This hypothesis paper (2012) proposes four unique but interrelated mechanisms in the domains of biochemical, physiological, and psychological pathways and transcendent experiences, through which ayahuasca may exert anti-addictive effects.
Ayahuasca is a medicinal plant mixture utilized by indigenous peoples throughout the Amazon River basin for healing purposes. The “vine of the soul” or “vine of death,” as it is known in South America, contains a combination of monoamine oxidase inhibitors and N,N-dimethyltryptamine (DMT). When ingested together, these medicines produce profound alterations in consciousness. Increasingly, ayahuasca is being utilized to treat addictions. However, the mechanism of action by which ayahuasca treats addictions remains unclear. We offer four hypotheses to explain possible biochemical, physiological, psychological, and transcendent mechanisms by which ayahuasca may exert its anti-addiction effects.
Liester and Prickett situate ayahuasca as a traditional Amazonian plant preparation used for healing and spiritual purposes for millennia. The brew combines Banisteriopsis caapi, which contains beta-carboline monoamine oxidase inhibitors (MAOIs), with plants such as Psychotria viridis that contain N,N-dimethyltryptamine (DMT). When taken together these constituents produce profound alterations of consciousness, and ayahuasca has increasingly been reported as a treatment for substance addictions. Despite growing clinical and popular interest, the mechanism by which ayahuasca might reduce addictive behaviours remains unclear. This paper sets out to synthesise existing biochemical, physiological, psychological, and historical literature in order to generate mechanistic hypotheses. Rather than report new empirical data, Liester and Prickett propose four interrelated hypotheses—biochemical, physiological, psychological, and transcendent—that together might explain ayahuasca's putative anti-addiction effects and identify directions for future research and validation.
Papers cited by this study that are also in Blossom
Mangini, M. · Journal of Psychoactive Drugs (2011)
Osmond, H. · Annals of the New York Academy of Sciences (2010)
Riba, J., Urbano, G., Morte, A. et al. · Psychopharmacology (2001)
Papers in Blossom that reference this study
Griesfeller, A. F., Kooman, L., Kloft-Heller, L. et al. · Psychopharmacology (2026)
The extracted text does not describe a formal methods section or a systematic literature search strategy. Instead, the paper presents a narrative synthesis: a historical overview of ayahuasca use, a review of its known biochemistry and reported subjective effects, and an integration of these sources with selected neurobiological and psychotherapeutic literature to generate four hypotheses about anti-addiction mechanisms. Sources cited within the narrative include archaeological and ethnographic reports on ayahuasca use, biochemical analyses of plant constituents (DMT and beta-carbolines), neuroendocrine findings (hormone changes after ingestion), pharmacologic and imaging studies relevant to serotonergic and dopaminergic systems, and historical clinical literature on psychedelic-assisted treatments (for example, LSD therapy approaches). The authors do not report inclusion/exclusion criteria, databases searched, or a formal risk-of-bias assessment, and no new experimental or clinical data are presented in the extracted text.
The paper first summarises historical and ethnobotanical background: archaeological evidence indicates ayahuasca-like plant use in the Amazon for thousands of years; modern ceremonial and religious uses spread to Brazilian churches and beyond; and nontraditional synthetic preparations have emerged in Western contexts. Biochemistry and acute effects are described in detail. Banisteriopsis caapi provides harmine, harmaline and tetrahydroharmine—reversible MAOIs—while Psychotria viridis supplies DMT. DMT is a short-acting, potent agonist at several serotonergic receptors including 5-HT2A and 5-HT2C; when combined with MAOIs it remains orally active. Reported biochemical effects include DMT action at serotonin receptors, MAOI-mediated increases in monoamines (serotonin, dopamine, norepinephrine), and short-term hormonal changes: elevated prolactin, cortisol and growth hormone within 120 minutes of ingestion. The authors note an association between chronic ayahuasca use and increased numbers of serotonin receptors on platelets, though they state the clinical significance of this finding is unknown. Physiologic effects reported by users typically last six to 12 hours and include gastrointestinal symptoms (nausea, vomiting, diarrhoea), neurological signs (tremor, dizziness, mydriasis, synaesthesia), cardiovascular changes (increased heart rate and blood pressure), and altered temperature perception. Psychological effects encompass vivid closed‑eye visual imagery, shifts in emotion and cognition, intensified affect, enhanced rate of thinking focused on personal material, and a residual sense of well‑being after acute effects subside. Transcendent or mystical phenomena are also emphasised: feelings of unity, ineffability, altered time and space perception, encounters with spirit beings, out‑of‑body sensations and intuitive insights. From these observations the authors formulate four hypotheses regarding anti‑addiction mechanisms. Hypothesis 1 (biochemical): ayahuasca reduces dopamine release in the mesolimbic ‘‘reward’’ pathway via agonism at 5-HT2A receptors (DMT) and actions of beta‑carbolines, thereby decreasing the rewarding impact of addictive substances and cues. They support this with evidence that 5-HT2A stimulation can inhibit dopamine release both directly and indirectly through excitation of GABA interneurons, positron emission tomography and radioligand binding studies that link serotonergic activity to altered dopamine release, and the finding of raised prolactin after ayahuasca ingestion—interpreted as an index of lowered dopaminergic inhibition of prolactin secretion. Hypothesis 2 (physiological): by reducing dopaminergic signalling in the mesolimbic circuit (ventral tegmental area, nucleus accumbens, prefrontal cortex), ayahuasca may interfere with synaptic plasticity that underpins the conditioned learning of addictive behaviours. The authors draw on the concept that repeated dopamine release reorganises neural circuits—‘‘diabolical learning’’—and cite pharmaconeuroimaging evidence that acute D2 receptor blockade can produce reversible structural remodelling in striatal pathways within hours, suggesting neuroplastic change is attainable on a similar timescale. Hypothesis 3 (psychological): ayahuasca assists recovery by facilitating emotional processing, trauma resolution, increased insight into the consequences of choices, and improved decision‑making. The paper situates this hypothesis within the historical literature on psychedelic‑assisted psychotherapy (psycholytic and psychedelic models), the importance of set and setting, and prior reports that hallucinogens have aided access to personal material, enhanced therapeutic rapport and reduced symptoms such as depression and compulsions. Hypothesis 4 (transcendent): ayahuasca may produce mystical or transcendent experiences that precipitate lasting behavioural change. The authors reference historical accounts such as Bill W.'s conversion experience and note earlier LSD research in the 1960s that reported approximately 50% of treated individuals remained sober or significantly reduced alcohol use after high‑dose psychedelic sessions. They argue that a powerful spiritual experience can alter values and motivation in ways relevant to abstinence. Throughout these sections the authors compare ayahuasca's pharmacology with antipsychotic medications: atypical antipsychotics block about 70% of D2 receptors and antagonise 5-HT2A receptors, typical agents block nearer 90% of D2 sites, and these differences relate to extrapyramidal side effect risk and potential for dopaminergic supersensitivity. The paper notes that DMT does not bind D2 receptors and that traditional ayahuasca dosing (infrequent sessions) might avoid some adverse adaptations seen with daily dopaminergic blockade.
Liester and Prickett interpret their synthesis as support for a multi‑level model in which ayahuasca's anti‑addiction effects arise from interlocking biochemical, physiological, psychological and transcendent mechanisms. They suggest that serotonergic agonism (notably at 5-HT2A sites) combined with MAOI action could reduce mesolimbic dopamine release and thus diminish drug‑related reward, that this reduction may disrupt maladaptive synaptic plasticity underlying conditioned addiction responses, and that concomitant psychological and mystical experiences may foster insight, trauma processing and motivation for behaviour change. The authors place their hypotheses within earlier research on psychedelics and addiction, drawing parallels to historical LSD treatment models and to observations from antipsychotic pharmacology, but they refrain from presenting new clinical trial evidence. Several uncertainties are acknowledged in the extracted text: the clinical significance of platelet serotonin receptor changes is unknown; many mechanistic links are inferential rather than directly demonstrated for ayahuasca; and the narrative approach means results rely on disparate data types (biochemistry, imaging, ethnography, anecdote). The paper therefore concludes that further empirical study is required to test these hypotheses and to evaluate both potential benefits and adverse effects in controlled research settings.
For at least four thousand years, indigenous peoples of South America have utilized a plant admixture known as "ayahuasca" for healing and spiritual purposes). This brew is prepared by boiling two or more plants found in the Amazon rain forest until a concentrated liquid remains. This liquid is then ingested orally and the results are said to facilitate healing, prophesy, and divination. Recently, this medicine has been utilized to treat addictions. For example, The Takiwasi Center in Tarapoto, Peru was established by Jacques Mabit, M.D. in September 1992 to utilize ayahuasca for the treatment of addictions. The term "ayahuasca" is derived from the Quechua language. "Quechua" refers both to a a Private practice, Monument, CO. b PGY-1, Department of Psychiatry, University of Arizona, Tucson, AZ. Please address correspondence to Mitchell B. Liester, M.D., PO Box 302, Monument, CO 80132; phone: 719-488-0024, email: liester@ aol.com collection of related indigenous groups in South America as well as the common language they speak. Quechua people are found primarily in Ecuador, Peru, Bolivia, Chile, and Argentina. The term "ayahuasca" is derived from the Quechua roots aya meaning "dead person, spirit, soul, or ancestor" and huasca meaning "rope or vine". Thus, common translations of the term ayahuasca are "vine of the soul" or "vine of the dead". These translations also incorporate ayahuasca's purported ability to transport individuals who ingest this medicine beyond time and space. Ayahuasca is known by many different names in South America including: caapi, yaje, and hoasca (Brazil). At least 72 different indigenous groups in South America currently use ayahuasca. Recently, a growing body of literature has touted ayahuasca as a treatment for addictions. A 2010 story from the Voice of America described ayahuasca's potential to treat alcohol and drug addictions. Articles supporting ayahuasca's anti-addiction properties have appeared in newsletters, books, and the esteemed medical journal, The Lancet.
Archaeological evidence dates the earliest use of ayahuasca by indigenous people to more than four thousand years ago. This evidence includes pottery vessels, snuffing trays, and tubes that indicate plant hallucinogens were used in the Ecuadorian Amazon as early as 1500 -2000 B.C.E.. Europeans first became aware of this medicinal plant when Spanish and Portuguese explorers ventured into the Amazon rain forest early in the sixteenth century. These explorers encountered indigenous people who ingested a plant mixture that when drunk would "deprive of the senses, because it is very powerful, and by this means they communicate with the devil, because he talks to them when they are deprived of judgment with the said drink, and deceive them with different hallucinations, and they attribute it to a god they say is inside the seed" (as quoted by. Believing the effects to be the work of the devil, the Holy Inquisition of 1616 condemned the ceremonial ingestion of hallucinogenic plant medicines. Individuals who openly utilized ayahuasca and other plant medicines risked accusations of heresy and witchcraft, charges that could result in horrible tortures and death. In the modern era, the first written documentation of ayahuasca use occurred in 1851 when the British botanist Richard Spruce encountered indigenous Tukanos in Brazil drinking ayahuasca. The first published report of the use of ayahuasca occurred in 1858 when the Ecuadoran geographer Manuel Villavicencio wrote about ayahuasca being used in the Rio Napo region. In the 1920s, Brazilian churches began using ayahuasca as a part of their religious ceremonies. Today, three Brazilian churches use ayahuasca as their primary sacrament. These churches are: (1) Santo Daime, (2) the Uniao de Vegetal (UDV), and (3) Barquinia. In 2005, Brazilian churches were found in 23 different countries including Germany, Spain, Holland, Canada, Mexico, and the USA, as well as countries in Africa, Asia, and Central America. Due in part to the difficulty of obtaining ayahuasca's active ingredients, medicines similar to ayahuasca are now being synthesized around the world via nontraditional methods, particularly in Western countries. These methods involve either: (1) combining synthetic ingredients rather than utilizing plants substrates, or (2) substituting other plant sources for the active ingredients found in the plants from the Amazon rain forest.
Traditionally, ayahuasca is prepared by boiling the bark or vine of the plant Banisteriopsis caapi with one of up to 75 different plants, most often Psychotria viridis. Other commonly used plants come from the Solanaecous genera, which includes tobacco and the Brugmansia species. For a detailed discussion and listing of other constituents of ayahuasca please seeBanisteriopsis caapi is a South American jungle vine of the Malpighiaceae family. In the Quechua language, it is known as chacruna. This plant contains beta-carboline alkaloids including harmine, harmaline, and tetrahydroharmine that serve as potent monoamine oxidase inhibitors (MAOIs). MAOIs are a variety of naturally occurring and synthetically produced chemicals whose primary uses in Western medicine are to treat Parkinson's disease and major depressive disorder. MAOIs exert their therapeutic effects by blocking the activity of enzymes known as "monoamine oxidases," a family of enzymes that catalyze the oxidation of endogenous and exogenous monoamines. Monoamines are a group of chemically similar molecules that serve as neurotransmitters and neuromodulators. They contain one amino group connected to an aromatic ring by a two-carbon chain. Monoamines include catecholamines (e.g. dopamine, norepinephrine, and epinephrine), tryptamines (e.g. serotonin, melatonin, and DMT), and trace amines (e.g. tyramine, histamine, and thyronamines). When ingested orally, monoamines are generally degraded by monoamine oxidase enzymes found in the gastrointestinal tract. However, in the presence of MAOIs, these monoamines are not metabolized to simpler compounds in the gastrointestinal tract. Psychotria viridis is a shrub from the coffee family, Rubiaceae. The leaves of this plant contain many alkaloids, N,N-dimethyltryptamine (DMT) being the predominant psychoactive constituent. DMT is a naturally occurring tryptamine alkaloid, which is found throughout the plant and animal kingdoms. DMT is also a short acting, potent medicine that induces a rapidly altered state of consciousness when smoked or snorted. First synthesized in 1931 by a Canadian chemist, DMT was isolated from a South American tree 15 years later by
Hypotheses Regarding the Mechanisms of Ayahuasca a Brazilian ethnobotanist. DMT is now known to exist in hundreds of plant species worldwide. In 1965, a German team isolated DMT from human blood and in 1972, NIH scientist and Nobel Prize winner Julius Axelrod discovered DMT in human brain tissue. DMT is structurally similar to serotonin and other indole ring containing molecules. It is a relatively small molecule, 188 molecular units, only slightly larger than the glucose molecule. It is easily synthesized from indole or tryptamine in vitro, and a simple two-step process from L-tryptophan has been proposed for biosynthesis in vivo. DMT shows an affinity for serotonergic receptors, with agonist actions documented at the 5-HT2a and 5-HT2c sitesWhen ingested orally, DMT is broken down by the enzyme monoamine oxidase in the gastrointestinal tract into the inactive compound indoleacetic acid. However, DMT remains active when ingested orally in the presence of MAOIs, such as those found in Banisteriopsis caapi.
The experience produced by ayahuasca can be divided into three phases. The first phase involves vivid visual imagery that may include geometric designs, lights, animals, scenes from nature, and other imagery that may shift or move. Sensations of dizziness and nausea with vomiting may also occur during this phase. The second phase is said to consist of contact with the spirit world. Plant and animal spirit teachers are said to appear and communicate helpful information or lessons. In this phase, the types of information that may be obtained include the whereabouts of missing relatives or lost objects. The third phase involves a fading of visions, a decrease in nausea, and a state of physical lassitude. Brief visions may be experienced in this final phase as well.
The effects of ayahuasca can be divided into biochemical, physiologic, psychological, and transcendent categories.
Three unique biochemical effects of ayahuasca have been identified thus far. These biochemical effects result from the actions of ayahuasca's primary active ingredients, DMT and the MAOIs acting in concert. The first of ayahuasca's biochemical effects relates to DMT's action on the serotonin system. DMT is an agonist at most serotonin receptions, including 5HT2A receptors, which are the putative site of the action of hallucinogenic drugs such as LSD and psilocybin. DMT also binds to other serotonin receptors including 5HT1A and 5HT2C receptors. Chronic use of ayahuasca has been associated with an increased number of serotonin receptors on platelets. The clinical significance of this finding is not yet known. Second, the MAOIs found in ayahuasca increase monoamine levels including dopamine, serotonin, and norepinephrine by preventing breakdown of these amines by MAO enzymes. Increased dopamine levels in the mesolimbic pathway have been associated with a sensation of pleasure. Third, ayahuasca is associated with alterations in hormone levels. Increased levels of prolactin, cortisol, and growth hormone have been found within 120 minutes of ingestion of ayahuasca. The significance of increased prolactin levels will be discussed in the next section.
The physiologic effects of ayahuasca typically last six to 12 hours. These effects occur in a state of lucidity in which there is no loss of clarity of thought. Effects on the gastrointestinal tract include nausea, vomiting, and diarrhea. Neurologic effects include: tremors, dizziness, mydriasis (dilation of the pupils), synesthesia, and tingling sensations. Cardiovascular symptoms include: increased heart rate) and blood pressure. Metabolic changes include changes in perception of body temperature and skin sensitivity.
Ayahuasca's psychological effects include alterations in perception, emotions, and thinking. Typically, no loss of consciousness is associated with ayahuasca ingestion. However, profound alterations in consciousness may occur. Perceptual alterations frequently include visual imagery that occurs while the individual is awake but the eyes are closed. Common images include jungle animals such as snakes and jaguars. Visions of geometric patterns may also occur.
Hypotheses Regarding the Mechanisms of Ayahuasca Alterations in auditory perceptions are common. These may involve sounds of flowing water, falling rain, people singing, a brass band, or voices speaking. Some individuals report a capacity to communicate with nature. The emotional effects of ayahuasca may include intensified emotional reactions. Happiness, sadness, awe, amazement, anxiety, and fear have all been reported. Some individuals experience contradictory feelings simultaneously. Feelings of rejuvenation and hope are reported. In addition, a lingering state of well-being can persist even after perceptual, cognitive, and affective effects dissipate. Reported cognitive effects include an enhanced rate of thinking. Thoughts often center on personal psychological content and may provide new insight into personal concerns. When memories are experienced, they generally relate to personal matters.
Ayahuasca users often report experiences that are described as "transcendent." These aspects of the experience may include visions of a spiritual reality, an altered sense of space and time, ineffability, intuitive insights, out of body experiences, and feelings of oneness with the universe. A dissolution of boundaries between one's self and others may result in feelings of unity with nature. Feelings of oneness with the universe are also common. Ayahuasca experiencers often report visions of distant or supernatural realms. These realms are populated by deities, demons, or spirit beings. The sense of time may be altered. Such alterations may include a feeling of timelessness, a sensation of time speeding up or slowing down, or a sensation of traveling through time into the past or the future. Individuals may have difficulty communicating their experience to others. This difficulty may be due, in part, to the fact that their experience is outside of the perceptual framework of others who have not had similar experiences. This has been described as a sense of the ineffable. Intuitive insights may be experienced during the ayahuasca experience. Such insights include information about the location of missing relatives or lost objects. Individuals who have ingested ayahuasca frequently report experiencing their consciousness being separate from their body. An altered sense of space may be reported. Individuals may experience a sensation of traveling through space.
Addiction is a complex, multifactorial phenomenon in which biochemical, physiological, psychological, and transcendent factors may all play a role. Ayahuasca appears to treat addictions by facilitating changes at each of these levels. We offer the following four hypotheses to explain how ayahuasca treats addictions at each of these levels.
Various theories of addictions exist. One theory proposes that release of dopamine in the mesolimbic system by various drugs of abuse reinforces the use of these drugs. In fact, Pierce has suggested that the mesolimbic dopamine system is the final common pathway for the reinforcing effect of all drugs of abuse. The mesolimbic dopamine pathway, which is also known as the "reward pathway" or "pleasure center," is also involved in motivation, pleasure, and reward. Excessive or repetitive administration of drugs that increase dopamine also produce positive psychotic symptoms, such as delusions or hallucinations. On the other hand, drugs that decrease dopamine will reduce or stop psychotic symptoms. All antipsychotic drugs currently in use are predominantly blockers of the D2 dopamine receptor, which effectively reduces dopamine's effects on the brain. In summary, drugs that increase dopamine in the brain are associated with pleasure, reward, and addiction. Excessive or repetitive dopamine release is associated with positive symptoms of psychosis. Hypothesis #1 is that ayahuasca exerts its antiaddictive properties by reducing brain dopamine levels in the mesolimbic pathway. This occurs via ayahuasca's effects on serotonin receptors. Two lines of evidence support the theory that ayahuasca reduces dopamine in the mesolimbic pathway. First, DMT is a potent 5HT2A agonist. The beta-carbolines (MAOIs) in ayahuasca are partial agonists at the 5HT2A receptor as well. It is known that stimulation of 5HT2A receptors reduces dopamine release in the mesolimbic, nigrostriatal, and mesocortical pathways. This occurs via two mechanisms. The first mechanism involves a direct connection between serotonin neurons and dopamine neurons. Agonism of postsynaptic 5HT2A receptors by serotonin on dopamine neurons has a direct inhibitory
Hypotheses Regarding the Mechanisms of Ayahuasca action on the release of dopamine. The second mechanism involves indirect connections between serotonergic neurons and dopaminergic neurons via GABA interneurons. Agonism at postsynaptic serotonin receptors excites GABA interneurons. These GABA interneurons then inhibit dopamine release. Inhibition of dopamine release via 5HT2A receptor agonism has been supported by radioreceptor labeling and positron emission tomography (PET) scans. When imaging studies are performed on patients with schizophrenia who have been treated with atypical antipsychotic medications, binding at 5HT2A receptors is observed and dopamine release is reduced. Atypical antipsychotics are 5HT2A receptor antagonists. Typical antipsychotic medications have little action at serotonin receptors. Imaging of dopamine receptors in the nigrostriatal pathway under the influence of a typical antipsychotic drug reveals an almost total blockade (approaching 90% of receptor sites). However, when the same imaging procedure is utilized under the influence of an atypical antipsychotic drug, which has 5HT2A antagonist effects in addition to dopamine antagonistic effects, the blockade of dopamine receptors is significantly attenuated (∼%70). These imaging results demonstrate that antagonism of 5HT2A receptors due to administration of an atypical antipsychotic drug results in a relative increase in dopamine levels. This increase in dopamine, especially in the nigrostriatal pathway, is suggested as the explanation for the reduced appearance of extra pyramidal side effects (EPS) when using atypical versus typical antipsychotic medications. The theory that ayahuasca reduces brain dopamine levels is supported by a second line of evidence-the finding of increased prolactin levels in users of ayahuasca. Dopamine is known to be the primary regulator of prolactin release from lactotrophs in the anterior pituitary. This regulation is mediated by dopamine's inhibitory action on prolactin release. It is also known that 5HT2A agonism promotes prolactin release from the anterior pituitary. Thus, elevated prolactin levels in ayahuasca users are indicative of decreased dopamine levels, which likely result from 5HT2A receptor agonism. Ayahuasca is hypothesized to reduce activity in the reward or pleasure center of the brain by inhibiting dopamine release. The net effect of this would be a reduction in the pleasure or reward effect associated with addictive drugs and associated stimuli. As reduced binding of dopamine at postsynaptic neurons is an effect shared by the DMT in ayahuasca and antipsychotic drugs, their pharmacologic differences and similarities should be discussed. Antipsychotic medications have been investigated as a treatment for addiction due to their dopaminergic blocking actions in the mesolimbic pathway. Typical antipsychotics, with their almost total blockade of D2 receptors, may cause a phenomenon known as mesolimbic dopaminergic supersensitivity or MDS. MDS is thought to be the result of a compensatory up regulation of dopamine receptors due to the potent receptor blockade of the typical antipsychotics (as demonstrated by the PET scans discussed above). This results in an increased sensitivity to dopaminergic stimulation. Studies exploring schizophrenics with nicotine addiction treated with long-term typical antipsychotic medication reveal that basal cigarette smoking increased and patients' ability to quit smoking decreased. MDS may explain why typical antipsychotics do not show significant efficacy as anti-addictive medicines despite lowering dopamine in the mesolimbic or reward pathway. Atypical antipsychotics, however, have been shown to possess anti-addictive properties and do not show a proclivity towards MDS development. Schizophrenics with nicotine addiction treated with atypical antipsychotics smoked fewer cigarettes and were able to quit smoking more easily, even when not specifically attempting abstinence. This may be related to a lower affinity for the D2 receptor as well as a synergistic increase in dopamine release due to 5HT2A antagonism. The result is an attenuated dopaminergic blockade. The effects of dopamine on postsynaptic neurons may be influenced by three variables: (1) the amount of dopamine released from presynaptic neurons, (2) the number of dopamine receptors on postsynaptic neurons, and (3) the availability or blockade of dopamine receptors on postsynaptic neurons. The interplay between these three variables may help explain the differing effects of ayahuasca, typical antipsychotics, and atypical antipsychotics at dopaminergic neurons. DMT is an agonist at 5HT2A receptors. Binding of DMT at 5HT2A receptors decreases the release of dopamine. Atypical antipsychotics act as antagonists at 5HT2A receptors, causing an increase in the release of dopamine. Typical antipsychotics have no affinity for 5HT2A receptors. DMT does not bind to D2 receptors. As mentioned above, atypical antipsychotics have been found to block 70% to 80% of D2 receptors in the nigrostriatial pathway whereas typical antipsychotics block nearly 90% of these same receptors. The combination of increased dopamine release along with partial blockade of D2 receptors is suggested to explain the reduced appearance of EPS when using atypical antipsychotic medications. A third variable modulating dopamine's effect is the number of dopamine receptors on the postsynaptic neuron. The ability of typical antipsychotics to block nearly all the postsynaptic D2 receptors may lead to MDS). Atypical antipsychotics do not show a proclivity towards MDS development. This reduced risk of MDS may be related to the atypical antipsychotics' lower affinity for the D2 receptor as well as their stimulation of increased dopamine release via antagonism at 5HT2A receptors. Atypical antipsychotics thus exert an attenuated dopamine effect relative to typical antipsychotics. DMT would not be expected to cause MDS. Its inhibitory effect on the release of dopamine and its lack of affinity for postsynaptic D2 receptors would not be consistent with MDS or an increase in postsynaptic dopamine receptors. The differing effects of typical and atypical antipsychotics on dopaminergic neurons may help explain not only their varying rates of EPS, but also their differing anti-addictive properties. Although both typical and atypical antipsychotic drugs reduce dopaminergic activity in the mesolimbic pathway, they do so to varying degrees. This difference in dopaminergic activity may be responsible for their differing anti-addictive effects. Typical antipsychotics do not show significant anti-addictive properties despite lowering dopamine levels in the mesolimbic pathway). Atypical antipsychotics, on the other hand, have been shown to possess anti-addictive properties. Another factor that may play a role in the antiaddictive effects of these medications is the frequency of dosing. The direct blockade of D2 receptors by antipsychotics is generally produced with daily dosing. It is possible that the less frequent dosing of ayahuasca, in traditional settings, may contribute to its different effects (e.g. reduced risk of MDS and increased anti-addictive effects). The net effect of ayahuasca at dopaminergic neurons is reduced activity in the reward or pleasure center of the brain. This is hypothesized to result in a reduction in the pleasure or reward effects associated with addictive drugs.
Dopamine exerts varying effects in the brain depending upon the location, the specific types of dopamine receptors activated, and the level of dopamine. For example, reduced dopamine synthesis in the niagra striata is associated with Parkinson's disease and reduced dopamine in the prefrontal cortex is associated with attentiondeficit/hyperactivity disorder. Increases in dopamine levels produced by pharmacologic intervention may ameliorate the symptoms of these disorders, but in excess may also lead to psychosis. Dopamine is the primary neurotransmitter involved in the mesolimbic pathway. The mesolimbic pathway involves three critical brain areas. These are the ventral tegmental area (VTA), the nucleus accumbens, and the prefrontal cortex. The VTA is a group of neurons which release dopamine when exposed to internal or external cues associated with an addictive behavior. The nucleus accumbens is a group of cell bodies that receive dopamine from the VTA and communicate with the prefrontal cortex. The prefrontal cortex is an area of the brain associated with an individual's personality, executive functioning, social functioning, and motivation. The prefrontal cortex communicates with the VTA directly and indirectly through the amygdala completing the classic "reward circuit". Release of dopamine in the mesolimbic pathway has been associated with synaptic plasticity, a process in which connections between neurons are altered. Synaptic plasticity has been associated with learning, and more recently with the development and maintenance of addiction. Release of dopamine in the ventral tegmental area has been hypothesized to reorganize neuronal circuits, leading to addictive behaviors. These changes are thought to be primarily related to changes in the amygdala, which has been implicated in learning having to do with reward, fear, and other emotional responses to stimuli. Stahl refers to this dopamine-fueled process as "diabolical learning." Through repeated use of a drug of abuse, or any addictive behavior, repeatedly increased levels of dopamine from the VTA to the amygdala result in adaptive neural architecture changes associated with conditioned and learned responses. These plastic changes result in activation of the reward circuitry when exposure to internal or external cues are experienced that were associated with the addictive behavior. Ultimately, this process is thought to mediate the psychological withdrawal, craving, and intense desire to experience the addicted behavior again and again. The reward circuitry has been, according to Stahl, "hijacked" by the addiction process. Using pharmaconeuroimaging, reversible structural remodeling has been shown to occur in striatal pathways within hours after acute blockade of D2 receptors. Although the mesolimbic pathway has not, to our knowledge, been investigated in this way, it is possible that similar structural and functional changes in neural architecture occur in this pathway as well. These experiments have shown that neuro-plastic changes in dopaminergic pathways are attainable in the timeframe for which ayahuasca and DMT exert their effects. This leads to our second hypothesis. Hypothesis #2 is that reduced dopamine levels in the mesolimbic pathway associated with ayahuasca interfere with the synaptic plasticity associated with the development and maintenance of addictions.
The psychological effects of ayahuasca include changes in perceptions, emotions, ideation, and behavior. Early research with hallucinogenic drugs, such as LSD-25, focused on their ability to produce a schizophrenic-like state, the so-called "psychotomimetic effect". It was believed these drugs provided an opportunity to study mental illnesses such as schizophrenia, an idea known as the "model psychosis concept". However, some individuals who ingested hallucinogenic substances reported experiences that were very different from mental illness. For example, some patients were able to talk about their problems more easily during LSD-induced states and were able to reevaluate the emotional meaning of their symptoms. Additional studies found that LSD improved depression, increased one's sense of well-being, reduced compulsions, and reduced anxiety. Individuals who ingested LSD were also found to exhibit enhanced rapport with their therapists and gained increased access to previously repressed memories. LSD was also found to alleviate pain in terminally ill cancer patients. LSD was even reported to produce religious and mystical experiences. Such experiences lead to questions about the model psychosis concept. In fact, Manfred Bleuler claimed that psychotomimetic drugs "contributed nothing to the understanding of the pathogenesis of schizophrenia". In 1957, the British psychiatrist Humphrey Osmond suggested the term "psychedelics" be used to replace the older term "hallucinogens" based upon these drugs' ability to produce life-changing visions and a "mind manifesting" or "mind expanding" state. Along with the Canadian psychiatrist, Abram Hoffer, Osmond initially began studying LSD with the intention of using it to produce a schizophrenic-like state to study psychosis. However, they later came upon the idea of using LSD to create a model of delirium tremens. This led to their conjecture that LSD could be used to treat alcoholism. They believed administering LSD to alcoholic patients would cause them to experience a state similar to delirium tremens. They hoped this would be such an unpleasant experience that patients would no longer drink alcohol. Hoffer and Osmond later discovered that a similar approach had already been employed by members of the Native American Church of North America. Church members used peyote to take away the desire for alcohol. From their studies,learned that the environment and the attitude of the people around the person had a profound influence upon the individual's reaction to LSD. This led to the recognition of the importance of the set (i.e. the expectations, motivations, and intentions of the individual) and setting (i.e. physical and interpersonal environment) upon the individual's experiences with hallucinogens. Awareness of LSD's beneficial effects led some researchers to begin exploring the use of this medicine as an aid to psychotherapy. Several treatment models were employed. The "psycholytic therapy" model involved the administration of small doses of LSD at one to two week intervals. A psychodynamic therapy approach was utilized to understand and integrate the phenomena resulting from the LSD sessions. The use of LSD and peyote to treat alcoholism parallels the use of ayahuasca to treat addictions. It is believed by those who utilize ayahuasca that this medicine allows access to unconscious emotional issues, thus reducing the likelihood of using alcohol in the future. Ayahuasca is also believed to help individuals heal traumas by allowing them to recognize how past experiences have influenced present-day experiences. Furthermore, it is believed that ayahuasca gives individuals an opportunity to experience the potential future outcomes of their choices, including the choice to use alcohol and/or illicit drugs. This facilitates improved decision-making, including the decision to abstain from addictive substances. Hypothesis #3 is that ayahuasca treats addictions by helping resolve traumas, encourage the understanding of potential outcomes of choices, and improving decisionmaking.
In addition to its biochemical, physiological, and psychological effects, ayahuasca may exert anti-addictive properties via a fourth mechanism. Ayahuasca is reported by those who drink it to provide a transcendent experience. Transcendent experiences have been previously reported to help individuals overcome addictions. The story of Bill W., the founder of Alcoholics Anonymous, is one example). Hospitalized for intractable alcoholism, Bill had a transcendent experience that resulted in his giving up alcohol. He explained: Lying there in conflict, I dropped into black depression. Momentarily my prideful obstinacy was crushed. I cried out, "Now I'm ready to do anything". . . Expecting naught, I made this frantic appeal: "If there be a God, will he show himself!" The result was instant, electric, beyond description. The place lit up, blinding white. I knew only ecstasy and seemed on a mountain. A great wind blew, enveloping and permeating me. It was not of air, but of Spirit. Blazing, came the tremendous thought, "You are a free man!" Then ecstasy subsided. Still on
Hypotheses Regarding the Mechanisms of Ayahuasca the bed, I was now in another world of consciousness which was suffused by a Presence. One with the Universe, a great peace stole over me and I thought, "So this is the God of the preachers; this is the Great Reality." But reason returned, my modern education took over. Obviously I had gone crazy. I became terribly frightened. After this experience, Bill W. never took another drink. Utilizing plant medicines to provide transcendent experiences represents a unique, although not entirely novel paradigm for the treatment of addiction. Ingestion of hallucinogenic drugs, such as LSD and mescaline, has also been reported to facilitate transcendent experiences. In addition to the previously described "psycholytic therapy" model employing LSD, another model termed the "psychedelic therapy" model was developed by. This model utilized generally one, but sometimes as many as three, relatively high dose sessions with LSD. This approach was intended to induce a so-called "psychedelic peak experience" which would assist the individual in overcoming their addiction. Studies performed in the 1960s reported that about 50% of individuals who were treated with LSD utilizing this model were able to remain sober or significantly reduce their use of alcohol. Due to a combination of social and political pressures, research with LSD and other psychedelics was terminated by the 1970s. Recently, however, research into the potential benefits of LSD and other psychedelics has gradually resumed. Hypothesis #4 is that ayahuasca treats addictions by facilitating transcendent experiences.
Ayahuasca is a medicine that is increasingly being used to treat addictions. We propose that ayahuasca exerts its anti-addictive properties via four unique but interrelated mechanisms. These include biochemical, physiological, psychological, and transcendent pathways. Further study is needed to explore the potential benefits and adverse effects of this medicine.
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