This review (2016) examines the therapeutic potential of ayahuasca based on a summary of its neurobiological, neuroregenerative, and psychophysiological mechanisms and effects on vegetative states and the central nervous system. It emphasizes highlights the therapeutic utility of ayahuasca on a biological level as an anti-inflammatory agonist of the Sigma-1 receptor while incorporating its effects on higher-order psychotherapeutic effects within a bio-psycho-socio-spiritual model.
Abstract
“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.”
Authors: Ede Frecska, Petra Bokor & Michael Winkelman
Summary
INTRODUCTION
Ayahuasca, a psychoactive Amazonian sacrament, is prepared by boiling two admixture plants, Banisteriopsis caapi and Psychotria viridis, which contain the psychoactive alkaloid DMT. The name ayahuasca is a compound word in Quechua language, meaning “vine of the soul”.
Ayahuasca has been used as a central element of religious, magical, curative, initiation, and other tribal rituals for millennia. It is also used in three Brazilian syncretic churches, and has a striking discrepancy between the indigenous South American and official Western view1 on ayahuasca use.
Due to the growing popularity of ayahuasca, people from all over the world travel to the Amazon to participate in ayahuasca rituals. These rituals are characterized by improved insight, personal growth, emotional healing, and contact with a sacred nature.
Several publications have been written with the goal to summarize our knowledge about ayahuasca from various perspectives. This article will explore every level in the following order: biochemistry, neuropharmacology, physiology, brain imaging, psychological effects, social ramifications, and finally addressing spiritual implications.
THE NEUROBIOLOGICAL BACKGROUND OF AYAHUASCA
The main ingredients of ayahuasca are DMT and the -carboline derivative alkaloid harmine, harmaline, and tetrahydroharmine. These alkaloids inhibit the A-type isoenzyme of the monoamine oxidase and exert selective serotonin reuptake inhibitor (SSRI) effects.
Endogenous hallucinogens have many biological functions and may act on serotonin (5-HT) receptors as well as trace amine associated receptors. However, the Sig-1R action of DMT may be more revealing about its physiological function.
Dimethyltryptamine (DMT) exerts anxiolytic effects through 5-HT1A receptor agonism, and its psychedelic effect is connected to its 5-HT2A receptor-activating capacity. However, 5-HT itself and some 5-HT2A agonists are not hallucinogenic, and DMT does not precipitate tolerance upon repeated use.
DMT’s action on the Sig-1R receptor is mediated by the chaperone Sig-1R, which is concentrated in the brain, retina, liver, lung, heart, immune system, and tumor lines. Sig-1R regulates cellular bioenergetics, particularly under stressful conditions.
Sig-1R is an intracellular receptor localized at the MAM, which integrates many signaling pathways. It is critical in ion channel activities and neuronal differentiation, and it also protects the cells against reactive oxygen species and activates the antioxidant response elements.
The Sig-1R ER chaperone function is essential for the metabotropic receptor signaling and the survival against cellular, particularly ER stress. It has been implicated in numerous diseases, including Alzheimer’s disease, Parkinson’s disease, cancer, cardiomyopathy, retinal dysfunction, perinatal and traumatic brain injury, and major depression.
THE POSSIBLE ROLE OF DMT IN TISSUE PROTECTION AND NEUROREGENERATION
Dimethyltryptamine (DMT) is a natural ligand of the Sig-1R, which regulates cellular survival against oxidative stress and regulates immune processes. It is assumed that DMT might be involved in the DMT-induced psychedelic effects, but recent research indicates that DMT may have a more physiological role.
DMT regulates the immune system in a bidirectional process, influencing both innate and adaptive immune responses. Ayahuasca 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, such as insulin resistance, certain cancers, neuropsychiatric diseases, and osteoporosis.
Chronic LGI is closely related to oxidative stress and ER stress, and together they form a molecular web. ER stress can be caused by hypoxia, hyperglycemia, hyperlipidemia, viral infections, disturbances in cellular calcium levels, redox regulation, or by endogenous reactive oxygen species production.
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. Targeting Sig-1R by agonists may regulate ER stress and UPR, manage ER perturbations, and prevent the cell-killing apoptotic pathways.
Ayahuasca and DMT are effective in fighting the vicious cycle of oxidative stress caused by the malfunctioning molecular web involved in inflammatory processes, leaky gut, ER stress, protein folding deficit, glutamate excitotoxicity, mitochondrial dysfunction, calcium overload, death receptor pathways, and Sig-1R involvement.
Ayahuasca’s therapeutic potentials include its DMT content, above the neurobiological level, and its -carboline alkaloids, which act as selective, reversible MAO-A inhibitors with almost no effect on MAO-B. Moreover, the -carbolines themselves have medicinal properties, such as anthelmintic, antimicrobial, and vasorelaxant effects.
Ayahuasca has been shown to have antidepressant properties due to the Harmala alkaloids, and many native users ascribe sacramental respect to the B. caapi and not the DMT containing plant constituents.
Ayahuasca contains a significant amount of bioactive substances in addition to the indole and -carboline alkaloids, which may explain the observed immunomodulatory effects. The brew may also exhibit neuroprotective and neurorestorative qualities, and may be used therapeutically in Parkinson’s and other neurodegenerative diseases.
VEGETATIVE AND ADVERSE EFFECTS OF AYAHUASCA
Serotonin stimulation affects the whole organism not just the brain. Ayahuasca increases blood pressure, pulse rate, nausea, vomiting, and pupil dilation, and induces endocrine response.
DMT can cause cardiac stress when intravenously injected, but it is less burdensome if taken orally. The safety margin for ayahuasca consumption is approximately 20 mg/kg, and there is only one fatal case of ayahuasca consumption.
Ayahuasca’s MAO-A inhibition may lead to increased levels of serotonin in the neural pathways, but the condition is usually mild or moderate. Ginseng, St John’s-wort, dextromethorphan, 3,4-methylenedioxy-N -methylamphetamine, SSRIs or MAO inhibitors may negatively interact with ayahuasca.
A tendency for psychosis or family history of mental illness predisposes to ayahuasca triggering a psychotic episode or long-term depersonalization syndrome. However, without proper screening the statistical probability of such cases seems to be low.
There is not yet any scientific evidence that ayahuasca use elicits substance dependence. However, a feeling of emptiness or grayness may arise after the experience fades away.
CENTRAL NERVOUS SYSTEM EFFECTS OF AYAHUASCA
Single-photon emission computed tomography revealed that the anterior insula, fronto-medial cortical anterior cingulate of the right hemisphere and the left amygdala were affected by ayahuasca ingestion.
Ayahuasca stimulates the Brodmann areas BA10, BA17, BA30, and BA37, which are involved in visual perception, memory, and intention. This stimulation correlates significantly with perceptual changes measured by rating scales.
Ayahuasca intake increased power in the slow gamma band at left occipito-temporo-parietal electrodes, with tendencies to power decreases in theta and delta bands. The coupling of brain oscillations between anterior and posterior recording sites changed in the following pattern: frontal structures decreased their influence over posterior sites.
Ayahuasca effects on the electroencephalogram revealed a biphasic feature, with increased slow- and fast-gamma power between 75 and 125 min. This effect correlated significantly with the circulating levels of ayahuasca’s main ingredients, such as DMT, harmine, tetrahydroharmine, and some of their metabolites.
Gallimore’s work suggests that ayahuasca’s pharmacology is related to the promotion of gamma oscillations, and that the psychedelic state may be characterized by an increase in integration compared to a normal waking state.
Ayahuasca affects the central nervous system in a way that is different from our normal resting mental states. Ayahuasca decreases the functional connectivity within the prefrontal cortex and in connections with other areas of the brain.
Decoupling of high-level networks in the medial temporal lobe results in increased somatic awareness and subjective feelings, but lacking the metacognitive ability for self-reflection on personal behavior and one’s mentalization.
Ayahuasca may increase activity in the right hemisphere’s anterior insula, anterior cingulate/fronto-medial cortex, and left hemisphere’s amygdala/parahippocampal gyrus structures, which allows users to reprocess repressed memories in more constructive ways.
NEUROCHEMICAL AND PSYCHOPHYSIOLOGICAL MECHANISMS PROPOSED AS A BASIS FOR AYAHUASCA’S EFFECTS ON ADDICTION
Ayahuasca can effectively address addictions through a variety of biochemical and physiological mechanisms. DMT and harmine alkaloids contribute to the effects, but separate studies are necessary to distinguish their different contributions.
Ayahuasca’s anti-addictive properties may act on four levels: (1) reducing brain DA level in the MDP through effects on the 5-HT receptors; (2) interfering with the synaptic plasticity; and (3) enhancing decision making capabilities.
Ayahuasca may affect the release of neurotropic factors through the GABAergic and glutamatergic systems, and may affect the existing neural circuits that mediate maladaptive addictive habits by stimulating the production of new circuits supporting new behaviors.
PSYCHOLOGICAL AND PSYCHOSOCIAL EFFECTS OF AYAHUASCA
Ayahuasca induces an intense modified state of consciousness that lasts approximately 4 h. The visual effects are characterized by visions, autobiographic and emotional memories, which increase mindfulness capacities, and intellectual and spiritual insights.
Ayahuasca experiences are a constant flow of mental contents, during which knowledge is gained by intuition rather than logic. The participants are often forced to face their deep thoughts and emotions, which can lead to abreaction, relief, and remission.
Ayahuasca experiences often follow a sine wave, with an initial “contractile frightening state” followed by distressful somatic symptoms and a sudden transformation of the experience into transcendental experiences, reflections, changed worldview and/or new orientation to life.
Scientific interest toward ayahuasca has grown rapidly over the last decades, but the illicit legal status of the brew imposes heavy impediments to its scientific understanding.
A study by Grob et al. (1996) suggested that long-term use of ayahuasca results in positive behavioral and lifestyle changes in the participants’ lives, including an unexpected anti-addictive effect.
Barbosa’s team concluded that ayahuasca use increased assertiveness, joy of life and liveliness among members of the Brazilian syncretic churches, while da Silveira and others found that adolescents who regularly consume ayahuasca show less signs of anxiety, are more optimistic, self-confident, insistent, and emotionally mature than their peers.
Ayahuasca based treatments provide prolonged social contact among participants, which enhances bonding among participants and provides a sense of belonging that motivates lasting behavioral changes. DMT is a very potent 5-HT agonist, which can explain the traditional indication of ayahuasca use in crisis prevention and occasioning redemption.
PSYCHOTHERAPEUTIC AND SPIRITUAL EFFECTS OF AYAHUASCA
Ayahuasca experiences often reflect psychodynamic effects that contribute to therapeutic outcomes through elevating repressed memories into consciousness and facilitating self-reflection. This allows participants to resolve personal conflicts and provide solutions to maladaptive lifestyles.
Ayahuasca’s effects appear to evoke psychodynamic mechanisms and psycholytic effects that facilitate the release of repressed emotions and the reconstruction of the nature of oneself. This can lead to a healing process and a new perspective on one’s patterns of behavior.
Ayahuasca’s therapeutic effects are similar to those of intense psychotherapy, and are caused by its ability to lower defenses and reveal ego defense mechanisms. This allows repressed unconscious materials to enter consciousness and extinguish the emotional charge of past traumatic experiences.
Ayahuasca can help treat many conditions by bringing unconscious psychological conditions into consciousness. However, the experience is most effective when guided by a qualified person who can help the person integrate the visions and personal meanings that emerge.
Frecska (2011) hypothesizes that the experience of deconditioning and reintegration consists of repeated sequences of deconditioning and reintegration. Echenhofer (2012) draws parallels with experiences from other spiritual traditions.
Ayahuasca produces transcendent and mystical experiences, which can change the individual’s personal awareness, self-perceptions and worldview. These experiences can sometimes have a life changing effect on those bearing them, sometimes setting them off on a path of spiritual mission.
The psychotherapeutic effect of psychedelic experiences depends on how much the insights gained during the experiences are integrated into the participants’ everyday life afterward.
Ayahuasca ceremonies can lead to spiritual bypassing, which is a psychological problem that can only be solved by psychotherapy. However, the number of therapists familiar with handling such unusual experiences is very low.
USE OF AYAHUASCA IN THE TREATMENT OF ADDICTIONS
Ayahuasca administration in substance use disorders may be beneficial by enhancing body awareness, reducing drug-craving, triggering different types of emotional processes, generating inner resources for coping with emotions or urges to use, and enhancing self-efficacy.
Ayahuasca treatment involves a range of physical effects, including the purgative and emetic effects, bodily sensations, evoked visions and the recall of significant past memories. The physical experiences are interpreted within the ritual context, one’s personal circumstances and with respect to the recovery processes.
The Takiwasi Center for Rehabilitation of Drug Addicts and for Research on Traditional Medicines in Tarapoto, Peru, uses ayahuasca rituals and medicine to treat addiction and integrates traditional Amazonian medicine with Western psychotherapy and modern social techniques.
The Institute of Applied Amazonian Ethnopsychology uses ayahuasca in its treatment of addictions, and 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.
Some centers have developed structured studies to monitor the therapeutic outcome of ayahuasca use. These studies have found that ayahuasca use can improve mindfulness, personal empowerment, hopefulness, quality of life, and connection with self, others, spirit and nature.
Ayahuasca users have fewer alcohol-related problems and less illicit drug use than control groups. It is unclear whether ayahuasca has anti-addictive properties per se or if social factors are the primary factor in producing these results.
DISCUSSION
Ayahuasca is a remedy of plant origin that may have different health benefits depending on the variety of the B. caapi plant used, the species of the DMT plant used, and the efficacy of the active DMT-uptake processes into the brain, neurons, and vesicles.
Ayahuasca cannot be camouflaged easily for double-blind administration and is not scheduled as rigorously as its DMT constituent. It also does not enjoy the financial support of pharmaceutics introduced and promoted by the industry.
Ayahuasca’s wide spectrum of effects, from biological to psychosocial (even spiritual), makes it more interesting and promising for future explorations. It could be used in psychedelic assisted psychotherapy, and in detention centers with young delinquents, and in combat-related post-traumatic stress.
Ayahuasca may improve treatment of PTSD through enhancing trust and social feelings, and may also elicit “moral lessons” with subsequent relief and redemption. Additionally, ayahuasca facilitated cognitive exposure therapy may cut down the long desensitization period necessary in the traditional psychotherapeutic approach.
The lack of double-blind clinical studies of ayahuasca therapies should not be seen as a reason to prohibit treatments with ayahuasca, but rather as an intricate approach toward evidenced based medicine.
Evidence-based medicine is the integration of clinical experience with evidence gained from trial based research. Ayahuasca treatment programs for drug addicts have shown considerable expertise on the side of clinical practice, and formal assessments support therapeutic ayahuasca use under certain conditions.
The use of double blind controls in randomized clinical trials is problematic for ayahuasca because the ritual elements are implicated in treatment success. 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.
Studies on ayahuasca as a therapy should isolate the physiological effects from ritual by controls, and should incorporate additional controlled trials to determine long term risks and benefits.
To date we lack controlled ayahuasca and DMT studies largely due to administrative prohibitions. However, we would argue 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.
Physicians and patients should make use of such treatments, but the current political climate regulates them. Public pressure on federal regulatory agencies is central to advancing experimental and treatment use of these substances.
AUTHOR CONTRIBUTIONS
All authors made significant contributions to the preparation of the manuscript, which was approved before submission.