508389 5201308389SMO0010.1177/2050312113508389SAGE Open MedicineSchenberg SAGE Open Medicine Original Article SAGE Open Medicine Ayahuasca and cancer treatment 1: 2050312113508389 © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2050312113508389 smo.sagepub.com Eduardo E Schenberg1,2 Abstract Objectives: Comprehensively review the evidence regarding the use of ayahuasca, an Amerindian medicine traditionally used to treat many different illnesses and diseases, to treat some types of cancer. Methods: An in-depth review of the literature was conducted using PubMed, books, institutional magazines, conferences and online texts in nonprofessional sources regarding the biomedical knowledge about ayahuasca in general with a specific focus in its possible relations to the treatment of cancer. Results: At least nine case reports regarding the use of ayahuasca in the treatment of prostate, brain, ovarian, uterine, stomach, breast, and colon cancers were found. Several of these were considered improvements, one case was considered worse, and one case was rated as difficult to evaluate. A theoretical model is presented which explains these effects at the cellular, molecular, and psychosocial levels. Particular attention is given to ayahuasca’s pharmacological effects through the activity of N,N-dimethyltryptamine at intracellular sigma-1 receptors. The effects of other components of ayahuasca, such as harmine, tetrahydroharmine, and harmaline, are also considered. Conclusion: The proposed model, based on the molecular and cellular biology of ayahuasca’s known active components and the available clinical reports, suggests that these accounts may have consistent biological underpinnings. Further study of ayahuasca’s possible antitumor effects is important because cancer patients continue to seek out this traditional medicine. Consequently, based on the social and anthropological observations of the use of this brew, suggestions are provided for further research into the safety and efficacy of ayahuasca as a possible medicinal aid in the treatment of cancer. Keywords Ayahuasca, N,N-dimethyltryptamine, harmine, cancer, sigma-1 receptor Introduction Used for centuries in the Amazon basin by healers and sha- by their doctors and felt well and healthy. Therefore, it is mans for many different purposes, including the healing and important to look at these cases in greater detail and investi- curing of illnesses,1 ayahuasca is a plant decoction that may gate the pharmacological and psychological effects of aya- be useful in the treatment of some types of cancer. The huasca to better understand its potential in the treatment of decoction is most commonly made of two plants in two pos- cancer and to evaluate possible risks of this practice. sible combinations: Banisteriopsis caapi with Psychotria viridis or B. caapi with Diplopterys cabrerana.2 Each of the Case descriptions plants is known by different vernacular names, with the most common shown in Table 1. Photographs of the plants are Oral reports of ayahuasca helping people with cancer are com- shown in Figure 1. mon among communities using ayahuasca, but unfortunately, There are at least nine reports of cancer patients who con- written reports with details and clinical data are scarce. A thor- sumed ayahuasca during their treatment.3–10 Four were ough review of the literature, including peer-reviewed scientific reported in a peer-reviewed article,3 one in an institutional journals indexed at PubMed, as well as lectures and books on the magazine,4,5 one in Internet sources,6,7 two in a scientific conference8 (later mentioned in a peer-reviewed article9), 1Departamento de Psiquiatria, Universidade Federal de São Paulo, São and one in a book.10 The origins of these cancers were the Paulo, Brazil prostate, colon, ovaries, breast, uterus, stomach, and brain.3– 2Instituto Plantando Consciencia, São Paulo, Brazil 10 Three of these cases showed improvements, as measured Corresponding author: by the prostate-specific antigen (PSA) or the carcinoembry- Eduardo E Schenberg, Rua Iraci 340, Jardim Paulistano, CEP 01457-000 onic antigen (CEA) level.4,5,8,9 According to some of these São Paulo, SP, Brazil. reports, the patients survived longer than initially predicted Email: [email protected] 2 SAGE Open Medicine 0(0) Table 1. Common names for the two most frequent forms of ayahuasca concoction, and the source plants in each, with their scientific and vernacular names, as well as main active principles.2 Concoction common name Plants most commonly used Known active principles Ayahuasca B. caapi (ayahuasca, caapi, mariri, jagube) Tetrahydroharmine, harmine, and harmaline + P. viridis (chacruna, chacrona, rainha) + N,N-dimethyltryptamine (DMT) Yagé or Yajéa B. caapi (ayahuasca, caapi, mariri, jagube) Tetrahydroharmine, harmine, and harmaline + D. cabrerana (chagropanga, chiripanga) + N,N-dimethyltryptamine (DMT) aPlease note that the Quechua term Ayahuasca (aya = spirit, ancestor; and waska = vine) is largely employed, sometimes referring to B. caapi alone, sometimes referring to all forms of the preparation, including some that use only B. caapi. Figure 1. (a) B. caapi growing in front of a tree, (b) B. caapi flowers, (c) P. viridis shrub, (d) P. viridis leaves with fruits, (e) preparation of ayahuasca brew at a community in Alter do Chão, Pará, Brazil, in February 2010, (f) detail of B. caapi leaves, and (g) detail of P. viridis leaves. topic of ayahuasca resulted in nine published reports of cancer Topping was diagnosed with colon cancer around 1988 at the patients who consumed ayahuasca as part of their treatment. age of 58 and was given a grim outlook for survival. When The first and best published report is the detailed case of given a recommendation for immediate surgery, he requested Donald Topping,4,5 a former professor at the University of a natural healing approach. A 4-month trial of a natural heal- Hawaii and the president of the Drug Policy Forum of Hawaii. ing approach was performed. This regimen included “various Schenberg 3 substances, vegetarian diet, visualization, exercise and rest,”4 improving her health. However, afterward, Blake underwent which resulted in an unexpected negative biopsy, followed by a complete medical examination, which did not reveal a sig- a positive biopsy 2 weeks later, which was performed given nificant improvement in her condition (personal communi- the doctor’s surprise with the first result. Topping then had cation). At the Ecology, Consciousness and Cosmos meeting, the surgery and was determined to be cured 5 years later. another patient with acromegaly reported positive experi- However, in September 1996, new examinations revealed ences with ayahuasca before it was outlawed in Britain,7 but cancer of the liver. In this case, the chances of survival were no additional data about this case were found. rated 20%–25% by one surgeon and 15% by another, which In 2010, four additional cases of ayahuasca use in cancer included the risks of the surgery. Additionally, after the sur- treatment were reported by Robert Forte.8,9 The first two gery, he would require a year of intensive chemotherapy. cases, which were only anecdotal, were of melanoma and Topping had half of his liver removed but refused to start breast cancer. Inspired by these ayahuasca healing stories, chemotherapy, claiming that the drugs used during and after Forte accompanied two patients on their travels and to the the surgery were excessive for him. He tried ayahuasca sessions and clinical examinations. One patient was a instead of the traditional chemotherapy. He then participated 66-year-old psychiatrist with prostate cancer who underwent in two sessions of ayahuasca at a Santo Daime church in surgery many years before trying ayahuasca. The surgery Hawaii and two shamanic healing sessions in Peru. After brought the PSA level to 0, but it began to rise again 10 years these sessions, he returned to an oncologist to discover that later. The second patient was a 50-year-old schoolteacher his CEA count was unexpectedly below normal. One year with advanced ovarian cancer with metastasis. Both patients after the original report, he published in a new article that the had clinical examinations before and after drinking the metastatic cancer was still in full remission and responded to Amazonian brew for healing purposes with Maestro Juan some of the many questions raised by his first report.5 He died Flores, an Ashaninka curandero in Peru, who also uses other in August 2003 at the age of 73.11 medicinal plants. The clinical examinations revealed signifi- A second report, from medical anthropologist Aprile cant improvements in PSA for the first patient and a CEA- Blake, was published online a decade after Topping’s pio- 125 drop from 4000 to 600 for the second patient.8 Robert neering report; unfortunately, no data from clinical examina- Forte intends to continue bringing interested patients to aya- tions were available in the report.6 After many ayahuasca huasca healers and documenting their stories, which can be a sessions with Shipibo healers in Peru, Blake claimed to have valuable resource for years to come. been cured of a “brain tumor, caused by a chronic degenera- In 2010, a peer-reviewed study was published investigating tive condition, called ‘acromegaly’ which had dogged me for people who tried ayahuasca as a treatment for different ill- 20 years”6 at the age of 37. A detailed account of the striking nesses, including cancer.3 Four cancer patients were identified: physical and subjective psychological effects of this treat- a 59-year-old man with prostate cancer, a 40-year-old woman ment was given. Afterward, at the 2011 Ecology, with uterine cancer, a 36-year-old woman with benign uterine Consciousness and Cosmos meeting at the October Gallery myoma, and a 43-year-old woman with stomach cancer. The in London,7 Blake described the inability to cope with the study does not include many details about each patient, but the biomedical treatment currently proposed for acromegaly, inclusion criteria “included a professionally diagnosed disor- which consists mainly of irradiating the brain tumor, because der by a medical expert.”3 The prostate cancer case was rated the pituitary gland would be damaged and the gland’s hor- as “no effect,” the uterine cancer case was labeled a “complete mones would be replaced with pharmaceuticals. Fond of recovery,” the uterine myoma case was determined to be holistic and alternative medicine, Blake tried alternative “worse,” and the stomach cancer case was “unratable” because paths that included traditional Chinese medicine, guidance the patient reported feeling the remission of her cancer but from a Brazilian medium (João de Deus—John of God), and refused to undergo medical examinations. The uterine myoma several ayahuasca ceremonies. Blake tried ayahuasca for the was accompanied by borreliosis, and the authors determined first time in Brazil at the age of 34, followed by more ses- that this “could also be considered a normal course for her ill- sions in Europe. In October 2008, when her condition was ness.”3 Importantly, independent of any medical examinations determined to be terminal because the tumor was danger- or conclusions of being cured or not, all of the patients declared ously close to the optic nerves and the brain stem, which that ayahuasca had a positive impact and none criticized the would eventually cause blindness or death, Blake decided to rituals as negative or worthless. The effects of ayahuasca were embrace ayahuasca healing in South America (personal frequently described as profound, life-changing and contribut- communication). She started her search in Ecuador, but the ing to an individual’s general well-being. treatment was to be achieved mainly in Peru with Shipibo The final case reported here is from a musician, Margareth healers.6 Although the currently recommended biomedical De Wys,10 who described her journey to heal from breast can- treatment was not used, Blake is feeling much healthier than cer with a Shuar healer from the upper Amazon in a book. before her Shipibo experience. Blake declares that she Although she went to the Amazon with a diagnosis with breast learned a great deal about herself from the ayahuasca ses- cancer, she did not tell anyone there about her disease. sions, about her condition, how to cope with stress, and what However, the Shuar healer was able to “see through” her body foods and environments are beneficial or harmful to and diagnosed the cancer as a “Black Smoke” in her breast. 4 SAGE Open Medicine 0(0) This resulted in 11 healing trips to South America, mostly in The sigma-1 receptor is a molecular chaperone situated at Ecuador, between 2000 and 2003.10 The healing was centered the mitochondria-associated endoplasmic reticulum (ER) on the spiritual and healing powers of this Shuar master, aya- membrane (MAM).30 The spatial and temporal interaction huasca, other plants, and diet, which involved avoiding salt between the ER and mitochondria is crucial for controlling and oil and consuming only foods boiled in water. After the the fate of the cell through the regulation of calcium dynam- trips to heal with the Shuar, De Wys underwent medical exam- ics, the control of mitochondrial membrane permeabiliza- ination and no trace of the cancer was found. tion, and the initiation and/or propagation of apoptosis by the activation of the Bcl-2 protein family32 or by caspase- independent factors, such as apoptosis-inducing factors and Main effects of active principles regarding cancer endonuclease G.33 After activation, sigma-1 receptors at the The ayahuasca brew is one of the most sophisticated ethno- MAM disassociate from the binding immunoglobulin pro- medicines known, and more than 20 plants have been identi- tein (BiP), allowing it to act as a molecular chaperone to ino- fied as part of the preparation.1 However, it is usually made sitol 1,4,5-trisphosphate (IP3) receptors, stabilizing them from only two plants, B. caapi and P. viridis (or D. cabrerana, and protecting from degradation by proteasomes.34 This mainly in preparations from Colombia, as shown in Table 1). effect enhances calcium flow from the ER to the mitochon- P. viridis and D. cabrerana contain N,N-dimethyltryptamine dria, activating the tricarboxylic acid (TCA) cycle and (DMT) in the leaves, and B. caapi contains β-carbolines such increasing the production of adenosine triphosphate (ATP).34 as harmine, harmaline, and tetrahydroharmine in the stem.1 Importantly, sigma-1 receptors mediate calcium influx to the These harmala alkaloids receive their name from the Peganum mitochondria specifically from the ER through 1,4,5- harmala plant (Syrian Rue), where they were first identified, triphosphate receptor type III (IP3R3) but not from the cyto- which is used to treat cancer since ancient times.12 sol, which is mediated by 1,4,5-triphosphate receptor type I Given the increasing number of people drinking aya- (IP3R1),35 indicating a specific mechanism of action for cal- huasca in the last decade, especially in urban environments, cium dynamics. When stimulated by higher concentrations biomedical studies were conducted in humans, repeatedly of its ligands, sigma-1 receptors may translocate from the demonstrating the safety of consuming this brew in a variety MAM to the plasma membrane region. After translocation, it of settings.13–19 can exert inhibitory effects on many ion channels, including DMT is a simple molecule found throughout the plant and N-methyl-d-aspartate (NMDA) receptor modulation through animal kingdoms. It is found in human blood and cerebrospi- small conductance K+ (SK) channels,36 the K 1.4 channel,37 v nal fluid, and its formation has been proposed to occur in the Na 1.5 channel,26 the voltage-gated N-, L-, and P/Q-type V adrenal and lung, where high levels of the enzyme responsi- Ca2+ channels,38 the acid-sensing ion channel,39 and the vol- ble for its synthesis—indole-N-methyltransferase (INMT)— ume-regulated Cl− channel.40 The interaction between the have been reported.20 DMT is the only mammalian sigma-1 receptor and the volume-regulated Cl− channel may N,N-dimethylated trace amine known20–25 and the physiolog- have important implications for cancer because these Cl− ical functions of endogenous DMT remain unclear. However, channels modulate the cell cycle and influence cell volume it is well established that DMT has agonist properties at regulation.40 Also important for cancer treatment may be the 5-hydroxytryptamine (5-HT) receptors, mainly 5-HT and Na 1.5 channel, which is expressed in many cancers, includ- 2A V 5-HT .26 Furthermore, it was recently revealed that DMT ing breast and prostate, and is also associated with metastatic 2C binds to the sigma-1 receptor,27 which provides new oppor- processes.41,42 It is important to note that many of these tunities for understanding how ayahuasca may produce its effects were studied in different cells and tissues; therefore, marked effects on the body and mind and what might be the the sigma-1 receptor roles are most likely tissue dependent. role of endogenous DMT and how ayahuasca may have Consequently, cell- and tissue-specific effects are important effects on cancer. factors that must be considered in oncology studies related to The human sigma-1 receptor has been cloned and shows sigma-1 receptors. no homology with other mammalian proteins.28 Single- DMT binds sigma-1 receptors with moderate affinity (K = D photon emission tomography (SPET) analysis in humans 14.75 µM, approximately half the affinity for 5-HT and 1A revealed that these receptors are present in organs such as the 5-HT receptors) and, at high concentrations, is also capable 2A lung and liver and most concentrated in the brain.29 Sigma-1 of inhibiting voltage-gated sodium channels.27 Thus, DMT receptor activity has been implicated in a variety of diseases, may exert two types of effects through sigma-1 receptors: at including cancer, depression, and anxiety.30 Sigma-1 recep- low concentrations, it regulates calcium flow from the ER to tors are found in high densities in many human cancer cell the mitochondria, whereas at higher concentrations, it exerts lines, including lung, prostate, colon, ovaries, breast, and diverse effects at the plasma membrane region.30 The effect on brain; thus, sigma ligands are regarded as potential novel calcium influx into the mitochondria may be extremely impor- antineoplastic tools.31 Remarkably, there is much overlap tant for cancer treatment given that an energetic imbalance between the tissues identified with high sigma-1 receptor between excessive cytosolic aerobic glycolysis and reduced densities and the case reports presented here. mitochondrial oxidative phosphorylation (the Warburg effect) Schenberg 5 was recently suggested as the seventh hallmark of cancer.43 fact may be of importance because most brain tumors are of This metabolic profile of cancer cells is accompanied by a glial origin and involve excessive glutamate release, causing hyperpolarization of the mitochondrial membrane potential44 neurotoxicity.57 Also important for gliomas may be the bind- that may be reduced by the calcium influx triggered by DMT ing of harmine to imidazoline I2 receptors.58 These receptors binding to the sigma-1 receptor at the MAM. This effect may are highly expressed in gliomas,59 and their density increases facilitate the electrochemical processes at the electron trans- with malignancy in human cells.60 However, their physiolog- port chain inside the mitochondria, thus increasing the produc- ical role in these tissues remains unclear. tion of reactive oxygen species (ROS) and leading these cells Nonetheless, care should be taken because there are also to apoptotic pathways.43 When high DMT concentrations some contradictory reports regarding possible genotoxic or induce sigma-1 receptor translocation to the plasma mem- mutagenic effects of β-carbolines in different experiments brane, many cellular effects would occur due to the receptor’s with cell cultures. Although some of these reports focus spe- interaction with different ion channels. At high concentrations cifically on harman and horhaman,61 which are not found in of DMT, a calcium influx and mitochondrial membrane depo- ayahuasca preparations, others included research into larization might be enough to also activate the permeability harmine and harmaline. For example, it has been reported transition pore (PTP), inducing mitochondria swelling, rup- that harmine and harman are genotoxic in V79 Chinese ham- ture, and apoptosis.45 ster fibroblasts62 and may induce DNA lesions in For all these effects to help explain the available case Saccharomyces cerevisiae cell lines.63 On the contrary, it reports of ayahuasca on cancer treatment, DMT’s physiolog- was found that harman and harmine do not induce chromo- ical degradation by enteric monoamine oxidase (primarily somal alterations in Salmonela typhimurium and Escherichia MAO-A) after oral consumption should be inhibited, thus coli cell lines64 and that harmine and harmaline may even allowing the DMT to pass into circulation. The pharmaco- have antimutagenic and antigenotoxic activities related to logical activity of β-carbolines (primarily harmine) in aya- their antioxidant properties.65 It was also shown that harmine huasca inhibits MAO, with a high affinity for MAO-A.46 may inhibit tumors as assessed by Lewis Lung Cancer and Therefore, the specific effects of ayahuasca on the different S180 cell lines, although with some toxic effects.66 types of cancer could also vary depending on the predomi- nant MAO subtype, given that the ratio of MAO-A to Physiological effects of human consumption of MAO-B varies, for example, from 1:3 in the brain to 4:1 in ayahuasca the intestine,47 and the placenta has only MAO-A and blood platelets have only MAO-B.48 Another consequence of To explain ayahuasca’s effects on cancer, plant constituent inhibiting MAO in different tissues is interference with concentrations, concentrations in different ayahuasca prepa- apoptotic pathways,48 thus strengthening the synergistic rations, plasma levels and issues of bioavailability, clear- action of β-carbolines and DMT. ance, and volume of distribution must be considered. The In addition to allowing DMT to exert its effects on cancer present results do not offer enough data to make any definite tissues and cells, β-carbolines may have other important conclusions, but some important considerations can be made. roles. It was recently demonstrated that harmine activates Variability in the concentration of the major molecules in the pathways of apoptosis in B16F-10 melanoma cells;49 it brew was reported.67 The plasma concentrations of harmine inhibits tumor-specific neo-vessel formation, both in vitro were highly variable ranging from approximately 5.0 ng/ and in vivo in mice, through a series of mechanisms involv- mL68 to 114.8 ± 61.7 ng/mL (mean ± standard deviation ing decreased serum levels of pro-angiogenic factors and an (SD)),69 with one study failing to detect harmine in the increase in antitumor factors50 and displays an inhibitory plasma after consumption of freeze-dried, encapsulated aya- effect on cell proliferation against human carcinoma cells.51 huasca.70 The doses used in these studies were mainly deter- Harmine and harmaline were also shown to reduce cell pro- mined by the DMT content in the original tea, but the liferation in the human leukemia cell line HL60.52 Harmine available data showed that the harmine content was approxi- was also shown to induce apoptosis in the human hepatocel- mately 1.5 mg/kg. This value is lower than the 10 mg/kg lular carcinoma cell line HepG2.53 Harmine may also be ben- dose used in the studies of harmine on cancer in rodents50 but eficial in cancer treatment due to its inhibitory effect on the caution must be exercised when comparing studies con- DYRK1A kinase.54 This kinase is implicated in the resist- ducted in rodents with humans. Additionally, ayahuasca con- ance of many cancerous tissues to pro-apoptotic stimuli and sumption by humans usually involves more than one dose the enhancement of proliferation, migration, and reduced per session, and in some therapeutic cases, many doses and cell death.55 Another pharmacological effect of harmine that sessions are conducted over time, with plasma levels poten- may be important in brain cancer is its role on the EAAT2 tially reaching much higher values than observed in the labo- glial glutamate reuptake transporter.56 Harmine was identi- ratory. The plasma concentrations of DMT were measured in fied as one the most efficient molecules to upregulate this a series of published reports. The C values (mean ± SD) max transporter in glial cells among a library of 1040 Food and ranged from 15.8 ± 4.4 ng/mL69 to 17.44 ± 10.49 ng/mL,68,70 Drug Administration (FDA)-approved substances.56 This with a peak at 32.57 ± 20.96 ng/mL17 in the first study using 6 SAGE Open Medicine 0(0) two repeated doses of ayahuasca in a laboratory environ- tissues in DMT kinetics should be expected. A specific ment. This range on the order of nanogram per milliliter mechanism for how DMT enters cells is also important in seems low compared with the concentrations in the original regard to its possible effects on sigma-1 receptors, given that brew used in these studies: 0.24 mg/mL69 and 0.53 mg/ these are intracellular proteins. Recently, a study of radiola- mL.17,68,70 In addition, in comparison to a K of 14 µM in the beled DMT injected intravenously in rabbits revealed that i in vitro experiment showing DMT’s action on sigma-1 DMT reaches the brain rapidly (10 s) and is also detected receptors,27 the detected plasma concentrations may be low. primarily in the heart and liver.77 Although DMT was not To estimate the bioavailability of DMT after ayahuasca con- detected in the urine after 24 h, it was still present in the sumption, the data from blood collected after ayahuasca brain after 48 h and was found in small amounts (0.1 %) 7 ingestion and the data from intravenous DMT were com- days after the injection; this corroborates the idea that DMT bined and a tentative value of 10%–15% was determined.71 is rapidly absorbed in some tissues and cleared from the Furthermore, the important differences between the data blood. The rapid clearance, metabolism, and transport of from oral ayahuasca consumption and intravenous DMT DMT through the cell membrane makes it difficult to obtain originated from different experiments with a limited number clinical data about DMT in humans; however, it is a reminder of subjects; this suggests that only a small amount of DMT of the physiological safety of the use of this naturally occur- in the brew reaches systemic circulation, posing challenges ring substance, whose metabolism is finely regulated in the regarding DMT metabolism that remain unresolved. With human body. the inhibition of MAO, DMT can be metabolized to DMT-N- In summary, it is hypothesized that the combined oxide both in vitro and in vivo; this metabolite was recently actions of β-carbolines and DMT present in ayahuasca found in urine72 and blood73 after freeze-dried ayahuasca may diminish tumor blood supply, activate apoptotic path- administration to human volunteers. The metabolization of ways, diminish cell proliferation, and change the energetic DMT to DMT-N-oxide still leaves considerable amounts of metabolic imbalance of cancer cells, which is known as the DMT available in the blood;73 however, the amount is low Warburg effect (Figure 2). Therefore, ayahuasca may act compared with the K of DMT at sigma-1 receptors and the on cancer hallmarks such as angiogenesis, apoptosis, and i administered doses of DMT. One possible solution for this cell metabolism. This hypothesis gives some scientific dilemma comes from a recent in vitro discovery that DMT credibility to the cases reported and supports the realiza- exhibits substrate behavior at the serotonin uptake trans- tion of more scientific studies of ayahuasca and cancer. porter (SERT), with a K value of 4.00 ± 0.70 µM (mean ± However, to improve the safety and efficacy of those who i SD), and also at the vesicle monoamine transporter eventually search the use of ayahuasca for the treatment of (VMAT2), with a K value of 193 ± 6.8 µM.74 This mecha- cancer, more studies should be performed considering the i nism of sequestering DMT to the intracellular space may be remarkable psychological effects of the ritual use of aya- responsible for the discrepancy in plasma concentrations huasca and its possible influences on cancer patients. between ayahuasca ingestion and in vitro studies. Recently, other authors suggested this same mechanism to explain how Psychological effects of the ritual use of ayahuasca DMT concentrations may reach higher values inside the cells than in the blood, through a “three-step mechanism”75 Ayahuasca has very powerful psychological effects, generally involving active transport of DMT through the blood–brain described as psychedelic effects. These experiences, in gen- barrier, transport across cells membrane via SERT, and eral and with ayahuasca, evoke powerful subjective percep- finally a sequestration into synaptic vesicles mediated by tions and feelings, which are usually termed “hallucinogenic” VMAT2.75 These same authors also highlight possible anti- in the medical and scientific literature but held in high regard tumor effects of DMT through regulations of the immune by ancient cultures that consider these experiences as sacred. system, such as increased numbers of circulating NK-cells Apart from cultural discrepancies reflected in the meaning and production of interferons and argue that the downregula- and terminology for these experiential states, these experi- tion of the INMT gene (Inmt) in malignant prostate and lung ences include the perception of colored and vivid images with cancers might also point to an important role of DMT, the eyes closed, the exacerbation of emotions, feelings of numi- Inmt final product, in suppressing tumors in these tissues.75 nousness, peacefulness, insights, or distressing reactions, and Corroborating these suggestions of positive interactions of the triggering of deep, transformative spiritual experiences.78 DMT with the immune system in cancer, a recent study has The complete outcome of the experience is highly dependent shown that DMT inhibits the indoleamine 2,3 dioxygenase on the context and meaning attributed to it. These character- enzyme. This enzyme, when upregulated, is associated with istics, known as set and setting, are important in understand- malignant cells escaping immune surveillance, and thus ing the complete healing effects of ayahuasca. The set is a DMT may help increase immune functions against malig- complex and dynamic composition of the personal motives, nant cells.76 purposes, intentions, and beliefs of the person, as well as the Importantly, as the in vitro results were obtained from physical characteristic, genetics, and the emotional and cog- specific cell lineages, differences between various human nitive state at the time of the experience. The setting includes Schenberg 7 Figure 2. An explanatory model of ayahuasca’s effects in cancer treatment. ATP: adenosine triphosphate; DMT: N,N-dimethyltryptamine; ER: endoplasmic reticulum; MAO: monoamine oxidase; MIT: mitochondria; PTP: permeability transition pore; SERT: serotonin uptake transporter; TCA: tricarboxylic acid cycle; VMAT2: vesicle monoamine transporter. things such as the physical environment where the experience The idea of considering other variables in cancer treat- is to occur, the person(s) who will be guiding the experience, ment, such as set and setting, emotions, patient beliefs, cul- and the person(s) who will be accompanying the experience. tural values, and spiritual experiences, is not a new and Both set and setting can occur in short and long time frames radical suggestion; it is part of some alternative cancer treat- and include the preparations before and the activities after the ment approaches for many years. These include the method experience itself.79 Thus, set and setting may also be described pioneered by Simonton et al.,81 which employs visual as the who, what, where, when, how, and why of the experi- imagery, later popularized by other authors,82 the model ence. A careful approach considering these factors is crucial if known as the Bonny Method of Guided Imagery,83,84 and any psychedelic experience or therapy is to succeed, as clearly also other approaches that employ imagery85,86 (for a critical demonstrated by the classic experiments using lysergic acid review of guided imagery as an adjuvant cancer therapy, see diethylamide (LSD) to treat alcoholism during the 1950s79 Roffe et al.87). These imagery techniques may be especially and as highlighted recently.80 important regarding ayahuasca in the treatment of cancer, 8 SAGE Open Medicine 0(0) given that visual imagery is a common phenomenon during To further test the hypothesis presented here that ayahuasca ayahuasca sessions, where visualizations are strongly poten- may have important effects in helping to treat cancer, data tiated due to the powerful effects of ayahuasca on visual should be gathered from many different fields. The systematic imagery, with brain activations, as measured by functional collection of more case reports, with detailed clinical data, magnetic resonance imaging (fMRI), reaching the occipital would help elucidate which types of tumors ayahuasca may pole, including primary cortical visual areas.88 Other alterna- provide beneficial effects. Furthermore, it is important to con- tive cancer treatment techniques employ music therapy,84,89 sider when ayahuasca was used in the time course of the dis- and this may be also important to consider, given that music ease. Systematically gathering more cases may also uncover has a central role in ayahuasca ceremonies.90 negative results that were unreported, due to patients who may The original model proposed by Simonton et al., as well have been discouraged to discuss a treatment that did not help as some of the others mentioned, focuses on specific psycho- them. This factor could also reveal the possible risks of physi- logical interventions to evaluate beliefs and attitudes and cally ill patients, some having undergone surgery, consuming minimize distress, emotional pain, depression and anxiety, ayahuasca. It should be noted that apart from the chemical dif- thus aiming to improve the quality of life.81 Issues such as ferences between ayahuasca and other psychedelic substances, hope, purpose, and spiritual beliefs are considered,81 resem- such as LSD and N,N-dipropyltryptamine (DPT), they were bling the set and setting approach of responsible and used with cancer patients to treat anxiety and depression and informed psychedelic science and of some carefully per- were well tolerated. The adverse effects observed in these formed ayahuasca healing ceremonies. This holistic approach patients were reported as manageable and similar to the effects to treat cancer is also in agreement with the proposition that observed in physically healthy individuals.98,99 Experiments therapeutics with ayahuasca work in three domains: psycho- with ayahuasca’s active principles both individually and in logical, spiritual, and organic.91 According to these authors,91 combination with cell and tissue cultures are important. ayahuasca “is a disinhibitor of energy blockages perceived Further studies need to be conducted to confirm which cell as thoughts at a mental level, as feelings at an emotional lineages and tissues are more susceptible to ayahuasca and to level, and as symptoms at the physical body.”91 Even the evaluate the possible role of ayahuasca in cancer treatment. spiritual experience, a more controversial topic from a These efforts would be important to validate safety and effi- Western scientific point of view, has recently been shown to cacy for patients seeking this alternative treatment. be regularly, safely, and reproducibly induced by another To advance the ideas put forward in this article, scientists psychedelic tryptamine, 4-phosphoryloxy-DMT, or psilocy- must overcome common misconceptions about shaman- bin, which is structurally similar to DMT.92 In fact, DMT ism100 and should engage with healers in a clear dialogue to was shown to trigger powerful spiritual experiences when foster communication and develop common research pro- injected in normal volunteers,93 and psilocybin was recently jects.101 This approach might help to improve the treatment shown to be effective in treating anxiety in advanced-stage available for and the quality of life of cancer patients and to cancer patients.94 Therefore, a holistic approach to cancer avoid the possible underreported dangers of ayahuasca use treatment that includes the ritualistic or religious use of aya- by cancer patients, such as the dangers of the so-called drug huasca may help not only to treat the organic aspects of the tourism102 and issues created by outlawing ayahuasca, such cancer but also to treat anxiety, depression, and associated as preventing safe contexts for use and fostering the danger- psychological conditions and to improve the patient’s quality ous practices of drug tourism. A holistic framework, such as of life, survival time, and, ultimately, their quality of death the one presented here, may indeed spark even more interest and dying. in ayahuasca use, especially by cancer patients, and thus, to In this regard, ayahuasca, which translates to “vine of increase safety and efficacy, a responsible approach is neces- the soul” (see Table 1), may have important effects, given sary.103,104 Ayahuasca use for healing purposes is not allowed the observed benefits of psychedelic experiences in allevi- in most countries. Legislation tends to interfere with set and ating fear of death and dying.95–99 This alleviated fear is setting issues; in a prohibitionist culture, both set and setting important not only to patients but also to families and doc- are negatively affected because of anxieties, prejudices, and tors, given the repressive culture western medicine has fears related exclusively to the penalties of infringing the law developed toward death.99 This repression becomes a very or using an unconventional healing path. If ayahuasca is sci- important aspect of cancer treatment, once that many of entifically proven to have the healing potentials long these patients will, inevitably, face the final transition, recorded by anthropologists, explorers, and ethnobota- which in the current culture is dealt with very anxious nists,105 outlawing ayahuasca or its medical use and denying behaviors marked by professionals shying away from deal- people adequate access to its curative effects could be per- ing with the subject in order to help the patient to accept the ceived as an infringement on human rights, a serious issue inevitable. This anxious situation can be soothed by guided that demands careful and thorough discussion. In view of the psychedelic experiences95–99 and probably through well- current expansion of ayahuasca use, careful international guided ayahuasca rituals, as reported by some of the cancer regulation may also help to reduce the harm and maximize patients whose cases were reviewed here.4–6 the benefit of ayahuasca use.103 Schenberg 9 In conclusion, the data available so far is not sufficient to tury, San José, CA, 15–18 April 2010. http://www.maps.org/ claim whether ayahuasca indeed helps in cancer treatment or videos/source3/video14.html (accessed 1 March 2013). not. However, there is enough available evidence that aya- 9. Labate BC and Cavnar C. The expansion of the field of huasca’s active principles, especially DMT and harmine, research on ayahuasca: some reflections about the ayahuasca track at the 2010 MAPS “Psychedelic Science in the 21st have positive effects in some cell cultures used to study can- Century” conference. Int J Drug Policy 2011; 22: 174–178. cer, and in biochemical processes important in cancer treat- 10. De Wys M. Black smoke: a woman’s journey of healing, ment, both in vitro and in vivo. Therefore, the few available wild love and transformation in the Amazon. 1st ed. New reports of people benefiting from ayahuasca in their cancer York: Sterling, 2009. treatment experiences should be taken seriously, and the 11. The Drug Policy Forum of Hawaii. In Memoriam: Donald hypothesis presented here, fully testable by rigorous scien- M Topping, PhD, 2003, Volume XII (I): 1–3. http://www. tific experimentation, helps to understand the available cases maps.org/ayahuasca/dpfh_newsletter_august03.pdf and pave the way for new experiments. 12. Lamchouri F, Settaf A, Cherrah Y, et al. Antitumour prin- ciples from Peganum harmala seeds. Thérapie 1999; 54(6): Acknowledgements 753–758. 13. Da Silveira DX, Grob CS, de Rios MD, et al. 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