The genus Aristolochia: between poison and medicine

The genus Aristolochia includes about 500 species which are mainly distributed throughout tropical regions; the genus has attracted great interest due to its relevant biological activities and unique constituents (Kuo, Li, & Wu, 2012). Various species of Aristolochia have been used globally in folk and traditional medicines, and written records of their use are well documented in ancient Ayurvedic, Chinese and European traditional medicine texts (Scarborough & Fernandes, 2011). Nowadays this genus seems to be of interest mainly due to its toxicological aspect (Grollman & Marcus, 2016; Han, Xian, Zhang, Liu, & Liang, 2019), however several Aristolochia species still persist in herbal formulas, particularly those of eastern pharmacopoeias (Shaw, 2010; Tripatara et al., 2012).

According to local traditional medicines, the general indications attributed to the different Aristolochia species and preparations stem from their tonic, depurative and, above all, anti-inflammatory properties. Aristolochia is used especially in cases of gout, arthritis, rheumatism, and skin diseases, and can also be used to treat snakebites (Gifford, Gifford, Eddleston, & Dhaun, 2017; Perry & Metzger, 1980). A recent review on biological activities of the Aristolochia genus recognizes an even larger spectrum of effects of traditional preparations from different species, including anticancer, antibacterial and antiparasitic activities, among others (Lerma-Herrera et al., 2022). The phytochemistry of the genus has been widely investigated but lacks a systematic approach, usually including various organs from different plant species.

The chemical composition of different species in this genus indicates the presence of many chemical classes of secondary metabolites, such as aristolactams, aporphines, protoberberines, isoquinolines, benzylisoquinolines, amides, flavonoids, lignans, biphenyl ethers, coumarins, tetralones, terpenoids, benzenoids, and steroids (Kuo et al., 2012). A typical feature present in most of the species is a class of metabolites sharing a common phenanthrene origin, classed as aristolochic acids and esters. This class of metabolites includes a group of substituted nitrophenanthrene carboxylic acids mainly represented by 3,4-methylenedioxy-8-methoxy-10-nitrophenanthrene-1-carboxylic acid, known as aristolochic acid I, and the demethoxylated derivative, aristolochic acid II. Their presence is reported in all plant organs and is often combined with aristolactams, a pool of phenanthrene cyclic amides.

Aristolochic acids are reported to exert their toxicological effects as phytotoxins through the common use of Aristolochia as an ingredient in formulations to reduce body weight, nowadays called aristolochic acid nephropathy (Gifford et al., 2017). Relevant literature confirms the toxicological profile of aristolochic acids, which are recognized as highly carcinogenic and toxic metabolites with potential health implications both directly, in their interactions in culinary and medicinal uses, as well as indirectly, in the form of environmental pollutants (Lukinich-Gruia et al., 2022). Many countries do not allow the use of Aristolochia as herbal medicines or food supplements due to the toxicity of aristolochic acid constituents. Certain homeopathic preparations are allowed, however, due to high dilutions which can be considered below the risk of toxicity. Nonetheless, Aristolochia species continue to be used in local medicines around the world, such as in traditional Chinese medicine (Agency, 2005). Despite the risk of nephropathy linked to the use of some species of the genus Aristolochia, about one hundred species are used medicinally worldwide, especially for gastrointestinal problems (Heinrich, Chan, Wanke, Neinhuis, & Simmonds, 2009).

The study site and the concept of emesis

Takiwasi, located on the outskirts of the city of Tarapoto, in the Amazonian basin of Peru, is a therapeutic community recognized by the Ministry of Health of Peru which combines the use of psychotherapy and medicinal plants for the treatment of mental health and, more specifically, addiction (Berlowitz et al., 2017). The novel addiction treatment protocol implemented at Takiwasi has been presented in several studies (Berlowitz et al., 2017; Giovannetti, Arce, Rush, & Mendive, 2020; Giove, 2002; Politi, Friso, & Mabit, 2018), as have the different medicinal plants used in it (Cervi et al., 2019; Horák, 2013; Politi et al., 2018). Takiwasi welcomes patients from Peru (42%), other Latin American countries (34%) and North America / Europe (24%) (Berlowitz et al., 2020a). Patients mainly suffer from dependence on cannabis (72%), alcohol (52%), and cocaine / coca paste (48%), among other substances. Several studies have shown how the use of multiple substances or polydrug addiction is a common characteristic in those seeking treatment, affecting 84% of Takiwasi patients (Berlowitz et al., 2020; DM, 2018).

As part of the therapeutic protocol of Takiwasi, several plants with emetic effects are offered to patients in order to provide physical cleansing, and to combine with this physical cleansing additional purported effects on an energetic or spiritual level. Herbal preparations with emetic activity are considered relevant therapeutic tools from both cultural and clinical perspectives within the context of Amazonian medical traditions (Fotiou & Gearin, 2019; Politi, Tresca, Menghini, & Ferrante, 2021; Sanz-Biset & Cañigueral, 2013). One such major example is the liquid preparation of Tobacco, especially Nicotiana rustica L. (Berlowitz et al., 2020). Emesis is considered a detoxification strategy within medical traditions other than those of Amazonia, including one Buddhist drug rehabilitation program in Thailand (Barrett, 1997). In the modern biomedical approach, emesis sits on a subtle border between being considered either a problem or a solution: gastric lavage, for example, is used only in cases of severe and acute poisoning, and neither as a prevention tool, nor as a "cure" for chronic poisoning. It is noteworthy to mention, however, the role of emesis as a key protective reflex of the body which involves multiple systems, including the respiratory, gastrointestinal, and abdominal muscles, and which can serve as a potential therapeutic option (Chai, Jiang, & Li, 2016).

At Takiwasi, emetic plants are considered to act on precise somatic zones which have their own symbolic correspondences (Politi et al., 2018): we can observe that Rosa Sisa (Tagetes erecta L.) is used in cleansing the mind of excessive rationalization; Azucena (Lilium candidum L.) is considered useful for sexual cleansing and balance; Verbena (Verbena litoralis Kunth) acts on the liver and the anger symbolically linked with it; Sauco (Sambucus peruviana Kunth) is beneficial for cleansing the respiratory system. Yawar Panga (Aristolochia didyma S.Moore) is considered to be the most important emetic/purgative plant in the Takiwasi addiction treatment protocol (Mabit, Rengifo, & Hidalgo, 2014), since it offers deep cleansing and proves very useful in disabling the withdrawal syndrome in the first phase of the treatment for drug addiction (Politi et al., 2018).

Between the 1980s and 2000s, due to increased civil unrest and narcotics trafficking, illicit drug consumption and substance use disorders became a prominent problem in the San Martín region in which Takiwasi is located (Fotiou & Gearin, 2019; Mabit & Mariscal, 2013). The use of psychotropic plants for ceremonial purposes in Latin America has been documented for thousands of years with no report showing the presence of notable addictive behaviors in traditional societies (Politi et al., 2018). The spread of addiction during the second half of the 20^th century therefore represented a relatively new phenomenon. Traditional healers in several regions of Peru responded by returning to methods linked to traditional ethnomedicine, similarly as in the case of the use of the mescaline cactus to treat alcoholism (Costa & M, 1976; Seguín, 1979).

Takiwasi was founded in 1992, drawing inspiration from such examples, and following 6 years of preliminary research centered in active observation of the work of Amazonian healers, especially those employing ancient plant remedies in the treatment of drug addiction (Mabit & Mariscal, 2013; Politi et al., 2018). Yawar Panga was introduced as part of Takiwasi’s therapeutic protocol as a potent detoxifying plant following the indications of traditional healers from the Kichwa Lamista ethnic group of the Chazuta valley, located 50 km to the southeast of Tarapoto. Between 1987 and 1993, one of Takiwasi’s founders, Dr. Jacques Mabit, completed an apprenticeship in traditional Amazonian medicinal practices in the Chazuta valley, becoming apprentice to several renowned master healers (Mabit & Mariscal, 2013). These healers included Don Aquilino Chujandama and Don Guillermo Ojanama (Villarreal & A, 2012), whom have both now passed away; the latter pioneered the traditional use of Yawar Panga at Takiwasi both before its foundation as well as during the first years of the center’s activities (1989-1995). Ojanama utilized Yawar Panga to treat indigenous people who suffered from addiction to cocaine paste as a consequence of working as macerators of coca leaves for drug trafficking organizations. The Huallaga valley where Chazuta is located was, at that time, the main region for drug production in Peru.

The use of Yawar Panga (in this case spelled “Yawar Panka”) by traditional healers in the Chazuta area as a therapy for the rehabilitation of individuals with tobacco and cocaine addiction has been recorded by Sanz-Biset and Cañigueral (Sanz-Biset & Cañigueral, 2013), who identified this plant as the species cognate Aristolochia leuconeura Linden and noted its use as a treatment for cough and bronchitis, and as a depurative and laxative. Again in the Chazuta area, Sanz-Biset et al. (Sanz-Bizet, Cruz, Epiquien-Rivera, & Canigueral, 2009) identified “Yawar Panka macho” (male) as Aristolochia fosteri Barringer, and documented its use as an emetic, as well as for cough and bronchitis. Jauregui et al. (Jauregui, Clavo, Jovel, & Pardo-De-Santayana, 2011) identify “Yawar Panga” as Aristolochia cauliflora Ule in the area of Pucallpa, Ucayali region, and describe its uses within the Shipibo-Konibo ethnic group as a potent emetic and detoxifying medicinal plant that is used for purification and cleansing. The authors themselves testify that “[…] the end of the sessions brings with it a profound sensation of wellbeing, lightness, mental clarity and a tranquil and relaxed countenance that lasts for two or three days”.

Yawar Panga (Aristolochia didyma) state of the art

Within the context of Takiwasi Center, the plant known with the common name Yawar Panga has been identified as Aristolochia didyma S.Moore (family Aristolochiaceae). This identification was made taking into account the Field Museum (Field Museum, 2022) isotype; the legitimate scientific name was verified in Tropicos (Tropicos & Org, 2022), which is up to date with the APG IV Group. A synonym of A. didyma is Aristolochia rodriguesii Hoehne (Moore, 2022; Tropicos & Org, 2022), although according to González and Pabón-Mora (González & Pabón-Mora, 2018), the accepted name is actually Aristolochia trilabiata Glaz and its synonyms are A. didyma and A. rodriguesii. In World Flora Online (Online, 2022), however, only A. didyma appears as an accepted name and has no synonymy, whereas A. trilabiata has not yet been considered.

Wanke, González, and Neinhuis (2006) mentions Aristolochia leuconeura Linden in their analysis of the Aristolochioideae, however does not include A. didyma. Both species, however, have a morphological resemblance: both have seeds with glutinous aril and glabrescent leaves, for example, among other similarities. These two species, furthermore, are found in the same habitat or type of forest. The previously mentioned studies by Sanz-Biset and Cañigueral (Sanz-Biset & Cañigueral, 2013) and Sanz-Biset (Sanz-Bizet et al., 2009) describing the utilization of Aristolochia leuconeura Linden in cocaine and tobacco addiction were performed in the Chazuta valley, an area nearby to Takiwasi and similar in habitat. In this sense, A. didyma is probably within the same group of the subgenus Aristolochia, so it likely shares a phylogenetic and metabolic relationship with A. leuconeura. Despite these two Aristolochia species being well known locally and additionally being used as important plant remedies, scientific studies on both plants are rare. Apart from Júnior, Conserva, Corrêa, and Guilhon (2002) and Pacheco and Oliveira (2009), as far as we know, no other phytochemical data on A. didyma are present in the literature.

Fieldwork with experts in Yawar Panga purge

Direct information about the Yawar Panga purge as practiced at Takiwasi was acquired through fieldwork performed between April and July 2021 as part of an ethnobotanical survey on purging plants at Takiwasi, authorized by the national authority “SERFOR” (authorization code AUT-IFL-2021-024). This research task was based on a participant-observation approach aimed at collection of plant material for botanical identification as well as descriptions of the method of preparation and administration of the Yawar Panga purge at Takiwasi.

The collection of botanical samples and the preparation of voucher specimens were performed at the Botanical Garden of the Takiwasi Center, Tarapoto, Peru. The vouchers were then sent and deposited at the Herbarium HTIN of the Universidad Nacional Agraria de la Selva, Tingo María, Peru, for botanical identification. The identification of the species was carried out using the taxonomic keys of Gentry and Vásquez (Gentry, 1993), Vásquez and Rojas (Martínez & González, 2004), and Mostacero et al. (León, Coico, Rosas, Cruz, & Castillo, 2017), and their classification was determined according to the APG IV (Group et al., 2016). Certificate C-011-2021-HTIN-FRNR-UNAS was issued as a result of this identification process.

The information regarding the practice of the Yawar Panga purge at Takiwasi was collected through semi-structured interviews, lasting an average of 1.5h each, with 7 different therapists, healers, and an ethnobotanist of the Center, who are considered experts in this traditional Amazonian herbal practice. These individuals will hereafter be referred to as informants. All interviews were performed in Spanish and recorded and subsequently transcribed verbatim to be used for the analysis. Formal approval by the Institutional Review Board for Research of the Takiwasi Center was acquired for this research task (document of approval CIRICT0012021), and all informants signed written informed consent. Some of the questions given to the informants included: How is the Yawar Panga purge prepared? Why and when is it used? How is it administered? What are the effects and benefits recognized by therapists and healers?

Retrospective study

This research task analyzed experiences of the Yawar Panga purge among residential inpatients being treated for addiction at Takiwasi. We specifically examined written records of psychotherapy sessions held with patients following the purge. These data are stored in the Takiwasi clinical data management system (Rojas, Friso, Romero, & Politi, 2018). Formal approval by the IRB of Takiwasi Center was acquired for this task (document of approval CIRICT0012021). Takiwasi is an accredited therapeutic community recognized by the Ministry of Health of Peru (resolution Nº039-DG-DIRES/SM-96). In accordance with article 15 of Law No. 29765 (Decreto Supremo Nº006-2012-SA), all care received by patients of therapeutic communities must be registered in a clinical history, which includes, among other elements, a psychological sheet. The psychological sheet of Takiwasi patients who received the Yawar Panga purge was consulted for the purpose of this analysis. The maintenance of the clinical history is audited by the Ministry of Health periodically. The analysis of this clinical data is intended to provide descriptive support to the interviews and participant observation and has no claim to be clinical research of any sort.

Participants came from 19 different countries; the most frequently represented countries were Peru (56), France (11), and Spain (10). All patients were male (n=114), as Peruvian law for therapeutic communities requires that all patients be of the same biological sex (Decreto Supremo Nº006-2012-SA). Patients’ average age was 31 years. The goal of this analysis was to outline the subjective effects of the Yawar Panga purge and to specify its relevance within the context of addiction treatment.

Psychotherapy sessions during which patients recounted their experience were held within one week following the purge. Patients were questioned in an open-ended format, allowing them to highlight whichever parts of their experience were most notable. The psychotherapy sessions were conducted in Spanish and later summarized and uploaded by the psychotherapists into Takiwasi’s internal online archive. All patients sign an authorization form for the use of their de-identified data for research purposes at the beginning of treatment (Rojas et al., 2018).

The data was analyzed using Microsoft Excel and Atlas.ti 9. The analysis was conducted using conventional content analysis, which permits derivation of representative categories directly from written texts without placing strong emphasis on the source of the material (Hsiesh & Shannon, 2015). This method is useful when little is known about the topic under investigation. The examined data was gathered between 2008 and 2021. A total of 664 Yawar Panga purges were administered to residential inpatients during this period, which resulted in a total of 194 written testimonies that were then subjected to a preliminary reading. Those that did not provide substantive information were excluded. The final number of testimonies utilized was 172.

Analysis of this data consisted of an initial review of each testimony during which lexical descriptions were given to each entry. The testimonies were then reviewed a second time, utilizing the descriptions from the first analysis as guidelines to assist in the derivation of representative codes. After being assigned codes, the testimonies were reviewed once more so as to corroborate the accuracy of each code as it pertained to each testimony. From these codes emerged the final categories which represent common effects and experiences perceived as a direct result of the Yawar Panga purge. The reports given by psychotherapists varied in both length and content, so it was usual for each testimony to be assigned more than one representative category. The results include those categories which appeared more than 20 times.

In silico analysis

Putative targets were identified through the bioinformatics method described byGu et al. (2020). Briefly, chemical structures were prepared and converted into canonical “Simplified Molecular Input Line Entry System” (SMILES) using ChemSketch software (12.0 version).

The SMILES were then processed by the SwissTargetPrediction (http://www.swisstargetprediction.ch/) and SwissADME (http://www.swissadme.ch/index.php) platforms to predict putative targets and pharmacokinetic profile, respectively. The names of identified targets were normalized in accordance with the UniProt database (https://www.uniprot.org/). Finally, Cytoscape software (3.8 version) was used to create a component-target network.

Preparation and administration of Yawar Panga purge

The Yawar Panga purge is prepared using fresh leaves which are ground mechanically in a hand-operated grinder until a liquid extract comes out. The liquid is then recollected and filtered. The plant extraction is always prepared on the same day as the purge ceremony.

The administered dose for one person is one tablespoon of the recollected liquid. The liquid is then diluted with some water to facilitate its intake. The plant preparation is administered thereafter in a ritualistic context, in the so-called ceremonia de purga (purge ceremony). The context in which the plant is administered is considered to be crucial by Takiwasi informants and includes the use of some Traditional Amazonian Medicine (TAM) tools. Such tools may include chanting sacred melodies (icaros), blowing tobacco smoke on specific parts of the body such as the hands, chest, or top of the head (soplada), or sucking out the illness-causing agent (chupada) González, Lopez, and Horák (2022); Mabit (2006).

During the ceremony, which lasts 2 to 3 hours, the Yawar Panga preparation is ingested and followed by 5-8 liters of water, which is consumed to facilitate absorption of the plant and to induce vomiting. The Yawar Panga purge is not pleasant; it induces strong and persistent vomiting which may last for several hours. After the ceremony the participants are advised to take a shower without soap and rest until the next morning without eating or drinking, save for an herbal tea if necessary.

Yawar Panga was the first emetic plant to be administered to patients when Takiwasi first opened as a therapeutic community in the 1990s. Currently, however, after several decades of experience, Takiwasi therapists may choose to give newly admitted patients a less demanding emetic plant (see introduction) to begin treatment and to allow them to work their way up to Yawar Panga.

According to the informant accounts, the Yawar Panga purge must be administered with care. One informant told of a person who died taking Yawar Panga: “I heard cases of the brother of a patient who died. He died taking Yawar Panga, for example. An alcoholic patient went to take a purge with a curandero, that curandero did not check the patient's background and gave him a purge. The most potent one. This patient who was a relative of a patient here in Tarapoto died”. At Takiwasi, therapists strongly emphasize the importance of the medical evaluation (health declaration) and the patient interviews before any treatment is considered. Nevertheless, there was one instance of a Takiwasi patient being brought to the hospital following a Yawar Panga purge. The process during the ceremony went well for this individual, but intense nausea persisted afterwards. The medical doctor and curandero attended to him, but as soon as he manifested pain in the stomach, they brought him to the hospital for precautionary reasons. It was later revealed that this patient had been traveling extensively before arriving at Takiwasi and had maintained an improper dietary regimen before the ceremony which included spicy food, ceviche, grilled chicken and other strongly flavored foods. Yawar Panga, like other ceremonially-used plants, can manifest its toxic qualities in the absence of appropriate preparatory conditions on the part of the participant. Following a strict dietary regimen before and after ingesting the plant is one such condition. This situation properly exemplifies the principle of pharmakon, whereby a substance can act as a poison or medicine depending on the context of its use.

Informants’ accounts on Yawar Panga purge effects

According to the informant accounts, Yawar Panga is considered the strongest of all purging plants, as it can clean deep into the bottom of the stomach and internal organs. This purge is believed to work principally on three levels: the physical-biochemical, the psychological-emotional, and the energetic-spiritual. The latter is described at Takiwasi as a non-metaphorical plane of reality populated by both good and evil spirits (DM, 2018), and is considered a central component in the center’s concept of illness etiology. Furthermore, the psychological effects induced by the purge can be subdivided into three distinct levels: the cerebral-cortical, the limbic and the brainstem. The purge can influence all three of these levels, leading, respectively, to effects on one’s cognitive processes, affective responses, and autonomic mechanisms such as temperature regulation.

If taken in the absence of proper oversight and without following the prescribed restrictions, adverse reactions up to and including death have been known to occur. In addition to administering an appropriately sized dose, the ritualized context plays an important role in controlling the external environment and regulating the internal state of the participants. Furthermore, the ritual framework potentiates the effects of the purge, enabling greater influence on the psychological-emotional and energetic-spiritual levels. The ritualized context gives a structured framework within which the plant can work without transgressing the desired effects of the purge.

Yawar Panga is considered unpleasant to drink but is at the same time a versatile and efficient purge, as it can detoxify an individual from different loads, whether they be energetic-spiritual, psychological-emotional or physical in origin. This powerful cleansing effect, however, can be difficult to endure because it induces strong vomiting. Some informants report patients having vomited several hours into the night, sometimes until 3am. Some patients report expelling bile in which can be smelled odors of drugs and chemical products or undigested food from previous days. Occasionally, participants may persist with nausea and vomiting for hours after the ceremony ends. In such cases the patient may be given a small piece of ginger to chew on, like a small caramel. The ginger juice alleviates the emetic effect of the plant and reduces nausea, calming the patient.

Informants report that the positive effects of the purge are often only felt the day following the ceremony. Many patients may say “never again” after completing the purge only to realize the next day how valuable the effects of the plant can be.

Informants report that patients who have been using drugs for many years have a saturation of the substance in their circulatory system. After having cleansed their blood and the cardiovascular system with Yawar Panga, patients tend to experience fewer withdrawal symptoms. Afterwards they may hold a better disposition toward continuing treatment, as their symptoms of physical dependence on the drug have weakened. Informants say that the multifaceted cleanse offered by Yawar Panga, detoxifying the body on the physical, psychological, and spiritual level helps patients to understand more clearly their reasons for seeking addiction treatment. Due to the intensity of the purge, patients might also experience an intense state of awareness or have vivid dreams about their relationship with drug consumption. The Yawar Panga purge is additionally considered helpful when one is very anxious or irritable: it can offer emotional stabilization and help to recalibrate a sense of balance within the individual. This effect can become well known during the course of treatment, and the patients even joke around with it. When one is very irritable or agitated, other patients respond “Te falta una Yawar Panga” (“You need a Yawar Panga”) or “Ah te viene una Yawar Panga” (“ah you will get a Yawar Panga”).

Yawar Panga names and symbolism

The name Yawar Panga consists of two words from the Quechua language. “Yawar” means blood and “Panga” signifies leaf. The Yawar Panga’s sap is as red as blood and among locals this name stands for its ability to purify the blood. Different names for this plant are used in other parts of the Amazon. The Asháninka ethnic group, for example, call the plant Huancahui Sacha. Huancahui refers to a falcon bird (Herpetotheres cachininans) that hunts poisonous snakes. Another name used in the Amazon is Machacuy Huasca. Machacuy (machaco or Bothrops bilineatus) is a poisonous snake and huasca refers to its characteristic of being a climbing plant.

At Takiwasi a symbolic connection is found between Yawar Panga and the elements of nature: Yawar Panga is mainly considered an “earth plant” but contains, however, certain characteristics from other elements, such as air (Mabit et al., 2014). Therapists at Takiwasi relate that Yawar Panga can be used to eliminate poisoning, witchcraft, or other negative energies particularly on the spiritual level. Herein lies the connection with the bird Huancahui, as Yawar Panga is considered to have the ability to “see” where there are bad energies and bad spirits and eliminate them (Mabit et al., 2014). Yawar Panga thus demonstrates its dual symbolic nature: in its healing aspect, when used with proper knowledge and in a ritualized context, it possesses the power of air (bird) that dominates the venomous snake; in its destructive aspect it represents the power of earth (snake) that is poisonous and can kill (Mabit et al., 2014).

Figure 1

Terpene compounds present in A. didyma (Pacheco & Oliveira, 2009): ent-Kauran-16β-ol [(–)-kauranol] (1); ent-Kauran-16β,19-diol [ent-16β,19-dihydroxykaurane] (2); [ent-16β,17-Dihydroxy-(–)-kauran-19-oic acid (3); ent-16ß,17-Dihydroxy-(–)-kauran-19-oic acid (4); ent-Kauran-16ß-ol [(–)-kauranol] (5); [ent-3ß,18-dihydroxykaur-16-ene] (6).

Insights from the retrospective study

In silico analysis

An in silico study was conducted in order to predict putative targets and pharmacokinetics of characteristic phytochemicals of this plant. According to the study previously published by Pacheco and Oliveira (2009), the in silico prediction considered the following terpenoid compounds: ent-Kauran-16β-ol [(–)-kauranol] (1); ent-Kauran-16β,19-diol [ent-16β,19-dihydroxykaurane] (2); [ent-16β,17-Dihydroxy-(–)-kauran-19-oic acid (3); ent-16ß,17-Dihydroxy-(–)-kauran-19-oic acid (4); ent-Kauran-16ß-ol [(–)-kauranol] (5); [ent-3ß,18-dihydroxykaur-16-ene] (6) (Figure 1).

The structures of the above-mentioned compounds were run on the bioinformatics platforms SwissTargetPrediction and SwissADME, in order to predict putative targets and pharmacokinetics, respectively. Most of A. didyma terpenes were predicted to interact with various targets involved in steroid hormone pathways (Figure 2); however, only ent-Kauran-16β-ol [(–)-kauranol] could bind to GABA B receptor.

Figure 2

Pharmacological profile of phytocompounds identified in Aristolochia didyma. Molecular target and pharmacokinetic profile were predicted through SwissTarget Prediction (http://www.swisstargetprediction.ch/) and SwissADME (http://www.swissadme.ch/index.php) platforms, respectively. Finally, a component-target analysis was carried out through Cytoscape software (3.8 version).

Recently, the GABA B receptor agonist baclofen has been showed to inhibit emesis stimulus, in shrew (Konno et al., 2022). The pharmacokinetics predictions also pointed to a high probability of gastrointestinal absorption and blood-brain barrier permeation for ent-Kauran-16β-ol [(–)-kauranol]. This is consistent, albeit partially, with pharmacological data available for the kaurene diterpene compound steviol, which can be absorbed in the colon only in the aglycon form (Mohammed et al., 2022). Overall, the present in silico and literature data would make rational and probable the absorption of ent-Kauran-16β-ol [(–)-kauranol] and the involvement of GABA B receptor in mediating the emetic effects induced by A. didyma preparations, in Takiwasi-assisted patients.

Future studies should look to unravel the bioavailability of such compounds and to elucidate the molecular interactions between ent-Kauran-16β-ol [(–)-kauranol] and GABA B receptor, aimed at a final goal of verifying whether the compound affinity toward the receptor is consistent, albeit partially, with plasma concentrations following oral administration.