
stress-related and endogenous inhibitor mediated changes; see
Obata, 2007). Since the enzyme may not be fully saturated by
the competitive inhibitor, or it can be overloaded with other
monoamines, the same DMT content may result in different
plasma levels. Moreover, the same plasma DMT level can lead to
different intraneuronal concentrations depending on the efficacy
of the active DMT-uptake processes into the brain, neurons,
and vesicles (reviewed in Frecska et al., 2013). The ayahuasca’s
effect on suggestibility interferes with the conditions of set
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Frecska et al. Therapeutic Potentials of Ayahuasca
and setting (Barbosa et al., 2005) and favors stronger placebo
response. To make this issue more difficult: ayahuasca cannot
be camouflaged easily for double-blind administration. While in
most of the countries ayahuasca is not scheduled as rigorously
as its DMT constituent, this doesn’t mean that its legal status
is unambiguous and it can be studied on par with other plant
remedies (St. John’s wort, for example). Plant medicines do not
enjoy the financial support of pharmaceutics introduced and
promoted by the industry. Patenting ayahuasca would violate
indigenous people’s right over their intellectual heritage and
such use could constitute biopiracy; these circumstances further
undercut potential financial interest and industrial support.
The wide spectrum of ayahuasca’s effects—as was outlined
in the text—from biological to psychosocial (even spiritual)
may also complicate the issue, but on the other hand it
makes this plant remedy more interesting and promising
for future explorations. The Sig-1R mediated action places
ayahuasca research in the new stream of medical investigations,
namely, it fits nicely into the emerging unifying concept of
systemic and degenerative illnesses. It would be intriguing
to see how a shamanic potion can be useful against wide
array of civilization diseases. Ayahuasca-induced psychological
effects like increased insight, reframing of cognitive structures,
increased imaginary, and cathartic emotions promise potentials
for ayahuasca use in psychedelic assisted psychotherapy by means
of facilitating interventions based on insight oriented, cognitive,
guided affective imagery, and cathartic techniques (Loizaga-
Velder, 2014). The anti-impulsive, prosocial, cohesive action of
ayahuasca should be tested in detention centers with young
delinquents, and there is another important field of interest:
combat-related post-traumatic stress.
Social isolation, lack of trust, violent outbursts, emotional
numbing, and vivid recollection of traumatic experiences are
often present in PTSD, a condition difficult to treat. Combat-
related PTSD patients have been significantly less responsive
to conventional therapies than other PTSD populations (e.g.,
victims of rape, survivors of natural disasters, participants of life-
threatening accidents, or members of rescue-teams facing mass
casualties). Veterans with PTSD may require treatment tailored
to the unique nature of combat, military culture, and their
individual circumstances (Yehuda, 2008). Generally, combat-
related traumatic experiences can be complicated by aggravating
factors: combat veterans are typically multi-traumatized over
an extended period of extremely distressful time, frequently
have survival guilt, guilt over killing enemy combatants, causing
collateral damage, being responsible for friendly fire, and
they usually witnessed the dismemberment and death of their
comrades (Frecska, 2011). Our hypothesis is that—similar to
methylenedioxy-methamphetamine (MDMA) which has already
been tested (Mithoefer et al., 2013)—ayahuasca can also improve
treatment of PTSD through enhancing trust and social feelings.
In addition to these beneficial core effects, in proper settings
it may also elicit “moral lessons” with subsequent relief and
redemption. Additionally, the induced visions can be integrated
into a cognitive re-exposure therapy with desensitization and
reprocessing. The latter is the most effective cognitive treatment
recognized by the National Center for PTSD. Ayahuasca
facilitated cognitive exposure therapy could possibly cut down
the long desensitization period necessary in the traditional
psychotherapeutic approach.
The ideal scientific assessment of ayahuasca therapies are
admittedly lacking, with the double-blind clinical studies a
practical challenge. From the perspective of medical and research
ethics, the lack of such studies should not be seen as reasons
for absolutely prohibiting treatments with ayahuasca, however.
In order to make our point, we would like to refer to the
statements of Sackett et al. (1996), who warned for an intricate
approach toward evidenced based medicine: “Evidence based
medicine is the conscientious, explicit, and judicious use of
current best evidence in making decisions about the care of
individual patients. The practice of evidence-based medicine
means integrating individual clinical expertise with the best
available clinical evidence from systematic research” (Sackett
et al., 1996).
In short, evidence-based medicine is the integration of
experience collected in clinical practice with evidence gained
from trial based research (evidenced based medicine =trial based
medicine +clinical practice). Indeed, Sackett and his coworkers
(Sackett et al., 1996) go on: “Evidence based medicine is not
restricted to randomized trials and meta-analyses. It involves
tracking down the best external evidence with which to answer
our clinical questions.” and “. . .some questions about therapy
do not require randomized trials (successful interventions for
otherwise fatal conditions) or cannot wait for the trials to be
conducted. And if no randomized trial has been carried out
for our patient’s predicament, we must follow the trail to the
next best external evidence and work from there.” Not only
the ayahuasca treatment programs for drug addicts have shown
considerable expertise on the side of clinical practice, but formal
assessments cited above support therapeutic ayahuasca use under
certain conditions. Therefore, while randomized controlled trials
are needed, these should not be seen as an absolute necessity to
justify further use. In our opinion, the studies that are available
do justify the application of ayahuasca at least in the treatment of
addictions.
Randomized clinical trials typically use double blind controls
to assess the role of placebo or expectancy effects. The use of
double blind controls is particularly problematic for ayahuasca.
Ideal double-blind clinical trials may be forever beyond the
methodological possibility given the ritual elements. Double-
blind clinical studies will be particularly challenging in terms of
appropriate pharmacological and ritual control conditions. What
would constitute a placebo substitute for ayahuasca might be
found, but the ritual aspect that is implicated in treatment success
also requires some control. But such studies are to separate
drug effects from set and setting—such as ritual. It is, however,
these combined physiological and ritual elements of ayahuasca
that appear to have the effects on treatment outcomes. The
shamanistic approaches attribute therapeutic effects to a variety
of factors, including pharmacological as well as psychological, but
most significantly the interactions of the biological and personal
levels with the spiritual. For example, the evidence for ayahuasca
as an effective treatment for addictions is from practices that
espouse a view that emphasizes the interaction of a sacrament
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Frecska et al. Therapeutic Potentials of Ayahuasca
with physiological effects with the interpersonal dynamics of
ritual. Consequently, the more one agrees to the importance
of addressing the spiritual aspects of human experiences as
part of therapy by extending the Engelian paradigm (Engel,
1977) to the biopsychosociospiritual model (Bishop, 2009), the
more one should adhere to the clinical practice side of the
Sackett’s equation, since targeting spiritual levels is beyond
current scientific approaches.
Nevertheless, studies on ayahuasca as a therapy can attempt to
isolate the physiological effects from ritual by controls. Double
blind studies will also be necessary to determine the effects
of the separate components (DMT vs. harmine) as well as
their interactions. These should have to incorporate additional
controlled trials to determine long term risks and benefits, and
relative effectiveness in comparisons with other procedures or
agents used to treat addictions.
To date we lack controlled ayahuasca and DMT studies
largely due to administrative prohibitions. The necessary phases
of evaluation for the psychedelic medicines have to rely
on an integration of various forms of validation through
a “triangulation” that combines data derived from: animal
research; epidemiological research on general risks and adverse
reactions; medical case studies and personal accounts of those
who have received these substances as treatments; and process
oriented research that assess pre and post-treatment conditions
with a variety of standardized tools—as Alper and Lotsof (2007)
pointed out in their assessment of ibogaine. While administrative
regulations considerably impede research, they have not entirely
obstructed it, but in terms of clinical applications they have been
absolutely prohibitive. We would argue, however, that although
treatment with these substances is ruled out by their Schedule I
classification, their use as remedies is justified in that they reduce
the patient’s severe suffering without causing disproportionate
harm to others (i.e., other people, or to the State’s interest).
We are not going to see major pharmaceutical companies
address the need for evaluation of ayahuasca or other plants
as medicines. There are no financial incentives. So how can
physicians and patients make use of such treatments? In addition
to patients’ predicaments their choices and preferences are other
factors which should not totally be ignored in good clinical
care. There are multiple levels of society at which we need
to act to change the current political climate that regulates
these substances. Public pressure on federal regulatory agencies
is central to advancing experimental and treatment use of
these substances. This influence involves general education,
education of the media, and activities in public health and
policy organizations, as well as private funding of research and
corporate developments. The arguments from the cumulative
scientific, clinical, ethnographic and cross-cultural evidence
regarding the immense potentials of these substances are the
basis for a public education approach to facilitate professional
development, media coverage and popular pressure upon the
government to change federal regulations and procedures. In
summary, education, public policy development, and collective
political action, rather than just more science, is necessary for
changing opportunities for the use of ayahuasca in treatment of
some of the most ravaging social diseases of our times.
AUTHOR CONTRIBUTIONS
All authors made significant contributions to the preparation
of the manuscript and approved it before submission. EF
developed the paper design, wrote the biological section, edited
the References, and finalized the manuscript. PB wrote the first
draft of the manuscript and elaborated on the psychological
components. MW worked on the addictological aspects and
revised the style of the manuscript.
ACKNOWLEDGMENT
We would like to thank Mr. Dániel Gyöngy for his help in
preparing the figures.
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