Front Pharmacol . 2016; 7: 35. doi: 10.3389/fphar.2016.00035 PMCID: PMC4773875 PMID: 26973523 The Therapeutic Potentials of Ayahuasca: Possible Effects against Various Diseases of Civilization ,1,* ,2 and 3 Ede Frecska 1Department of Psychiatry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Find articles by Ede Frecska Petra Bokor 2Doctoral School of Psychology, University of Pécs, Pécs, Hungary Find articles by Petra Bokor Michael Winkelman 3School of Human Evolution and Social Change, Arizona State University, Tempe, AZ, USA Find articles by Michael Winkelman Author information Article notes Copyright and License information Disclaimer 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 Edited by: Adolfo Andrade-Cetto, Universidad Nacional Autónoma de México, Mexico Reviewed by: Stephen O. Amoo, Agricultural Research Council, South Africa; Eduardo Ekman Schenberg, Instituto Plantando Consciência, Brazil *Correspondence: Ede Frecska, moc.liamtoh@akscerfe This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology Copyright © 2016 Frecska, Bokor and Winkelman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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. 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 (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 view1 on 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 (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.

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.

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 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.

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. 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).3 Although 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 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 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 virid is 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 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 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.

Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments We would like to thank Mr. Dániel Gyöngy for his help in preparing the figures.

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