a Department of Psychiatry (Neurochemical Research Unit) and Neuroscience & Mental Health Institute, University
of Alberta, Edmonton, Alberta, Canada; b Department of Neurosciences and Behavior and National Institute of Science and Technology (Translational Medicine), Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
* Address correspondence to this author at the Neurochemical Research Unit, Department of Psychiatry, Faculty of Medicine & Dentistry, 12-105B Clinical Sciences Building, University of Alberta, Edmonton, AB, Canada T6G 2B7; Tel: 1-780-492-5994; Fax: 1-780-492-6841; E-mail: ac.atreblau@rekab.nelg
Received 2017 Jul 26; Revised 2017 Nov 7; Accepted 2018 Jan 24. Copyright © 2019 Bentham Science PublishersThis is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
Ayahuasca, a traditional Amazonian decoction with psychoactive properties, is made from bark of the Banisteriopsis caapi vine (containing beta-carboline alkaloids) and leaves of the Psychotria viridis bush (supplying the hallucinogen N,N-dimethyltryptamine, DMT). Originally used by indigenous shamans for the purposes of spirit communi-cation, magical experiences, healing, and religious rituals across several South American countries, ayahuasca has been in-corporated into folk medicine and spiritual healing, and several Brazilian churches use it routinely to foster a spiritual experi-ence. More recently, it is being used in Europe and North America, not only for religious or healing reasons, but also for rec-reation.
To review ayahuasca’s behavioral effects, possible adverse effects, proposed mechanisms of action and potential clinical uses in mental illness.
We searched Medline, in English, using the terms ayahuasca, dimethyltryptamine, Banisteriopsis caapi, and Psy-chotria viridis and reviewed the relevant publications.
The following aspects of ayahuasca are summarized: Political and legal factors; acute and chronic psychological ef-fects; electrophysiological studies and imaging; physiological effects; safety and adverse effects; pharmacology; potential psychiatric uses.
Many years of shamanic wisdom have indicated potential therapeutic uses for ayahuasca, and several present day studies suggest that it may be useful for treating various psychiatric disorders and addictions. The side effect profile ap-pears to be relatively mild, but more detailed studies need to be done. Several prominent researchers believe that government regulations with regard to ayahuasca should be relaxed so that it could be provided more readily to recognized, credible re-searchers to conduct comprehensive clinical trials.
Keywords: Ayahuasca, hallucinogens, N,N-dimethyltryptamine (DMT), Banisteriopsis caapi, Psychotria viridis, monoamine oxidase (MAO)
For the current review, we searched Medline, in English, with the terms “ayahuasca,” “dimethyltryptamine,” “N,N-dimethyltryptamine,” “Banisteriopsis caapi,” and “Psychotria viridis”. In addition, we reviewed relevant and interesting references from the articles collected, including some references to books or sections of books.
Ayahuasca, meaning “vine of the soul” or “vine of the dead” in the Quecha language, is a traditional Amazonian decoction also known by the names of hoasca or oasca (the Portuguese transliteration), caapi or kahpi, daime (which means “give me” in Portuguese), yajé or yage, cipó, natema or natem, dapa, mihi, or vegetal [1, 2]. The psychoactive drink is made from the stem bark of the Banisteriopsis caapi vine, rich in beta-carboline harmala alkaloids, usually in combination with N,N-dimethyltryptamine (DMT)-containing leaves of the Psychotria viridis bush [3]. The harmala alkaloids harmine and harmaline are monoamine oxidase inhibitors (MAOIs), without which the DMT would be inactivated by the gut and liver MAOs, while tetrahydroharmine acts as a weak serotonin reuptake inhibitor without any MAOI action [4]. The combined action of the two plants has been empirically understood by Amazonian indigenous populations for at least 3000 years [5]. Originally used by Amazonian shamans in ritual ceremonies and by folk healers for a variety of psychosomatic complaints [6], worldwide interest in ayahuasca has been rising. It is now being used as a sacrament by three Brazilian churches, by tourists seeking a spiritual experience, and by recreational users all over the world. With growing interest and increasing use of ayahuasca, it is important to understand the safety, behavioral effects, and potential clinical uses. Research into medical use of ayahuasca indicates potential as a treatment in addictions, depression and anxiety [7], with a variety of other possible medical uses, though these require more research.
The use of ayahuasca dates back to the earliest aboriginal inhabitants of the Amazonian basin, where it was used by indigenous shamans for communication with spirits, magical experiences, rites of initiation, and healing rituals [8]. Ayahuasca was held in high regard among these populations, particularly for religious and healing purposes. These were small private ceremonies where the patient and the shaman, and perhaps one or two others, would consume ayahuasca. Shortly after consumption, vomiting and often intense diarrhea occur. But after this, visions begin to appear, and the nature of the disease and curative plants are revealed to the shaman and the patient [9]. Over the past several hundred years, the use of ayahuasca spread into Peru, Colombia, and Ecuador among indigenous Mestizo populations where it was integrated into folk medicine [8]. These practices evolved during the early 1930s [10] for use as a sacrament in three Brazilian syncretic churches which combine indigenous and Christian traditions, the União do Vegetal (the largest, more meditative), the Santo Daime (the oldest, livelier, with music), and Barquinha (an Afro-Brazilian church), during twice monthly ceremonies lasting approximately four hours [2, 4, 11-13]. Ayahuasca therapy has been used by witch doctors in treating addictions, and Lemlij [14] describes a group therapy model where participants come as many weeks as they need and may make a voluntary monetary contribution at the end.
The drink is becoming more popular in North America, Europe and beyond for religious, spiritual, and recreational use [2], so it is important that medical practitioners be aware of the subjective and objective effects that could affect patients they may see and understand any adverse effects, as well as explore potential medical uses. While a considerable amount of modern use of DMT and ayahuasca is for recreational purposes, Cakic et al. [15] found that a group of Australian users gained psychotherapeutic benefits from use. Cardenas and Gomez [16] examined motives for modern urban use by 40 residents of Bogota, Colombia. They found that subjects used ayahuasca to achieve mental wellbeing and also to enhance their ability to solve personal problems; in another study, the participants cited “healing” and “equilibrium” as reasons for use [17]. Kjellgren et al. [2] found similar motives among northern European users, including exploring their inner world, personal development, increasing self-awareness, examining psychological patterns, and enhancing creativity. Fiedler et al. [18] studied motives for use among Santo Daime members, and found that reasons were consistently religious or spiritual, as well as self-treatment.
Travelling in search of a transformative hallucinogenic experience is referred to in the literature as drug tourism, spiritual tourism, or modern shamanic tourism. Ayahuasca tourism is growing in popularity, and most often this involves nonindigenous tourists going on all-inclusive trips to the Amazon to partake in a shaman-led ayahuasca ceremony [19]. One article analyzes the internet’s role in the evolution of ayahuasca tourism, specifically by examining the website of one such tour company, Blue Morpho Tours, and suggests that such experiences represent the quest for “the authentic, ethnic Other” [19]. Modern shamanic tourism is discussed in a dissertation by Fotiou [20] and in articles by Winkelman [21] and Arrevalo [22], both of whom collected data showing that motivations to participate in such an experience are usually not excuses for drug experimentation, but are genuinely sought out as spiritual pilgrimages.
Kavenska and Simonova [23] examined the motivations, perceptions, and personality traits of 77 study participants who had gone to South America to use ayahuasca. Motivations included “curiosity, desire to treat mental health problems, need for self-knowledge, interest in psychedelic medicine, spiritual development, and finding direction in life”. Reported benefits included self-knowledge, improved interpersonal relations, and gaining new perspectives on life. Participants scored significantly above average on the Personality Style and Disorder Inventory (PSSI, Persönlichkeits-Stil- und Störungs-Inventar) scales of “intuition, optimism, ambition, charm, and helpfulness and significantly lower on the scales of distrust and quietness”. While most experiences of this variety with ayahuasca are relatively safe, Arrevalo [22] warns against inexperienced or false shamans using toxic plants as additives to the ayahuasca preparation. Balikova [24] reports on a “meditation session” in Prague in 2001 (named “releasing autohypnosis of forest medicine men”) that ended with many of its participants hypotensive, hyperthermic, with some even requiring mechanical ventilation. This was attributed to a synergistic effect between harmine and two anticholinergics, atropine and scopolamine, found in the brew allegedly made from plants named “Ikitos” or “Toe”. However, these anticholinergics are not found in ayahuasca.
Alexander Shulgin synthesized and personally tried hundreds of psychoactive substances. He and his wife, Ann Shulgin, wrote the book TIKHAL (Tryptamines I have known and loved), which contains a fictionalized autobiography and essays, along with a synthesis manual for 55 substituted tryptamines, and dosing suggestions and accounts of the subjective experience of taking these substances [25]. Research into ayahuasca really took off in 1993, when a multidisciplinary team began a comprehensive investigation into the immediate physiologic and psychological effects as well as the pharmacology of ayahuasca use in 15 male long term (greater than 10 years) adult members of the União do Vegetal church (UDV) called the Hoasca Project, which was conducted by an international team of researchers in the city of Manaus, Brazil [4, 8]. It was an observational study that compared these users with 15 matched male nonusers, and revealed some interesting and surprising results. Long term users scored slightly higher on cognitive tests than nonusers, and many users reported ayahuasca and UDV membership as having a very positive impact on their lives; in fact many reported that they were able to completely turn their lives around from previous dysfunctional behaviours such as alcoholism, violence, dishonesty and infidelity, and they lived happier, more meaningful lives. In addition, there were no signs of acute toxicity or adverse effects on health from ayahuasca use reported [10].
At a 2010 conference organized by the Multidisciplinary Association for Psychedelic Studies (MAPS), ayahuasca became one of the main topics of the conference because presenters submitted such high numbers of proposals on the topic [26]. As ayahuasca use spreads, interest among the general public is increasing as well. Ayahuasca was the subject of a 2011 episode of David Suzuki’s “The Nature of Things” on the Canadian Broadcasting Corporation network. Araujo et al. [27] provide a broad update on hallucinogens. New psychoactive substances continue to be synthesized, greater than 300 of them since the year 2000. Users are obtaining a variety of synthetic or naturally sourced substances through the internet or through specialized shops. They are often sold as “research chemicals” or “legal highs,” and labelled “not for human consumption”. Kowalczuk et al. [28] were able to purchase dried P. viridis leaves over the internet from several sources in Brazil, Peru, and Hawaii, and found that not all the specimens contained DMT. The authors concluded that proper identification and sale of P. viridis are problematic, and suggested that legislation regarding both DMT and P. viridis needs to change.
In 1970, DMT was classified as a Schedule I drug under the US Controlled Substances Act [27]. 1971 was the year of the United Nations (UN) treaty, the Convention on Psychotropic Substances, which replaced the Single Convention on Narcotic Drugs of 1961. UN Schedule I drugs are deemed to have no medicinal value, and include MDMA (3,4-methylenedioxymethamphetamine), psychedelics, and cannabinoids, and it is puzzling that far more dangerous drugs such as cocaine, methamphetamine, and opioids are categorized as Schedule II [28]. The International Narcotics Control Board is currently the control body in charge of implementing the conventions [29, 30]. These classifications have nearly halted research into many potential valuable treatments for a wide range of conditions. Not until 1987 was the use of ayahuasca in a religious context protected by Brazilian law [8, 31]. Members of the American ayahuasca churches kept their use quiet until 1999 when the United States' Drug Enforcement Administration (DEA) confiscated ayahuasca that had been smuggled in. The UDV began a federal lawsuit in 2000 [32], where under the Religious Freedom Restoration Act of 1993, they argued they could use ayahuasca on the basis of religious freedom, and the courts agreed [1]. The federal government appealed the decision several times until, in 2006, the US Supreme Court unanimously decided to allow the ceremonial use of ayahuasca in the UDV church, as they were unable to demonstrate that it had any detrimental effects [3, 33]. The Santo Daime religion fought a similar battle in Oregon, likely benefitting from the precedent set by the UDV church, and won an injunction allowing ceremonial use of ayahuasca in 2009. Even before that, the Oregon State Board of Pharmacy concluded in 2000 that in the Santo Daime religion, ayahuasca had a “nondrug” use, and was not subject to state regulation [1]. A topic of heated debate, the Brazilian government decided in 2010 that for pregnant women and children to consume ayahuasca is an “exercise of parental rights” [12].
In Canada, the Controlled Drugs and Substances Act is the federal law enacted in 1996 that regulates a great variety of illicit psychoactive substances, including opioids, hallucinogens, cannabis, and cocaine in accordance with international laws. Interestingly, there is a clause which allows certain exemptions, called Section 56.
“The Minister may, on such terms and conditions as the Minister deems necessary, exempt any person or class of persons or any controlled substance or precursor or any class thereof from the application of all or any of the provisions of this Act or the regulations if, in the opinion of the Minister, the exemption is necessary for a medical or scientific purpose or is otherwise in the public interest.”
Interestingly, compounds found in ayahuasca are controlled substances under the Controlled Drugs and Substances Act (CDSA), but the plants containing the substances are not. As an example, this is unlike cocaine, as both the plant itself, Erythroxylum coca, and the substance itself are both listed. A Canadian branch of the Brazilian Santo Daime church in Montreal, called the Céu do Montreal, sought an exemption from the Canadian Controlled Drugs and Substances Act in 2001, and in 2006, Health Canada in fact decided to authorize the church to import ayahuasca in the form of tea [34].
Gabor Maté, a Canadian physician, researcher, speaker, and columnist, held multiple day “Working with Addiction and Stress” retreats, which included 4 days of group therapy and two expert-led ayahuasca ceremonies in 2009 and 2010. The team holding the retreat included ayahuasca ceremonial leaders from Peru and Canada (British Columbia), and the participants were from the general Canadian public. In this small study, (N of 12 with no matched controls) data indicated reduced alcohol, tobacco and cocaine use from 6 month followup self-reports, but not for marijuana or opioids. As well, various validated scales pointed towards statistically significant improvements in hopefulness, empowerment, mindfulness, and quality of life [35]. In November 2011, Health Canada determined that Dr. Maté should discontinue his retreats, and in October 2012, the Health Minister determined that ayahuasca use, even ceremonial, was not in the best interest of the public [35].
Indeed more and more people are feeling compelled to speak up on behalf of religious and ceremonial use of ayahuasca and to speak out against government drug policies that hinder scientific research of hallucinogenic substances, just as scientists did in a 1951 “Statement on Peyote” regarding the use of peyote by the Native American Church. In their “Statement on ayahuasca,” Anderson et al. [36] argue that current policies are not based on scientific evaluations and add that sensationalized media portrayals of ayahuasca as a street drug have not aided the cause.
The ayahuasca experience begins approximately 40 minutes following ingestion, peaking between 60 and 120 minutes, with subjective effects fading by approximately 4 hours. Mabit [5] reports that ayahuasca users do not lose consciousness but experience alterations in it, while Strassman [37] reported that with IV DMT injection, users experience a transient loss of their normal awareness lasting only a few minutes, with effects subsiding almost completely in half an hour. Some of the psychological effects during ayahuasca ingestion are reported by Mabit [5] and include a powerful sense of self-confidence, a new perspective and reinterpretation of intrapsychic conflicts; users may reveal intimate truths, and ayahuasca may be powerful in facilitating psychotherapy.
Kjellgren et al. [2] described the “transcendental circle,” a cycle of experiences consistent among different users following ayahuasca ingestion. Approximately 30 minutes after ingestion, subjects noted changing perceptions and shaking, and felt vulnerable and easily influenced. Shortly after, participants developed feelings of confusion, paranoia and fear; psychological defenses were diminished and participants experienced traumatic memories and gained new insight into personal matters [38]. This terrifying state peaks with intense vomiting, after which most participants noted an abrupt shift into an expansive state. Participants describe a transcendental experience in a spiritual world, encountering plant and animal spirits and even contact with a higher power, feelings of oneness with the universe, profound peace and ecstasy, and newly gained understandings of death and what comes after. Sense of time is altered, and users experience feelings of timelessness, time speeding up or slowing down, or traveling in time [39, 40]. Users remain aware of their surroundings and are able to speak [3]. Beyer [41] refers to a similar pattern and describes three phases, the first with visual imagery and sometimes nausea or vomiting; the second phase is contact with a spiritual world in which users report useful lessons from spirit teachers, and the third phase involves fading visuals and feeling physically drained.
Several studies used the Hallucinogen Rating Scale (HRS), which measures subjective effects of psychedelic ingestion on six scales, including Somaesthesia (somatic effects), Affect (emotion and affect), Volition (willful desire to interact), Cognition (thought process and content), Perception (sensory experiences), and Intensity (the strength of the experience). This rating scale was developed by Dr. Rick Strassman, and is loosely based on the components of the mental status exam [37]. Riba et al. [13] found that at least 75% of 18 healthy volunteers with experience in psychedelic use responded positively to 14 selected items in the HRS with a dose of 0.85 mg of DMT/kg of body weight, and described the effects of increased activation, euphoria, and wellbeing. They also reported perceptual changes and increased emotional lability. They also found a correlation between subjective effects of DMT and plasma concentration, and both peaked between 1.5 and 2 hours. Significant dose-dependent increases in all scores on subscales of the HRS have been found [42-44]. When compared to IV DMT, ayahuasca produced a relatively mild high as measured by the HRS [8].
With regard to visual effects, objects appear to vibrate or increase in brightness, colours intensify, moving geometric patterns and intricate images occur with eyes closed or open [3]; kaleidoscopic imagery or visions of people, beautiful scenery, or snakes or jungle animals are common [38, 45, 46]. Effects peak between 60 and 120 minutes [47]. Visual creativity may be heightened for some time even after acute effects wear off [48]. Visual phenomena tend to linger even after acute effects subside, and this may be related to neurochemical changes in the visual cortex and the claustrum. The claustrum, a serotonergic nucleus in the brain, connects nearly all parts of the cerebral cortex. It is theorized that cortical areas with related functions tend to have overlapping claustral projections. Layer 6 (innermost) of the visual cortex and the claustrum have parallel circuits, both of which generate end-inhibition of layers 1 to 4 of the visual cortex through inhibitory interneurons. LSD and other hallucinogens are thought to also excite these inhibitory interneurons. Layers 1 to 4, important in interpreting shorter lines, have a property called end-stopping, in which they respond to lines up to a certain length; beyond these lengths, they are inhibited. Uncoupling of claustral and visual cortex sources of edge information, along with abnormal end-stopping properties and erroneous signalling, may explain some of the well known effects like trails, halos, wavy edges, and misinterpretation of contours [48]. Synesthesia is common, particularly auditory to visual synesthetic effects, and usually they are associated with music. The tempo and feel of the music are often reflected in the movements of the visions and how often the images change [49]. Shanon [49] also noted enhanced improvisation and improvements in their ability to play their instruments by the musicians during Santo Daime rituals, as well as in himself at the piano.
Grob et al. [8] performed a small study comparing 15 syncretic church ayahuasca users versus 15 matched controls as a part of their Hoasca Project. They found that among the ayahuasca users, all alcohol, depressive, and anxiety disorders remitted after joining the UDV. As with the adolescent studies, it is hard to separate the effects of a strong supportive community and religious belonging from the actual effects of the substance, and to determine whether people with particular traits are drawn toward ayahuasca use or church involvement. In the same study, the Tridimensional Personality Questionnaire revealed that users scored significantly lower in the areas of novelty seeking and harm avoidance, but similarly on reward dependence compared to controls [50]. On neuropsychological testing with the World Health Organization, University of California, Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT), users scored significantly higher in the area of word recall on the fifth trial. They also scored better in number of words recalled, delayed recall, and words recalled after interference, though these were not statistically significant. Grob et al. [8] reported that long term ceremonial use does not appear to negatively affect neuropsychological function [8]. Regular users of ayahuasca scored lower on two of the Addiction Severity Index subscales, Alcohol Use and Psychiatric Status, and ritual use does not seem to be associated with the negative psychosocial impacts of many other drugs of abuse [51]. Of 32 members belonging to the American Santo Daime church, 19 reported previous psychiatric histories, but all reported good mental health and only two currently had an active psychiatric disorder [1]. Harris and Gurel [52] reported that ayahuasca users scored higher in the areas of Joy in Life and Relationship to the Sacred, and had an experience just as spiritual as the Catholic retreat participants, and also had reduced alcohol consumption, healthier eating, better mood, and self-acceptance.
Barbosa et al. [17] reported on 23 subjects just prior to their first ayahuasca experience in a religious setting and six months following, using three surveys, the Clinical Interview Schedule-Revised Edition (CIS-R), Short Form-36 Health Survey (SF-36), and the Temperament and Character Inventory-125 items (TCI-125). They found no adverse effects on quality of life, measured by the CIS-R, and some participants showed significant improvements in mental health on the SF-36 as well as in minor psychiatric symptoms on the CIS-R. They also found that regular users (>9 sessions in six months) scored significantly higher on social and emotional functioning domains of the SF-36 questionnaire than less frequent users. In a previous study, Barbosa et al. [11] reported on 28 first time ritual users and also found the same reduction of minor psychiatric symptoms in a shorter time frame of 1 to 2 weeks following use. In another more recent study, Barbosa et al. [53] looked at regular ayahuasca users within a religious setting. Using assessments including the Profile of Mood States (POMS), Big Five Inventory (BFI), Medical Outcomes Study Short Form-36 (SF-36), Addiction Severity Index (ASI), and the California Verbal Learning Test (CVLT), the authors showed that the regular ayahuasca users scored better in terms of mood, having more positive personality traits, better health, improved addiction problems, and better scores on the CVLT. Barbosa et al. [53] concluded that religious use of ayahuasca “does not adversely affect neuropsychological functioning and may have positive effects on substance abuse and mood”. One study assessed the effects of ayahuasca on creativity using the Torrance Tests of Creative thinking, and found that ingestion had no effect on the areas of “fluency,” “relative flexibility,” or “relative originality”; however, it increased participants’ ability to come up with “highly original solutions” to tasks [54]. In addressing the possibility that more creative individuals may seek out a consciousness-altering experience, they found that baseline creativity scores did not differ when compared to controls. Soler et al. [55] found that ayahuasca intake resulted in increased decentering ability (measured by the Experiences Questionnaire), as well as reduced inner reactivity and reduced judgmental processing of experiences on the Five Facets Mindfulness Questionnaire.
In a 2012 study, Bouso et al. [56] compared a variety of psychological measures in ayahuasca users against matched controls. They found that ayahuasca users scored lower on psychopathology measures (on The Symptom Check-List-90-Revised/SCL-90-R psychopathology questionnaire), performed better on cognitive tests (such as the Stroop Colour and Word Test and the Wisconsin Card Sorting Test), and scored higher on the Purpose in Life Test, Spiritual Orientation Inventory, and Psychosocial Well-Being Test. These differences remained the same at one year followup, and there was no evidence of any deleterious effect on mental health and no signs of cognitive impairment among ritual ayahuasca users. Kuypers et al. [57] looked at ayahuasca's effect on creative divergent thinking, a way of thinking believed to enhance psychological flexibility and allow for new cognitive, emotional, and behavioural strategies. Assessing participants before and during the acute effects of ayahuasca, the authors found significantly increased divergent thinking while the subjects were on ayahuasca, and suggested this may facilitate psychotherapeutic interventions. In a research study based on results from the Ayahuasca Researcher's Behavioral Observation Scale (ARBOS), Shamanic Experience and Net Benefit scales, and the Temperament and Character Inventory Predictor scale, Burton [58] suggests we can predict which patients would benefit from or be harmed by participating in an ayahuasca ceremony.
In a questionnaire, 25 Northern European ayahuasca users reported increased self-awareness, being more loving, more empathetic, having greater creativity and new interests especially with nature, and having a more meaningful inner world [2]. Winkelman [21] reported similar effects including new insights and access to deeper levels of the self. Serious reflection on life, nature, and consciousness were consistent themes [3]. Cakic et al. [15] reported that increased “psychospiritual insight” was the most commonly reported positive effect among 12 Australian recreational DMT users, a finding in keeping with studies of religious and ceremonial ayahuasca use. Many users reported that prior to entering the church, they had alcohol problems and violent behaviour, and described themselves as impulsive, disrespectful, oppositional, and irresponsible. All 15 members involved in the Hoasca Project reported that ayahuasca had a profound influence on their lives, allowing them new insight into their self-destructive ways and motivating them to take control of their lives. They also reported better memory and concentration, and a consistently positive mood; however they all recognized the importance of the sense of community and guidance provided by ritual use within the church [8].
Dr. Jacques Mabit runs an addiction clinic in Peru and uses ayahuasca as a part of the treatment. He reports many positive effects: that ayahuasca increases intellectual capacity and concentration, reduces anxiety, increases tolerance of frustration, improves self-esteem, facilitates individuation processes, allows users to see beyond their own worldview and increases openness to new perspectives. Reports from his patients indicate that ayahuasca facilitates introspection and self-discovery, forgiveness without blame, recognition of mistakes, improved decision making ability, motivation to change, increased quality and quantity of dreams, reflections on life as a part of nature and discovery of previously unknown dimensions of life. As well, users seem to benefit from a structured, spiritual, religious, ritual manner of use [5]. Loizaga-Velder and Verres [59] interviewed 14 ritual participants who had long histories of severe substance dependence, and many had several unsuccessful treatments prior to ayahuasca assisted therapy. All participants reported ayahuasca rituals were pivotal to attaining abstinence or achieving less harmful patterns of drug use; they also reported ayahuasca was instrumental in understanding the causes of their addictions. Over half reported reduced cravings. In a study by Cavnar [60], self-identified gay and lesbian ayahuasca users reported feeling affirmation of their sexual orientation.
Using topographic quantitative electroencephalography (QEEG), Riba et al. [61] found patterns in line with previously described EEG findings for other psychedelics, and that ayahuasca shares EEG features with other serotonergic and dopaminergic drugs. The changes occurred as early as 15-30 minutes, peaked between 45 and 120 minutes, and then by 4-6 hours were at baseline. There was a decrease in absolute power in all bands, particularly the theta band. They also found dose-dependent decreases in power density in alpha-2, delta, and beta-1 frequency bands, and these were found mainly in the temporo-parieto-occipital junction, whereas similar findings were found for theta waves in the temporomedial cortex and frontomedial regions. A mild increase in relative global beta power was found with ayahuasca consumption; there were significant relative increases in power in the faster beta-3, beta-4 and beta-5 bands on EEG, and these were more intense and longer in a dose-dependent manner [42-44, 62, 63].
Schenberg et al. [64] showed a biphasic effect of ayahuasca on EEG, with reduced power in the alpha band (8-13 Hz) found 50 minutes after ingestion, and this effect was mainly found at the left parieto-occipital cortex. In the range 75 to 125 minutes, increased slow gamma power (30-50 Hz) was found at the left centro-parieto-occipital, left fronto-temporal and right frontal cortices. Fast gamma increases were observed at the left centro-parieto-occipital, left fronto-temporal, right frontal, and right parieto-occipital cortices [64]. Another study found that ayahuasca increases power in the 36-44 Hz band from the left occipito-temporal-parietal scalp electrode particularly with eyes closed, and hypothesizes the link between theories of the role of 40 Hz brain activity in consciousness and the location of the activity being consistent with ayahuasca’s ability to enhance visual imagery [65]. As well, they found increases in 14-30 Hz beta bands. Confirming these findings, Stuckey [66] also reported similar findings in the 50-64 Hz bands, frequencies implicated in cross-modal sensory processing, and hypothesized a link between this and the intense synesthesia experienced during ayahuasca experiences. Valle et al. [67] noted ayahuasca induced decreases in power in delta, theta, and alpha frequency bands on EEG, and found that alpha band current density in parietal and occipital lobes was inversely correlated with intensity of the visual imagery.
Alonso et al. [68] mentioned some of these recent studies which highlight several of the same ayahuasca-induced EEG changes, such as decreases in current density in the frontomedial regions, but explained that hallucinogen-induced changes in frontal to posterior interactions are only starting to be explored. They used EEG and transfer entropy, a measure of the directional transfer of information between two processes. Transfer entropy analysis showed that frontal sources had decreased influence over central, parietal, and occipital locations, and posterior locations had increased influence over frontal signals. The authors noted a correlation between intensity of subjective effects and decreases in anterior-to-posterior transfer entropy, and postulated that psychedelics confer their effects in part by disrupting the normal state of top-down neural control and allowing greater bottom-up transfer of information in the human brain. The timing of these transfer entropy findings coincided with subjective effects and DMT plasma concentrations.
In a study of cerebral blood flow using single photon emission computed tomography (SPECT) with 15 male volunteers, Riba et al. [69] reported that ayahuasca produced an activation of frontal and paralimbic brain regions and increased blood perfusion bilaterally in the anterior insula; greater intensity was observed in the right hemisphere and in the anterior cingulate and frontomedial cortex of the right hemisphere (areas involved in somatic awareness, subjective feelings, and arousal of emotion). Additional increases were observed in the left amygdala and parahippocampal gyrus, a structure also involved in emotional arousal. Sanches et al. [70] reported increased blood perfusion in the left nucleus accumbens, right insula, and left subgenual area eight hours after ayahuasca ingestion and that ayahuasca was well tolerated. Riba et al. [69] indicated that these findings suggest an interaction of ayahuasca with neural systems is important in introspection and processing of emotion and imply a modulatory role of serotonergic neurotransmission in these processes.
Ayahuasca causes a statistically significant increase in activation of many occipital, temporal, and frontal areas, including the primary visual area on magnetic resonance imaging during closed eye imagery [71]. Even with eyes closed, on ayahuasca the levels of activation in the visual area were consistent with seeing a natural image. This action was seen bilaterally in the occipital cortex, which includes Brodmann areas (BA) 17, 18, 19, all involved in vision. BA 17 has also been correlated with perceptual changes and psychotic effects such as hallucinations. Areas involved in episodic memory were also activated, including the parahippocampal gyrus (BA 30) and the middle temporal cortex (BA 37). The frontal cortex (BA 10) is also activated. Emotions and memories were intensified and past experiences were seen through vivid imagery, which gave the whole experience a “status of reality” [71]. The posterior cingulate cortex (PCC) is key component of the default mode network, a group of neural pathways involved in inwardly focussed thought, conception and awareness of self, remembering the past and envisioning the future. Bousa et al. [72] found an inverse correlation between cortical thickness in the PCC and intensity and duration of previous ayahuasca use, as well as scores on a personality trait called self-transcendence, a leaning toward spirituality and religiosity and suggested that regular use of psychedelic drugs could result in structural changes in brain areas involved in attentional processes, self-referential thought, and internal mentation. Ayahuasca caused decreased activity in the default mode network, and also decreased connectivity between various components of the default mode network on functional MRI [73].
When considered all together, the changes in these particular combinations of brain areas found on imaging fit with the reported experiences of altered awareness, re-experiencing negative memories, and developing new perspectives on problems causing emotional distress. The amygdala, with its increased “utilization rates” [74] of monoamines, brings back the full emotional intensity of the memories. The insula, with its increased blood flow on SPECT imaging [70], could represent the sense of heightened consciousness and increased self-understanding, especially in terms of emotion and relating to others. Many areas of the neocortex show more action, reflected by alterations in perception, cognition, reasoning, and behaviour. The default mode network showed decreased activity on functional MRI, related to alterations in metacognition and self-awareness. The loosening of top-down control over information processing certainly plays a role in the novelty of the experience, as well as the intensified emotional and sensory experience [75]. Ayahuasca-induced changes in many areas of the brain involved in feelings, memories, vision, and consciousness allowed for amplified introspection and problem-solving related to past and current life stressors, and for powerful envisioning and strategizing of solutions for a more hopeful future.
One human trial showed that ayahuasca at 1 mg/kg, compared to 20 mg of dextroamphetamine, did not affect subjective sleep quality, initiation or maintenance as measured by polysomnography, decreased REM, and increased slow-wave sleep power [76]. Luke [77] hypothesizes that DMT may play a role in dreaming. DMT depresses startle response in rats [78]. A further experiment showed that low doses (0.25 and 0.5 mg/kg) augmented startle response while a high dose (4.0 mg/kg) depressed it [79]. Another study found that harmine decreased acoustic startle amplitude [80]. A 2002 study assessing sensory and sensorimotor gating showed that with increasing ayahuasca doses there were dose-dependent reductions in P50 suppression [44, 65]. P50 suppression is a test of sensory gating in which paired clicks are heard 50 milliseconds apart, and normally with the second click the amplitude of brain waves (auditory evoked potentials) is much lower, as the brain perceives it as redundant. As an example, in people with schizophrenia, the amplitude is reduced much less than in people without schizophrenia, indicating difficulty with sensory gating. Riba et al. [44, 63] also showed no significant effect on sensorimotor gating, as measured by prepulse inhibition of startle response. Vomiting results from increased serotonin (5-HT) stimulating the vagus nerve centrally, and diarrhea may be a result of excessive intestinal stimulation by 5-HT peripherally [47].
Morgenstern et al. [81] reported that almost no hallucinogen users had difficulty cutting down or controlling use, unlike many other drugs. In a study of rhesus monkeys, Fantegrossi et al. [82] found reinforcing effects of the hallucinogens DMT, mescaline, and psilocybin, and suggest that the patterns of self-administration demonstrate weak reinforcing effects, and possibly mixed reinforcing and aversive effects. Ayahuasca does not seem to have the negative psychosocial implications caused by many drugs of abuse [51]. Mixed results were found in studies of drug tolerance in animal studies [83-85] as well as in human studies [3], particularly to the psychoactive effects, which is unique among other known hallucinogens. Callaway et al. [86] found that some physical tolerance may develop in humans with regular use. In a study by dos Santos et al. [43], acute tolerance failed to develop for any measures aside from growth hormone (GH), which showed decreased release on second administration, as well as a slightly lower response in the systolic blood pressure (SBP) and heart rate (HR). Another study similarly showed tolerance with heart rate, adrenocorticotropic hormone (ACTH) and prolactin [87]. Another study found that there was little to no tolerance with DMT in cats [84].
Beta-carbolines can induce tremor in mice, thought to be due to the interaction of these compounds with tryptamine binding receptors [88]. An experiment by Louis et al. [89] suggests we should be cautious with beta-carbolines, as they are found endogenously in higher levels in essential tremor patients, and that harmine and harmane may be tremorigenic. Bouso et al. [90] compared two groups of ayahuasca users, one with long term experience and the other with occasional use. The study found that acute use does impair working memory, but having greater prior exposure was associated with less incapacitation during administration, and detrimental effects on cognition were mainly seen in the occasional use group. Those findings suggest there may be neuromodulatory or compensatory effects induced by long term use.
There is conflicting information on whether endogenous DMT levels are higher in psychotic disorders, and research thus far has been inconclusive [27]. Checkley et al. [91] suggested that levels are higher during psychosis but normal after recovery, while Gillin et al. [92] argued that DMT levels do not differ significantly between schizophrenics and normal controls, and that DMT does not mimic symptoms of schizophrenia. Another theory proposed that DMT may even serve to suppress psychotic activity, acting as a homeostatic agent [27]. Based on rates of psychotic episodes in the UDV, Gable [3] also concludes that ayahuasca is not a trigger for sustained psychosis. While ayahuasca and other psychedelics could precipate psychosis in predisposed individuals, rates of psychosis in the UDV are comparable to the general population in Brazil [36]. Paterson et al. [93] provided a case report of a 42-year-old male without significant psychiatric history who presented with substance-induced psychosis in the context of recent and repeated DMT use as well as long term cannabis use. He improved with quetiapine, divalproex, and hydroxyzine. Warren et al. [94] also suggested that recreational DMT use could be a contributor to psychosis. Another case report discussed a man with preexisting bipolar disorder who had a manic episode following ayahuasca consumption [95].
Callaway et al. [47] reported both GH and prolactin increasing but returning to baseline by 360 minutes, and cortisol increasing to a maximum at 60 minutes, and dipping below basal levels at 360 minutes. GH and prolactin are also influenced by the serotonergic system, so their findings fit with other studies showing an increase in prolactin levels with DMT and other serotonergic drugs such as MDMA, fenfluramine, and citalopram [96, 97].
Dos Santos et al. [42] found that relative to placebo, ayahuasca increased total lymphocytes at 1.5 hours, and decreased them at 4.5 hours compared to placebo and to amphetamine, although there was no difference at 24 hours [42]. There were significant decreases in both CD3 and CD4 lymphocytes at 1.5 and 2 hours, no significant changes in CD8 and CD19 lymphocytes, and significant increases in natural killer (NK) cells at 1.5 and 2 hours compared to placebo. No tolerance or sensitization was found with repeat doses [43]. Davydova et al. [98] and dos Santos [99] highlighted previous findings and postulated that DMT may activate peripheral 5-HT2A receptors on leukocytes with impacts on cytokine secretion and cell differentiation, and that increased glucocorticoid levels may have modulatory or inhibitory effects on immunity. Amphetamine and MDMA both induce changes similar to ayahuasca, with decreases in CD3 and CD4 lymphocyte levels and increases in NK cell levels [42]. Frecska et al. [100] found that DMT caused significantly increased levels of secreted interferon-β and interferon-γ in cultured human NK cells, and suggested that DMT's action at the sigma-1 receptor could be the mechanism for this effect. In an in vitro study on human primary monocyte-derived dendritic cells, DMT and 5-MeO-DMT reduced production of several pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and chemokine IL-8, while they increased the secretion of the antiinflammatory cytokine IL-10 [101, 102]. The authors found that these effects were mediated through the sigma-1 receptor, and also noted that both DMT and 5-MeO-DMT impaired the ability of T helper 1 and T helper 17 cells to activate immune responses. House et al. [103] noted that harmaline caused a dose-related suppression of CD8 activity, IL-2 and IL-4 production, B cell proliferation, and NK cell function.
DMT causes dose-dependent elevations in pupil size [43, 91]. Callaway et al. [47] reported that pupillary diameter increased to a maximum of 4.9 ± 0.2 mm at 180 minutes, and returned to normal by 360 minutes. Mydriasis has been demonstrated in several IV DMT studies [91, 104]. Mean pupillary light reflex (PLR) amplitude was reduced and PLR latency was increased significantly compared to placebo [42]. A reduced PLR amplitude and increased PLR latency is typically associated with anticholinergics. Two studies found that the serotonin-noradrenaline reuptake inhibitor (SNRI) venlafaxine has the same effect, and they interpreted this as noradrenergic inhibition of parasympathetic transmission on the Edinger-Westphal nucleus, responsible for iris constriction [105, 106].
With respect to body temperature, dos Santos et al. [42] compared DMT (at a dose of 1 mg DMT/kg body weight), amphetamine, and placebo, and found that with placebo, body temperature steadily increased over the day, whereas both DMT and amphetamine caused a statistically significant decrease in body temperature during the first hour, followed by a gradual increase, which was larger for amphetamine. Studies involving IV DMT have shown inconsistent results, with one study showing increases and three others showing no change or ambiguous results [46, 104-106].
In a study of 18 volunteers, Riba et al. [13] showed maximum increases in diastolic blood pressure (DBP) of approximately 10 mmHg at 15 minutes, and a maximal systolic BP (SBP) rise of approximately 8 mmHg at 75 minutes following ingestion of ayahuasca containing a 0.85 mg/kg dose of DMT. With respect to heart rate, the maximum increase was approximately 5 beats per minute (BPM) at 60 minutes. Only two of the 18 volunteers had a SBP over 140 (maximum 146) at any point in time, and two volunteers had a DBP over 90 [96]. The same volunteer with the high SBP and DBP had a heart rate of 101 at 60 minutes. Callaway et al. [47] found maximal increases in BP at 40 minutes, 11 mmHg for SBP and 9 mmHg for DBP. Heart rate, at its maximal increase, was 7 BPM above baseline at 20 minutes (79 BPM), decreased to a low of 7 BPM below baseline by 120 minutes (65 BPM), then returned toward baseline by 240 minutes. The return to baseline may be due to increasing levels of central 5-HT, mediating cardiac response through the vagus nerve [47]. Another study demonstrated significant increases in HR, SBP, and DBP relative to placebo, with a maximum HR of 150 and SBP of 147 mmHg, while no DBP values went above 90 mmHg [43].
Strassman and Qualls [87] found dose-dependent elevations in HR and BP with IV DMT. They found a larger and more rapid increase than with oral ingestion, reporting that a 0.4 mg/kg IV dose raised HR by approximately 26 BPM at 2 minutes, as well as SBP by 35 mmHg and DBP by 30 mmHg. In the same study, peak heart rates were approximately 150 BPM while some were no higher than 95 BPM. Gable [3] analyzed several studies to compare changes in HR, SBP, and DBP brought on by various psychoactive substances, and concluded that the hemodynamic effects of ayahuasca appear less hazardous than IV DMT, oral alcohol, insufflated cocaine, smoked marijuana, and oral MDMA (Table 1 1 ).
Heart rate and blood pressure changes induced by various psychoactive substances (as reported by Gable [3]).
| Heart Rate Increase (BPM) | Systolic Blood Pressure Increase (mmHg) | Diastolic Blood Pressure Increase (mmHg) | |
|---|---|---|---|
| DMT | 6.4-9.2 | 8.8-13.8 | 8.6-10.4 |
| Alcohol | 9 | -2 | 1 |
| Caffeine | 4 | 5 | 5 |
| Cocaine | 17 | 14 | 14 |
| MDMA | 28 | 25 | 7 |
As with any substance that causes acute hemodynamic changes, some adverse cardiac events are possible with the use of ayahuasca [3], although such minimal increases could be attributed to changes in physical activity or other reasons, along the same lines as suggested by Hartley et al. [107], who concluded that even just an anxiety-provoking stimulus increases these values more than caffeine; after 14 days of chronic administration, Pitol et al. [108] found flattening and stretching of vascular smooth muscle cells, and significant increases in media thickness as well as the ratio of the media thickness to the lumen diameter.
There have been a few reported cases of poisoning from P. harmala seeds. These included a 35-year-old male with abdominal pain, low BP, and convulsions, but this was after ingesting 150 g of P. harmala seeds. His symptoms resolved after several hours [109]. It is possible the convulsions could have been related to the inverse agonist effect of some of the beta-carbolines at the benzodiazepine receptor site on the GABA-A receptor [110, 111]. Another case involved a 27-year-old woman who had ingested 50 g of P. harmala seeds in a cup of coffee. She presented with hallucinations, bradycardia, nausea, and vomiting, but was discharged several hours later, and laboratory investigation results were all normal [109]. Several similar cases have been reported. In an attempt to investigate the toxicity of ayahuasca, Pic-Taylor et al. [112] administered ayahuasca doses 30 and 50 times higher than that typically used in religious rituals to female Wistar rats. While the authors could not calculate an LD50 based on their findings, they determined that the lethal dose is higher than 50 times a typical dose used in a religious setting. Pic-Taylor et al. [112] also found that the increased serotonergic activation from these high doses led to some neural degeneration, but no permanent alteration in brain structure or number of cells was found.
In our literature search, we found no reports of deaths directly attributable to ayahuasca use. There are a few reported deaths associated with ayahuasca-like herbal preparations, but in these cases it appears coingestion with other substances was to blame; for example, a 25-year-old male had ingested 5-MeO-DMT in addition to beta-carbolines and only trace amounts of DMT, and a 71-year-old diabetic female took a brew containing nicotine as an enema to avoid smoking, and died from nicotine intoxication [3, 113, 114].
A review by dos Santos [115] covers ayahuasca use in pregnancy, and concludes that while some animal studies show toxicity from in utero ayahuasca exposure, what little information there is on the topic indicates that there are no serious adverse effects of ayahuasca exposure in utero in humans, but more information is needed before its safety in pregnancy is fully understood [66]. Pregnant rats consuming high doses of ayahuasca (10 times the normal human dose) displayed decreased food consumption. The rats displayed decreased weight gain but increased relative liver weight, possibly indicating some hepatotoxicity [116]. As well, these researchers found a dose-response relationship, and fetal effects at 10 times the normal human dose include visceral and skeletal malformations, dilated lateral and third ventricles, along with decreased body weight, thought to represent intrauterine growth restriction (IUGR). A more recent study by Gardner et al. [117] discussed congenital malformations in livestock in parts of South America and Mexico, which have long been attributed to ingestion of the Mimosa tenuiflora shrub containing N-methyltryptamine (NMT) and DMT. Their findings showed increased rates of cleft palate, scoliosis, and skeletal deformities in rat pups compared to controls when pregnant mothers were fed diets including DMT, NMT, both, or extracts of the M. tenuiflora seeds and leaves.
The DMT in ayahuasca is from the Psychotria viridis or Diplopterys cabrerana vines, and ranges in concentration from 0.1% to 0.66% of the dry weight [3, 118]. The beta-carbolines come from Banisteriopsis caapi. These compounds represent 0.05% to 1.95% of the dry weight, and are much more concentrated in the seeds and roots than in stems and leaves [3]. DMT, a hallucinogen, can be smoked, ingested orally, given IV, or even insufflated [3]. However, when consumed orally, for DMT to exert its effects it is essential that it be consumed mixed with an MAOI to prevent degradation of the DMT by gut and liver MAOs, and to lengthen its action within the CNS [119, 120]. When ayahuasca is consumed, the DMT is taken in combination with beta-carbolines which act as reversible inhibitors of monoamine oxidase A (MAO-A), protecting the DMT from degradation [121].
In a review on ayahuasca, Gable [3] looked at previous data on the composition of one serving of various studies’ brews, and found a range of 8.8 mg to 42 mg for DMT, 17 mg to 280 mg harmine, 4.6 mg to 28 mg harmaline, and 4.2 to 150 mg for tetrahydroharmine; these wide variations are attributed to different composition of the plants as well as differences in preparation methods. A recent study on ayahuasca samples from Brazilian religious groups found DMT concentrations ranging from 0.17-1.14 g/L [120], which, assuming an average serving size similar to previous studies being around 150 mL, would give a dose ranging from 25.5 to 171 mg of DMT per serving.
Chemical profiling of the aqueous extract from B. caapi stems revealed a number of substances [119-123], some of which had not yet been identified in B. caapi. Wang et al. [124] found two new beta-carboline alkaloidal glycosides (Banisteride A and B) and their acetates, four known beta-carbolines (harmine, harmaline, tetrahydroharmine, and harmol), a new beta-carboline (tetrahydronorharmine), two proanthocyanides [(-)-epicatechin and (-)-procyanidin B2)] and their acetates, a new dissacharide (β-d-fructofuranosyl-(2→5)-fructopyranose) and its acetate, known saccharose and acetate, and β-D-glucose. Several studies found similar chemical profiles. Two quinazoline alkaloids, peganine and deoxypeganine, have also been isolated in a P. harmala seed infusion [125].
The toxic dose of ayahuasca would be approximately 7.8 litres for a 75 kg person. Given its highly unpleasant taste, it is unlikely anyone would ever reach this dose. In addition, vomiting and diarrhea occur long before this limit is reached [5].
DMT (Fig. 1 1 ) is a serotonin-like hallucinogen structurally resembling other indolealkylamines, including melatonin and psychedelic tryptamines such as psilocybin, and is known mostly for its activity as a 5-HT2A receptor agonist [15, 126]. DMT is found in fungi, marine sponges, tunicates, frogs, legumes, and grasses [27] and has been reported to be formed endogenously in human and rat brains [127] as well as to be found in human urine, blood, and CSF. DMT has affinity for 5-HT1A/1B/1D/2A/2B/2C/6/7 receptors, with proven partial agonist activity at the 5-HT1A/2A/2C receptors [80, 118, 128, 129]. Carbonaro et al. [130] proposed that the mGluR2 glutamate receptors may have some involvement in DMT's hallucinogenic effect. Current understanding is that psychedelic effects are mediated mainly by 5-HT2A/2C receptors. 5-HT2A receptor activation has also been associated with sympathetic activation which may explain some of the physiologic effects of ayahuasca administration [87, 131].
Structures of DMT and serotonin (5-HT).
DMT activity was demonstrated at the rat trace amine-associated receptor 1 (TAAR1) by Bunzow et al. [132], where tryptamine is also thought to act as a neurotransmitter [27]. Premont et al. [133] suggested that DMT may function endogenously as part of this system, and proposed that trace levels of endogenous DMT act to produce a calmer, more relaxed mental state and suppress psychosis.
DMT binds to sigma-1 receptors with a moderate affinity, and Fontanilla et al. [128] proposed that DMT is likely to serve as an endogenous sigma-1 receptor ligand. The function of this receptor is not well understood, although it is found in lung, prostate, colon, ovaries, breasts, and liver, and is most concentrated in the brain. This receptor may play a role in depression, anxiety, and cancer [134]. Sigma-1 receptors are molecular chaperones situated on the mitonchondria-associated endoplasmic reticulum membrane, although when stimulated with high concentrations of ligands, may translocate to the cell’s plasma membrane, where they inhibit several ion channels. DMT has also shown affinity for α1- and α2-adrenergic receptors as well as the dopamine D1 receptor [135].
Beta-carbolines (Fig. 2 2 ) are tricyclic indole alkaloids resembling tryptamines [10]. 6-Methoxy-tetrahydro-β-carboline has been found in the human pineal gland [136]. Several beta-carbolines are found in the B. caapi vine, including harmine, harmaline, and tetrahydroharmine. The first two act as selective and reversible monoamine oxidase A inhibitors (MAO-AIs), while tetrahydroharmine acts as a weak serotonin reuptake inhibitor without any MAO-AI action [47]. Beta-carbolines are found naturally in wheat, rice, corn, barley and throughout different body tissues [89]. They elicit their effects through several mechanisms.
Structures of harmine, harmaline and tetrahydroharmine.
Beta-carbolines without DMT have been shown to produce psychological and physiologic effects, as in a case of intoxication following Paganum harmala seed extract [137]. The effects, including nausea, vomiting [130], hallucinations, ataxia, confusion, and agitation were attributed to CNS stimulation by MAOI activity as well as the serotonin reuptake inhibition by tetrahydroharmine. Frison et al. [137] suggested that the hallucinogenic effects could be a result of the affinity of harmine and harmaline for 5-HT receptors. Beta-carbolines from the B. caapi vine taken without DMT are used by the Piaroa of Southern Venezuala. Piaroa shamans and people who use B. caapi describe enhanced empathy, stimulant-like effects, and increased visual acuity, and they also use it as a hunting aid [138, 139].
The main mechanisms of action proposed for beta-carbolines include the MAO-A inhibitory activity, dopamine efflux, and affinity for the 5-HT2A binding site [140]. Other less studied mechanisms include dopamine transporter (DAT) inhibition at high concentrations in particular of beta-carboline compounds [141], harmine as a specific tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) inhibitor [142], and affinity for the imidazoline (I2) binding site [143]. Harmine has also been found to regulate expression of the peroxisome proliferator-activated receptor gamma (PPAR-ɣ, also known as the glitazone receptor) and shows some antitrypanosomal activity [144]. Harmine upregulates the glutamate transporter (GLT-1, also called excitatory amino acid transporter 2, or EAAT2), the primary mechanism for inactivating synaptic glutamate [145]. Harmane, harmine, and norharmane have also been found to act as inverse agonists at the benzodiazepine binding site (between the α and ɣ subunits) of the GABA-A receptor [110]. Another study showed that 4 beta-carbolines (1,2,3,4-tetrahydronorharmane, norharmane, harmane, and 6-methoxyharmalan) act as competitive antagonists at the glycine receptor ligand binding site, leading to inhibition at the glycine receptor [111].
A recent study on neurotransmitter concentrations in the amygdala and hippocampus of rats killed 40 minutes after administration of an ayahuasca infusion reported that ayahuasca reduced levels of glycine and GABA in rat amygdala. This is suggestive of an increased release of these neurotransmitters in the amygdala, leading to greater inhibition, while in the hippocampus, it increased GABA levels, suggestive of a decrease in GABA release and excitation at this structure [74]. These opposite effects on the level of inhibitory neurotransmission in these two limbic structures may provide some explanation into the behavioural effects of ayahuasca, due to the importance of these structures in neural pathways involved in memory, learning, and emotion.
Harmine and harmaline affect dopamine pathways both by causing a significant increase in DA release from striatal cells and by acting as reversible MAO-A inhibitors. A study on the nucleus accumbens of rats [146] found that harmine increases electrically evoked DA efflux in the nucleus accumbens shell. Brierley & Davidson [140] proposed that, given harmine has some affinity for the 5-HT2A/2C receptors but not for the dopamine receptor [147], this effect has a 5-HT2A-mediated mechanism. Grella et al. [148] also found that certain beta-carbolines bind at the 5-HT2 receptor. In another experiment in rat striatum, dose dependent decreases in the levels of DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were also seen, as well as decreases in levels of the serotonin breakdown product 5-hydroxyindoleacetic acid (5-HIAA), though not to the same extent as with the dopamine metabolites [149]. These effects are additive when mixtures of various beta-carbolines are used [123]. The dopamine transporter serves to actively shift dopamine from the synapse into the presynaptic neuron, acting as the primary mechanism for regulating dopaminergic activity [150]. Harmine was found to inhibit DA uptake through the DAT in rats. Dopaminergic neurotransmission is primarily modulated through regulation of the dopamine transporters, which act to shuttle extracellular dopamine back into the neurons. Harmine acts a potent ATP-competitive inhibitor of the DYRK1A enzyme, which inhibits synaptic vesicle endocytosis and DAT membrane trafficking, possibly by phosphorylating vesicle proteins taking part in clathrin-mediated endocytosis that serves to regulate DAT trafficking [151, 152]. DYRK1A overexpression has been implicated in defective neural development in Down Syndrome, and the protein has also been implicated in amyloid pathology as well as in tau protein phosphorylation (at serine 262/356/396) in both Down Syndrome and Alzheimer’s disease [153].
Ayahuasca was found to upregulate platelet serotonin transporters [86]. Disorders that have been suggested to be associated with low serotonin transporter densities include alcoholism (particularly with violent tendencies), suicidal behaviour, and severe depression [10]. The glutamate transporter GLT-1/EAAT2 is the main mechanism for extracellular glutamate uptake in the brain, and dysfunction may lead to excessive synaptic glutamate and excitotoxicity. Harmine has been found to activate the GLT-1 gene promoter, leading to increased gene expression and greater extracellular glutamate uptake [145]. Certain beta-carbolines have been found to bind at imidazoline binding sites, including harmine and harmaline found in ayahuasca [143]. Husbands et al. [143] suggested that the imidazoline type 2 (I2) receptors may play a role in the hallucinogenic nature of ayahuasca given that harmine and harmaline have much higher affinities for the I2 receptor than the 5-HT2A receptor. Harmine also increases superoxide dismutase and catalase activity, and these antioxidant effects may have relevance in depression and several neurodegenerative disorders [154].
Callaway [155] studied slow versus fast metabolizers and cytochrome P4502D6 (CYP2D6) variations in humans. The main isozymes involved in O-demethylation of harmaline into harmalol are CYP1A1, CYP1A2, and CYP2D6, while CYP1A1, CYP1A2, CYP2C9, CYP2C19, and CYP2D6 catalyze the O-methylation of harmine into harmol. These metabolites are then excreted as glucuronates and sulphates [156, 157]. Harmane may break down into harmine [89]. Only one case report attempted to quantify and compare concentrations and amounts of harmine and harmaline in an ayahuasca infusion and urine; however, it was difficult to draw any conclusions given the amount of uncertainty surrounding the preparation and ingestion [137].
Compared to DMT from ayahuasca, smoked, IV and insufflated DMT all have a very rapid onset of activity, with peak cognitive effects lasting 3-10 minutes and episodes 5-15 minutes. Ayahuasca produced a cognitive peak between 60 and 120 minutes and effects lasting approximately four hours [10]. Recreational DMT users describe the experience as short, intense, and pleasurable [158]. In addition, ayahuasca has somatic effects that appear approximately 20 minutes after consumption, including nausea, tingling, and increased body temperature [3].
With respect to plasma peak levels, Callaway et al. [47] showed an average time to reach maximum concentration (Tmax) of 107.5 ± 32.5 minutes with 15 volunteers, and the half life (T1/2) was 259 minutes. dos Santos et al. [42] noted a median Tmax of 1.8 hours, with a range of 1-4.5 hours. Riba et al. [13] found a median Tmax for orally consumed DMT of 1.5 hours for both high and low doses (0.6 mg/kg and 0.85 mg/kg), but showed a correlation between higher doses and a larger Tmax. This aligns with the finding of a cognitive peak
between 60 and 120 minutes reported by Gable [3], as well as peaking along a similar timeline as EEG activity [65]. The threshold for hallucinogenic effects for DMT was 0.2 mg/kg by IV. IV DMT administration also differs in that the effects come on more rapidly and last for a shorter time, displaying peak blood levels and subjective effects within 2 minutes; both were neglible at 30 minutes [3, 87]. Gable [3] noted a median lethal dose (LD50) for DMT of 47 mg/kg intraperitoneally and 32 mg/kg IV in mice, which is similar to the IV LD50 in rodents for other compounds resembling DMT structurally (psilocin, psilocybin, bufotenin, 5-MeO-DMT). In comparing toxicities of various psychoactive drugs, ayahuasca has a safety margin similar to those of codeine, mescaline, and methadone, with the lethal dose being approximately 20 times the usual effective dose [159]. Lanaro et al. [160] discussed differences between ritual oral ingestion of ayahuasca and recreational smoked DMT and noted that with smoked DMT the bioavailability and risk of overdose are much higher.
DMT is catabolised mainly by oxidative deamination as well as N-oxidation and N-demethylation [27]. Metabolic studies showed indole-3-acetic acid (IAA) and indole-3-aceturic acid (IAA conjugated with glycine) as the main urinary metabolites of DMT in rats [161]. Riba et al. [162] described urinary metabolites of oral and smoked DMT. Without the beta-carbolines found in ayahuasca, after oral ingestion of DMT, no psychoactive effects occurred; 97% of recovered compound was IAA, an MAO-dependent metabolite, and 3% was DMT-N-oxide (DMT-NO). DMT-NO does not appear to be a substrate for MAO. With smoked DMT, unmetabolized DMT and DMT-NO accounted for 10% and 28%, respectively, of recovered compounds, while IAA accounted for 63%. N-methyltryptamine (NMT), 2-methyl-1,2,3,4-tetrahydro-beta-carboline (2-MTHBC) and 1,2,3,4-tetrahydro-beta-carboline (THBC) have also been identified as minor metabolites of DMT [27].
A study by Callaway et al. [47] found Tmax values (minutes) for DMT of 107.5 ± 32.5, for harmine 102.0 ± 58.3, for harmaline 145.0 ± 66.9, and for tetrahydroharmine (THH) 174.0 ± 39.6 after an ayahuasca infusion. Riba et al. [13] reported that THH peaked later in the serum than DMT and harmaline. Compared to low dose, high dose ayahuasca seemed to show slightly longer Tmax values for these constituents. They were unable to obtain sufficient measurable plasma levels for harmine, but had measurable levels of harmol (metabolite of harmine) with plasma concentration peaks at 1.5 and 2 hours after low and high doses. They were able to measure harmaline, and Tmax was at 1.5 and 2 hours for the low and high doses. In general, the studies by Riba et al. [13] and Callaway et al. [47] (Table 2 2 ) show a trend of Tmax increasing from DMT through harmaline to THH. In terms of toxicity, Gable [3] found a median lethal dose/LD50 of 2 g/kg P. harmala seed beta-carboline admixture in rats.
Tmax findings for DMT, harmine, harmol, and harmaline, and THH in various studies.
| DMT | Harmine | Harmol (Metabolite of Harmine) | Harmaline | THH | |
|---|---|---|---|---|---|
| Callaway et al. [47] | average Tmax in minutes | 107.5 ± 32.5 | 102.0 + 58.3 | 145.0 + 66.9 | 174.0 + 39.6 |
| Riba et al. [13] | median Tmax in hours at low dose | 1.5 (1-2.5) | 1.5 (1-2.5) | 1.5 (1-3) | 2.5 (1.5-3) |
| Riba et al. [13] | median Tmax in hours at high dose | 1.5 (1-4) | 2 (1-3) | 2 (1-4) | 3 (1.5-6) |
| dos Santos et al. [42] | median Tmax in hours | 1.8 (1-4.5) |
