Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2017, Article ID 9439868, 28 pages https://doi.org/10.1155/2017/9439868

Review Article Medicinal from North and and the Caribbean Considered Toxic for Humans: The Other Side of the Coin

Angel Josabad Alonso-Castro,1 Fabiola Domínguez,2 Alan Joel Ruiz-Padilla,1 Nimsi Campos-Xolalpa,3 Juan Ramón Zapata-Morales,1 Candy Carranza-Alvarez,4 and Juan Jose Maldonado-Miranda4

1 Departamento de Farmacia, Division´ de Ciencias Naturales y Exactas, Universidad de Guanajuato, Guanajuato, GTO, 2Centro de Investigacion´ Biomedica´ de Oriente, Instituto Mexicano del Seguro Social, Metepec, PUE, Mexico 3Departamento de Sistemas Biologicos,´ Universidad AutonomaMetropolitana,UnidadXochimilco,MexicoCity,Mexico´ 4Unidad AcademicaMultidisciplinariadelaZonaHuasteca,UniversidadAut´ onoma´ de San Luis Potos´ı, Ciudad Valles, SLP, Mexico

Correspondence should be addressed to Angel Josabad Alonso-Castro; [email protected]

Received 14 August 2017; Revised 4 October 2017; Accepted 10 October 2017; Published 2 November 2017

Academic Editor: Karin Kraft

Copyright © 2017 Angel Josabad Alonso-Castro et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The consumption of medicinal plants has notably increased over the past two decades. People consider herbal products assafe because of their natural origin, without taking into consideration whether these plants contain a toxic principle. This represents a serious health problem. A bibliographic search was carried out using published scientific material on native plants from Mexico, Central America, and the Caribbean, which describe the ethnobotanical and toxicological information of medicinal plants empirically considered to be toxic. A total of 216 medicinal plants belonging to 77 families have been reported as toxic. Of these plants, 76 had been studied, and 140 plants lacked studies regarding their toxicological effects. The toxicity of 16 plants species has been reported in clinical cases, particularly in children. From these plants, deaths have been reported with the consumption of Chenopodium ambrosioides, Argemone mexicana,andThevetia peruviana. In most of the cases, the principle of the responsible for the toxicity is unknown. There is limited information about the toxicity of medicinal plants used in Mexico, Central America, and the Caribbean. More toxicological studies are necessary to contribute information about the safe use of the medicinal plants cited in this review.

1. Introduction medicinal plants and related products, their toxicity remains to be evaluated. In addition, many medicinal plants require The use of herbal medicine has increased around the world scientific evidence for their medicinal use, particularly those due to its presumptive efficiency, availability, and general that are sold as food supplements. acceptance. Approximately 80% of the general population, Some medicinal plants might trigger undesirable side especially in developing countries, uses medicinal herbs effects for human health because of (a) pharmacodynamic for primary health care [1, 2]. Worldwide, the interest in interaction with prescribed drugs, (b) intrinsic effects, (c) medicinal plants by patients has increased over the past two pharmacokinetic interaction with prescribed drugs, and (d) decades. The global market for medicinal plants and plant- thepresenceofcontaminantsand/orpathogenicmicroor- derived drugs in 2015 was estimated at 25.6 billion dollars ganisms. Other factors that impact the toxicity of medicinal andisexpectedtoriseto35.4billiondollarsin2020[3].This plants in humans include the age of the patient, nutritional clearly indicates that the consumption of medicinal plants is status, and the presence of chronic diseases. The concentra- a current topic of interest. Despite the high consumption of tion of toxic metabolites in plants is determined by the season 2 Evidence-Based Complementary and Alternative Medicine of collection, nutrients in the soil, and growth stage, among (15%), seeds (14%), roots (8%), fruits (8%), bark (4%), latex others [4]. (3%), and other plant parts. The main reasons for focusing this review on medici- The signs and symptoms of toxicity induced by medicinal nal flora with supposed toxicological effects from Mexico, plants are reported in Table 1. The main toxic effects occur in Central America, and the Caribbean are as follows: (a) the the following order: nausea and vomiting (20%), dermatitis ancient importance of traditional medicine in this region, (14%), gastritis (9%), abdominal pain (9%), abortifacient (b)theirgreatbiodiversity,and(c)thecurrentuseof (8%), skin burns (8%), hepatotoxicity (7%), severe diar- herbal products. This review will be useful for physicians, rhea (6%), cardiotoxicity (5%), nephrotoxicity (2%), numb- toxicologists, pharmacologists, and general audiences. We ness (2%), dizziness (2%), and hallucinations (2%), among have tried to describe in detail some toxic symptoms reported others. with the consumption of the medicinal plants covered in this review. 3.1. Dosages. In most of the cases, the dose for the induction of toxic effects by medicinal plants is not indicated. Usually, 2. Methodology consumers of medicinal plants believe that increasing the A bibliographic search was conducted from July 2016 to consumption of these products will increase the efficacy of the May2017ofpublishedscientificmaterialonnativeplants treatment. In these cases, the daily dosage is exceeded, which from Mexico, Central America, and the Caribbean that triggers toxicity. For instance, the roots of Ipomoea purga, describes the ethnomedical and toxicological information a purgative agent, are used at a dose of 2 g/L/day. Admin- for medicinal plants reputed to be toxic for humans. The istration of higher doses induces vomiting and abdominal following keywords were searched in different scientific pain [15]. Fresh leaves of Prunus serotina,usedforthe databases: plant extract, toxicity, Mexico, and Central Amer- treatment of cough, or Zanthoxylum fagara,ananxiolytic ica. Additional data were acquired from undergraduate and agent, each must be consumed in a maximum quantity of postgraduate theses, as well as published and electronic five leaves in 250 ml of water per day. Higher doses pro- books. The admittance criteria for the selection of scientific duce spasms and nausea [26]. Approximately 5mL of an information in this review were as follows: (i) plants native infusion of Picrasma excelsa (10 g/L) should be administered to North and Central America and the Caribbean, (ii) plants three times per day. Higher doses induce hypotension. This used for medicinal purposes with or without toxicological infusion should not be prepared with ethanol and orally studies, (iii) plants with experimental reports on their in vitro administered. If a person consumes the hydroalcoholic infu- and/or in vivo toxicity, (iv) plants thought to be toxic for sion, the consequences could be lethal [35]. The maximum humans, (v) studies where the concentrations were presented consumption of Manilkara zapota seeds should be 10 seeds as weight/volume relationship in international units (mg/ml, per day. A higher consumption of these seeds might induce 𝜇g/ml), (vi) studies where the doses were presented as vomiting and gastroenteritis [26]. On the other hand, Sosa- weight/weight relationship in international units (mg/kg, Gomez´ [35] recommends the preparation of an infusion using g/kg), and (vii) plants with information obtained from a approximately 1–3 g Argemone mexicana leaves in 1 L of water. clear source. Scientific studies reporting the combination of This infusion should be taken 3 times per day. A higher dose plant extracts were excluded. Medicinal plants considered might induce immobilization. toxic were classified into two categories: (1) plants with Studies analyzing the range of doses considered safe for toxicological evidence reported in a scientific source and (2) human consumption remain to be performed. The use of plants without toxicological evidence. All plant names and natural products needs scientific evidence to corroborate the their distributions were confirmed at the Missouri botanical medicinal uses attributed to different plant species. Many garden [73]. Many of the medicinal plants cited in this review medicinal plants sold as “food supplements” lack warnings have no common name in English. Therefore, the common if the suggested dosage is exceeded. names were given in Spanish (Table 1). 3.2. Toxic Principles. In some cases, the toxic principle is 3. Medicinal Plants Considered to known. For instance, it is reported that cefalatin, the main Be Toxic for Humans toxic compound in Cephalanthus occidentalis bark, induces vomiting, anemia, and seizures, among other toxic effects. A total of 216 medicinal plants belonging to 77 families Similarly, hederagenin is the main toxic compound in Clema- reported as toxic were recorded. Of these plants, 76 had tis dioica, which is a caustic substance [4]. Monocrotaline is been studied, and 140 plants lacked studies regarding their the compound responsible for the toxic effects in Crotalaria toxicological effects (Table 1). Aristolochia (6 plant species), sagittalis. Cianhidric acid, one of the most toxic compounds Euphorbia (6 plant species), Solanum (5 plant species), and in plants, is found in Crescentia cujete fruit, Phaseolus lunatus Asclepias (5 plant species) are the plant genera most often whole plant, and Prunus serotina leaves and seeds [4]. In reported to induce toxicity (Table 1). Chemotaxonomic stud- Phaseolus lunatus, the concentration of cianhidric acid ranges iesshouldbeperformedtoidentifythetoxicprincipleinthese 6.8–533 mg/kg dw [74, 75]. There is limited information on genera. The parts of the plants considered toxic are listed in the major toxic compounds cited in this review. Therefore, the following order: aerial parts including branches, leaves the identification of toxic principles in medicinal plants is and flowers (22%), whole plant (22%), leaves exclusively necessary. Evidence-Based Complementary and Alternative Medicine 3

Table 1: Ethnobotanical information of medicinal plants from Mexico and Central America considered as toxic.

Common name in Signs of toxicity Family Scientific name Medicinal use Reference Spanish [plant part] Rheumatism, ∗∗ Nephrotoxicity Amaranthus spinosus L. QuelitedePuerco diuretic, wound [5] [whole plant] healing Amaranthaceae Nephrotoxicity Chenopodium ambrosioides abortifacient, ∗∗ Epazote Vermifuge, vomit [6] L. hepatotoxicity [whole plant] Numbness, nausea, Allium glandulosum Link & Cough, flu, Amaryllidaceae Cebolla de monte and vomiting [7] Otto tuberculosis [bulb] Antiviral, Skin burns [latex brownei (Jacq.) Urb. Chechem´ negro [8] Rheumatism from leaves] Toxicodendron radicans (L.) Headache, Hiedra venenosa Dermatitis [latex] [9] Kuntze rheumatism

∗∗ Diarrhea, Abortifacient Annonaceae Annona cherimola Mill. Chirimoya [10] dysentery [aerial parts, fruits] Hypertension and ∗∗ Apiaceae Conium maculatum L. Cicuta Body pain sweating [whole [11] plant] Nausea and Vermifuge, cancer, vomiting, muscle Asclepias curassavica L. Rompemuelas wound healing, [12] paralysis [whole diuretic plant] Cough, fever, Muscle paralysis Asclepias linaria Cav. Algodoncillo [13] purgative, diuretic [leaves] Venenillo Asclepias mexicana Cav. Warts Numbness [leaves] [12] cimarron´ Numbness, nausea, Asclepias oenotheroides Hierba lechosa Tooth ache and vomiting [5] Schltdl. & Cham [leaves] Asclepias subverticillata (A. Severe diarrhea Hierba lechosa Snake bite [5] Gray) Vail [leaves]

∗∗ Stomachache, Apocynaceae Plumeria rubra L. Zacalazuchil´ Dermatitis [latex] [14] toothache Diarrhea, nausea, and vomiting, ∗∗ Wound healing, Rauvolfia tetraphylla L. Cinco negritos hypertension, [15] rheumatism depression [aerial parts] Toothache, Cardiotoxicity Thevetia ahouai (L.) A. DC. Bola de venado [8] headache [fruits and seeds] Tooth loss [leaves, Thevetia gaumeri Hemsl. Campanilla Toothache, cancer [16] latex] Thevetia peruviana (Pers.) K. Cardiotoxicity ∗∗ Troncomin Stomachache [17] Schum. [leaves] Thevetia thevetioides (Kunth) Cardiotoxicity Yoyote Warts, analgesic [18] K. Schum [whole plant] Cardiotoxicity and Aquifoliaceae Ilex opaca Aiton American holly Digestive [19] vomiting [fruits] 4 Evidence-Based Complementary and Alternative Medicine

Table 1: Continued.

Common name in Signs of toxicity Family Scientific name Medicinal use Reference Spanish [plant part] Anthurium crassinervium Kiilbal chaak Warts Dermatitis [sap] [8] (Jacq.) Schott Hoja de Anthurium pentaphyllum Dermatitis [aerial reumatismo de Rheumatism [8] (Aubl.) G. Don parts] bejuco Anthurium schlechtendalii Hemorrhage Dermatitis [aerial Araceae Hoja de piedra [8] Kunth postpartum parts] Dermatitis, Caladium bicolor (Aiton) ∗∗ HeartofJesus Antiseptic diarrhea [aerial [4] Vent. parts]

∗∗ Dysphagia [aerial Monstera deliciosa Liebm. Ceriman´ Flu, rheumatism [20] parts] Snake bite, Hepatotoxicity Aristolochia foetida Kunth Guaco [21] headache [whole plant] Stomachache, Abdominal pain, Aristolochia grandiflora Sw. Flor de pato [15] snake bite gastritis [roots] Diarrhea, Nephrotoxicity and Aristolochia odoratissima L. Guaco stomachache, belly hepatotoxicity [22] Aristolochiaceae cramps [roots] Nephrotoxicity Aristolochia pentandra Jacq Camotillo guaco Fever, diarrhea [22] [roots] Texas dutchman’s Nephrotoxicity Aristolochia reticulata Nutt. Digestive [19] pipe [roots] Nephrotoxicity Aristolochia serpentaria L. Virginia snakeroot Digestive, diuretic [19] [roots] Nausea and Asparagaceae Yucca filifera Chabaud Palma Cough vomiting [aerial [14] parts] Hallucinations Acmella repens (Walter) Rich. Yerba de San Pedro Malaria [23] [aerial parts] Gastritis [whole Ambrosia confertiflora DC. Amargosa Diarrhea, vomiting [13] plant]

∗∗ Rheumatism, pain, Neurotoxicity Ambrosia peruviana Willd. Altamisa [24] fever [whole plant] Nausea and Ambrosia psilostachya DC. Estafiate Stomachache vomiting [whole [25] plant] Artemisia ludoviciana subsp. Numbness, mexicana (Willd. ex Spreng.) Estafiate Vermifuge, fever carcinogenic [14] D.D. Keck [aerial parts] Barkleyanthus salicifolius Fever, diuretic, Hepatotoxicity Jaral Amarillo [14] (Kunth) H. Rob. & Brettell rheumatism [whole plant] Nausea and Conyza filaginoides (DC.) Stomachache, Simonillo vomiting [whole [7] Hieron. diabetes, anxiolytic plant] Nausea and Wound healing, Eupatorium odoratum L. Rama de la cruz vomiting [whole [5] anti-inflammatory plant]

∗∗ Stomachache, Hepatotoxicity Flourensia cernua DC. Hojasen´ [13] diarrhea [leaves] Evidence-Based Complementary and Alternative Medicine 5

Table 1: Continued.

Common name in Signs of toxicity Family Scientific name Medicinal use Reference Spanish [plant part] Diuretic, Sleepiness, muscle Gymnosperma glutinosum ∗∗ Tatalencho rheumatism, paralysis [seeds, [5] (Spreng.) Less. analgesic leaves] Haplopappus gymnocephalus Body pain, Gastritis [aerial Arnica morada [14] DC. hemorrhoids parts] Asteraceae Gastritis and Helenium mexicanum Kunth Cabezona Flu [15] vomiting [flowers] Heliopsis longipes (A. Gray) ∗∗ Chilcuague Analgesic Narcotic [roots] [26] S.F. Blake Rheumatism, Abortifacient, Montanoa tomentosa Cerv. Zoapatle cough, menstrual respiratory failure [27] colic [aerial parts] Amenorrhea, Packera aurea (L.) A.´ Love¨ & Hepatotoxicity Life root menopause and [19] D. Love¨ [aerial parts] leucorrhea. Packera candidissima (Greene) Hepatotoxicity Chuca Cough [28] W. A . We b e r & A.´ Love¨ [aerial parts] Hypotensive, ∗∗ Stomachache, Parthenium hysterophorus L. Escoba amarga bradycardia [whole [29] headache plant] Nausea and Stomachache, Parthenium incanum Kunth Mariola vomiting [whole [13] diarrhea plant] Psacalium decompositum (A. Diabetes, Neurotoxicity Matarique [30] Gray) H. Rob. & Brettell rheumatism [roots] Diarrhea, ∗∗ Flor de muerto vermifuge, Tagetes erecta L. Gastritis [flowers] [31] (cempaxochitl) diabetes, rheumatism

∗∗ Stomachache, Abortifacient Tagetes lucida Cav Pericon´ [32] diarrhea, vomit [whole plant]

∗∗ Stomachache, Zinnia peruviana (L.) L. Mal de ojo Eye irritant [14] diarrhea Numbness, nausea, Berberis moranensis Schult. & Palo amarillo Rheumatism and vomiting [33] Schult. f. [aerial parts] Nausea and Caulophyllum thalictroides (L.) Dysmenorrhea, ∗∗ Blue cohosh vomiting, gastritis [11] Michx. rheumatism [seeds and roots] Berberidaceae Altered mental states, tachypnea, peripheral ∗∗ Podophyllum peltatum L. Mayapple Genital warts neuropathy, nausea [19] and vomiting, hypotension, and fever [whole plant] Vomiting, Crescentia alata Kunth Cuatecomate Cough, asthma abdominal pain [21] [fruit] Bignoniaceae Abortifacient, ∗∗ Cough, Crescentia cujete L. Guiro¨ severe diarrhea [18] tuberculosis [fruits] 6 Evidence-Based Complementary and Alternative Medicine

Table 1: Continued.

Common name in Signs of toxicity Family Scientific name Medicinal use Reference Spanish [plant part]

∗∗ Severe diarrhea Cordia dentata Poir. Uvita Cough [8] [fruits] Boraginaceae Asthma, anemia, Hepatitis [whole Heliotropium curassavicum L. Alacrancillo [11] snake bite plant] Bromelia pinguin L. Pinuela˜ Cough Dermatitis [fruits] [34] Bromeliaceae Bromelia plumieri (E. Morren) Timbiriche Inflammation Dermatitis [fruits] [8] L.B. Sm. Oregano de Cardiotoxicity Cereus marginatus DC. Rabies [13] zopilote [aerial parts] Coryphantha pycnacantha Rheumatism, Sedation in tongue Cactaceae Falso peyote [14] (Mart.) Lem. analgesic [fruit] Lophophora williamsii (Lem. Rheumatism, Hallucinations Peyote [30] ex Salm-Dyck) J.M. Coult. analgesic [whole plant] Hypothermia, vomiting, Lobelia cardinalis L. Lobelia Cough, flu [4] abdominal pain Campanulaceae [aerial parts]

∗∗ Asthma, muscle Hypotension Lobelia inflata L. Lobelia [35] relaxant [whole plant] Edema, Rheumatism, Canellaceae Canella winterana (L.) Gaertn. Curbana´ hemorrhage [36] stomachache [whole plant] Cardiotoxicity and Lonicera periclymenum L. Woodbine Diuretic, cough neurotoxicity [11] [fruits] Caprifoliaceae Nausea and Symphoricarpos albus (L.) S.F. vomiting, Snowberry Tuberculosis [11] Blake abdominal pain [whole plant] Gastritis, nausea Diuretic, Celastrus scandens L. Falsa dulcamara and vomiting, [11] Celastraceae tuberculosis diarrhea [fruit] Euonymus atropurpureus Jacq. Wahoo Purgative Vomiting [bark] [11] Edema, dermatitis Commelina elegans Kunth Hierba del pollo Conjunctivitis [8] [whole plant] Commelinaceae Cancer, wound Tradescantia spathacea Sw. Maguey morado healing, asthma, Skin burns [sap] [8] cough Hair loss, wound Ipomoea murucoides Roem. & Cazahuate healing, cough, Gastritis [bark] [37] Schult. diuretic Vomiting and Ipomoea purga (Wender.) Ra´ız de Jalapa Purgative abdominal pain [15] Hayne [roots] Convulvulaceae Neurotoxicity Ipomoea stans Cav. Tumbavaqueros Epileptic seizures [38] [roots] Hiedra de flores Hallucinations Ipomoea tricolor Cav. Analgesic [14] grandes [aerial parts] Fever, wound Hallucinations Turbina corymbosa (L.) Raf. Flor de pascua [4] healing [seeds] Evidence-Based Complementary and Alternative Medicine 7

Table 1: Continued.

Common name in Signs of toxicity Family Scientific name Medicinal use Reference Spanish [plant part] Hallucinations Coriariaceae Coriaria ruscifolia L. Huique Pneumonia [33] [aerial parts] Vomiting and Cucurbitaceae Apodanthera undulata A. Gray Gualaista Gastritis abdominal pain [14] [roots and seeds] Dioscorea floribunda M. Rheumatism, body Abortifacient Dioscoreaceae Barbasco amarillo [8] Martens & Galeotti pain [roots] Abdominal pain, ∗∗ Hepatotoxicity Equisetaceae Equisetum hyemale L. Carricillo urinary tract [39] [whole plant] infections Arbutus arizonica (A. Gray) Nausea and Madrono˜ Diuretic [14] Sarg. vomiting [fruit] Comarostaphylis discolor Nausea and Madrono˜ Diuretic [33] Ericaceae (Hook.) Diggs vomiting [fruit] Neurotoxicity, Kalmia latifolia L. Ivy brush Syphilis cardiotoxicity [11] [aerial parts] Acalypha monostachya Cav. Hierba del cancer Cancer Skin burns [latex] [14] Cav Adelia barbinervis Schltdl. & Dermatitis [aerial Espino blanco Body pain, wounds [8] Cham. parts] Cnidoscolus chayamansa Dermatitis [aerial ∗∗ Chaya Diabetes [8] McVaugh parts] Dermatitis [aerial Cnidoscolus souzae McVaugh Ch’iinchay Rheumatism [8] parts] Hypotension, skin Cnidoscolus urens (L.) burns, nausea and ∗∗ Ortiga Diuretic [24] Arthur vomiting [whole plant] Gastritis, excessive Croton ciliatoglandulosus Hierba de la cruz Constipation salivation [whole [4] Ortega plant] Skin burns [aerial Croton humilis L. ik’ja’aban Wounds [8] parts] Edema, dermatitis Dalechampia scandens L. Mo’ol koj Headache [11] [aerial parts] Euphorbia cotinifolia L. Lechero rojo Purgative Skin burns [seeds] [24]

∗∗ Hierba de la Skin burns [aerial Euphorbia hirta L. Stomachache [14] golondrina parts] Hierba de la Severe diarrhea, Euphorbia maculata L. Tooth ache [4] golondrina vomiting [seeds] Gastritis, ∗∗ Hierba de la Pain in the kidney, Euphorbia prostrata Aiton abdominal pain [31] golondrina wounds, diarrhea [whole plant] Euphorbiaceae Vomiting, Euphorbia pulcherrima Willd. diarrhea, ∗∗ Noche buena Wound healing [40] ex Klotzsch abdominal pain [whole plant] Irritation of the Asthma, skin mouth and throat, Euphorbia tithymaloides L. Redbird flower [20] cancer, warts vomiting [whole plant] 8 Evidence-Based Complementary and Alternative Medicine

Table 1: Continued.

Common name in Signs of toxicity Family Scientific name Medicinal use Reference Spanish [plant part] ∗∗ Hura crepitans L. Catahua Laxative Skin burns [seeds] [41] Skin burns [latex], Stomachache, body nausea and Hura polyandra Baill. Haba [15] pain, vomiting, gastritis [seeds and fruits] Dermatitis, ∗∗ Jatropha curcas L. Pinon˜ Fever, warts vomiting, diarrhea [36] [seeds, leaves] Cancer, Dermatitis, ∗∗ rheumatism, hair vomiting, muscle Jatropha dioica Sesse´ Sangre de grado [13] loss, wound paralysis [stem, healing fruits] Skin burns, ∗∗ Jatropha gossypiifolia L. Tua tua Cough, flu, fever abortifacient [42] [seeds, leaves]

∗∗ Wound healing, to Severe diarrhea Jatropha multifida L. Palmeado [43] purify blood [seeds] Poisoning and ∗∗ Wound healing, Manihot esculenta Crantz Yuca neurotoxicity [41] vermifuge [leaves] Skin burns [Aerial Tragia nepetifolia Cav. Ortiguilla Diuretic [44] parts] Dermatitis [aerial Tragia yucatanensis M i l l s p. P ’o op’ox R h e u m at i s m [8] parts] Stomachache, ∗∗ Abrus precatorius L Semilla de culebra Diabetes, asthma diarrhea [aerial [4] parts] Vomiting, fever, hypotension, Andira inermis (W. Wright) Yaba Vermifuge mental confusion, [36] Kunth ex DC. respiratory insufficiency [bark] Astragalus plattensis Nutt. Garbancillo Diuretic Vomiting [leaves] [26] Dermatitis and Caesalpinia pulcherrima (L.) ∗∗ Clavellina colorada Fever, pain, cough neurotoxicity [18] Sw. [Aerial parts] Calliandra grandiflora (L’Her.)´ Cabello de angel´ Fever Dermatitis [leaves] [45] Benth. Hepatotoxicity, Calliandra molinae Standl. Palo de corcho Hypertension hypotension [46] [leaves] Abdominal pain, nausea and Crotalaria pumila Ortega Tronador Cough, diabetes [14] vomiting [whole plant] Anoxia, gastritis, abdominal pain, Crotalaria sagittalis L. Cocuite Fever, snake bite [4] blood in feces [Aerial parts] Dalea bicolor Humb. & Bonpl. Vomiting [aerial Engordacabra Diarrhea [14] ex Willd. parts] Nausea and Diphysa robinioides Benth. Flor de gallito Fever, headache [47] vomiting [leaves] Evidence-Based Complementary and Alternative Medicine 9

Table 1: Continued.

Common name in Signs of toxicity Family Scientific name Medicinal use Reference Spanish [plant part] Abdominal pain To promote hair Entada polystachya (L.) DC. Bejuco de agua and severe diarrhea [4] growth [Fruits] Severe diarrhea Enterolobium cyclocarpum Bronchitis, sore ∗∗ Cascabel sonaja and abdominal [4] (Jacq.) Griseb. throat Fabaceae pain [Aerial parts] Immobilization, ∗∗ hypotension, and Erythrina americana Mill Colorin Diuretic [15] respiratory paralysis [seeds] Somnolence, vomit Erythrina standleyana Krukoff Cancer Cancer [8] [aerial parts] Nausea and Gliricidia sepium (Jacq.) Matarraton´ Vermifuge vomiting [roots, [24] Kunth ex Walp leaves, seeds] Yaga-cohui- Severe diarrhea Indigofera microcarpa Desv. Purgative [4] pichacha [leaves] ∗∗ Severe diarrhea Indigofera suffruticosa Mill. Anil˜ Vermifuge [4] [leaves] Leucaena esculenta (Moc. & Nausea and Guaje Wound healing [48] SesseexDC.)Benth.´ vomiting [seeds] Allergies, contact Myroxylon pereirae (Royle) Burns, wounds and ∗∗ Indian balsam urticaria and [49] Klotzsch ulcers dermatitis [resin] Seizures, Phaseolus lunatus L. Frijol ancho Fever, headache immobilization [4] [whole plant] Nausea and Prosopis juliflora (Sw.) DC. Mezquite Fever, diabetes [4] vomiting [seeds] Anorexia, hypothermia, Robinia pseudoacacia L. Black locust Diuretic, laxative [4] dyspnoea [bark, leaves and seeds] Senna multiglandulosa (Jacq.) Abortifacient Parral Diabetes [33] H.S. Irwin & Barneby [fruit] Gastritis, ∗∗ dermatitis, and Senna occidentalis (L.) Link Frijolillo Fever [4] conjunctivitis [fruit] Muscle paralysis Garryaceae Garrya ovata Benth. Cuauhchichic Diarrhea [26] [bark] Sedative, vertigo, Stomachache, Gelsemium sempervirens (L.) J. hypotension, Gelsemiaceae ∗∗ Retama asthma, headache, [10] St.-Hil. blurred vision rheumatism [whole plant] Moussonia deppeana (Schltdl. Abortifacient Gesneriaceae ∗∗ Cacahuapaxtle Diuretic, gastritis [50] & Cham.) Hanst. [aerial parts] Drummond’s false Abortifacient Hedeoma drummondii Benth. Muscle relaxing [26] pennyroyal [whole plant] Abortifacient, American Antispasmodic, Hedeoma pulegioides (L.) Pers. kidney toxicity [19] pennyroyal pneumonia [aerial parts] Cough, Abortifacient Salvia leucantha Cav Lana [27] stomachache [aerial parts] 10 Evidence-Based Complementary and Alternative Medicine

Table 1: Continued.

Common name in Signs of toxicity Family Scientific name Medicinal use Reference Spanish [plant part] Nausea and vomiting, Lamiaceae Satureja brownei (Sw.) Briq. Poleo Colic, cough dermatitis, [24] bleeding [whole plant] Giddiness, stupor, confusion, Nervousness, twitching of the Scutellaria lateriflora L. Scullcap headache, fever, [19] limbs, intermission anxiety of the pulse [whole plant] Rheumatism, Loasaceae Mentzelia hispida Willd. Pegajilla Vomiting [resin] [14] anemia Hypertension, Nausea and Psittacanthus calyculatus seizures, Loranthaceae ∗∗ Muerdago o injerto vomiting [whole [26] (DC.) G. Don rheumatism, plant] wound healing Numbness, nausea ∗∗ Cancer, wound Lythraceae Cuphea aequipetala Cav. Hierba del cancer´ and vomiting [10] healing [aerial parts]

∗∗ Nervousness, Magnoliaceae Magnolia grandiflora L. Magnolia Dermatitis [leaves] [51] menstrual colics Malpighiaceae Malpighia glabra L. Acerola Dysentery, fever Dermatitis [fruits] [19] Ceiba pentandra (L.) Diuretic, cough, ∗∗ Ceiba Dermatitis [seeds] [24] Malvaceae Gaertn. fever ∗∗ Nervousness, Hepatotoxicity Tilia mexicana Schltdl. Tilia [39] menstrual pain [flower] Anaemia, Edema, gastritis Marantaceae Thalia geniculata L. Kento [8] hemorrhoids [aerial parts]

∗∗ Nausea and Martyniaceae Martynia annua L. Una˜ de gato Snake bite [18] vomiting [seeds] Veratrum californicum Neurotoxicity ∗∗ California corn lily Cancer [11] Durand [whole plant] Melanthiaceae To prevent Trillium erectum L. Bethroot obstetric Skin burns [leaves] [19] hemorrhage Cardiotoxicity Menispermaceae Menispermum canadense L. Canada moonseed Warts [11] [fruits]

∗∗ Rheumatism, Neurotoxicity Myrtaceae Pimenta dioica (L.) Merr. Pimiento [19] stomachache [whole plant] Laxative, diarrhea, Narcotic [whole Nartheciaceae Aletris farinosa L. Unicorn root [19] rheumatism plant]

∗∗ Rheumatism, Severe diarrhea Nyctaginacea Mirabilis jalapa L Maravilla [4] stomachache, fever [roots and seeds] Oxalis alpina (Rose) Rose ex Poisoning [whole Oxalidaceae Acedera Gastritis [7] R. Knuth plant] Dermatitis, Wound healing, abortifacient ∗∗ Argemone mexicana L. Cardo santo fever, diuretic, immobilizing, [35] Papaveraceae analgesic neurotoxicity [whole plant] ∗∗ Skin cancer, polyps Sanguinaria canadensis L. Bloodroot Narcotic [root] [19] and warts Evidence-Based Complementary and Alternative Medicine 11

Table 1: Continued. Common name in Signs of toxicity Family Scientific name Medicinal use Reference Spanish [plant part] Nausea and Passiflora caerulea L. Pasionaria azul Epilepsy, anxiolytic vomiting, dizziness [24] [flower] Hallucinations, dizziness, confusion, ataxia, ∗∗ nausea and Passifloraceae Passiflora edulis Sims Maracuya Relaxing [39, 41] vomiting, drowsiness, and tachycardia; [flower] Nausea and Passiflora quadrangularis L. Badea Vermifuge, obesity vomiting, dizziness [24] [leaves and seeds] Varicose veins, Nausea and ∗∗ snake bite, wound vomiting, Petiveriaceae Rivina humilis L. Coralillo [11] healing, abdominal pain stomachache [whole plant] Blurred vision, Phytolacca americana L. Hierba carmine Warts vomit, vertigo [52] [whole plant] ∗∗ Cancer, vermifuge, Blurred vision, Phytolaccaceae Phytolacca icosandra L. Mazorquilla [14] rheumatism vomiting, [roots] Blurred vision, Phytolacca rivinoides Kunth & Headache, wound Mazorquilla vomit, vertigo [30] C.D. Bouche´ healing, vermifuge [whole plant] Diarrhea, ∗∗ stomachache, Hepatotoxicity Plantaginaceae Scoparia dulcis L. Culantrillo [39] asthma, [whole plant] nervousness Skin burns, Diabetes, wound Plumbaginaceae Plumbago pulchella Boiss. Jiricua vomiting [whole [14] healing plant] Monnina schlechtendaliana D. Nausea and Aguacatillo Dehydration [33] Dietr. vomiting [fruit] Polygalaceae Polygala senega L. rattlesnake root Cough, diuretic Gastritis [roots] [19] Vomiting, ∗∗ Rumex hymenosepalus Torr. Canaigre Wound healing abdominal pain [19] [Aerial parts] Headache, Arthritis, vomiting, delirium, Actaea alba (L.) Mill. White cohosh rheumatism, [19] circulatory failure dysmenorrhea [whole plant] Vomiting, abdominal pain, Actaea rubra (Aiton) Willd. Baneberry Dysmenorrhea [11] salivation [fruits and roots] Salivation, Body pain and abdominal pain, Anemone canadensis L. Meadow anemone [11] wound healing and salivation [whole plant] To manage some Vomiting, Cimicifuga racemosa (L.) ∗∗ Baneberry symptoms of abdominal pain [19] Nutt. menopause [fruit] Ranunculaceae Rheumatism, Clematis dioica L. Barba de chivo Skin burns [leaves] [10] cough, diuretic 12 Evidence-Based Complementary and Alternative Medicine

Table 1: Continued.

Common name in Signs of toxicity Family Scientific name Medicinal use Reference Spanish [plant part] For skin disorders Dizziness, (sores, cuts), Clematis virginiana L. Old man’s beard confusion, profuse [19] itching and salivation [leaves] venereal eruptions Gastritis, ∗∗ Hydrastis canadensis L. Sello dorado Laxative abortifacient [35] [rhizome] Ranunculus geoides Humb. Skin burns [seeds Pata de leon´ Cough [30] Bonpl. & Kunth ex DC and fruits] Nausea and Thalictrum strigillosum Hemsl. Hierba del zorro Cough vomiting [whole [7] plant] humboldtiana Immobilization, ∗∗ Tullidora Wound healing [53] (Schult.) Zucc. abortifacient [fruit] Immobilization Karwinskia mollis Schltdl. Capul´ın Wound healing [54] [fruit] California Gastritis [fruit and kcalifornica Eschsch Laxative [11] buckthorn bark] Spasm, nausea and Cough, diarrhea, Rosaceae Prunus serotina Ehrh. Capul´ın blanco vomiting [leaves [7] abdominal pain and seeds] Carapichea ipecacuanha Rhinitis or asthma Ipecac Dysentery [19] (Brot.) L. Andersson [whole plant] Vomiting, seizures, Cephalanthus occidentalis L. Guayabillo Fever [4] anemia [bark] Hypoglycemia, Rubarwiaceae hematologic disorders, Malaria, varicose ∗∗ urticaria, contact Cinchona pubescens Vahl Quino veins, internal [19] dermatitis, and hemorrhoids other hypersensitivity reactions. Hepatotoxicity, Hypertension, Casimiroa edulis La Llave & peptic ulcer, ∗∗ Matasanos diabetes, [46] Lex. hypotensive rheumatism [leaves] Rutaceae Dermatitis, ∗∗ Ruta chalepensis L. Ruda Analgesic abortifacient [18] [aerial parts] Zanthoxylum fagara (L.) Sarg. Colima Nervousness Narcotic [leaves] [26] Nausea and Phoradendron bolleanum Muerdago Diuretic vomiting [leaves [55] (Seem.) Eichler and seeds] Nausea and Phoradendron quadrangulare vomiting, Muerdago Cancer [ [11] Santalaceae (Kunth) Griseb. dehydration aerial parts] Nausea and vomiting, Phoradendron serotinum ∗∗ Muerdago Cancer, diabetes abdominal pain, [11] (Raf.) M.C. Johnst. dehydration [aerial parts] Evidence-Based Complementary and Alternative Medicine 13

Table 1: Continued.

Common name in Signs of toxicity Family Scientific name Medicinal use Reference Spanish [plant part] ∗∗ Sapindaceae Sapindus saponaria L. Jaboncillo Diuretic Skin burns [seeds] [24] Nausea and Pouteria sapota (Jacq.) H.E. Sapotaceae ∗∗ Zapote To eliminate louse vomiting, dizziness [35] Moore & Stearn [seeds] Neurotoxicity Scrophulariaceae Buddleja marrubiifolia Benth. Azafran de campo Diuretic [26] [seeds] Stomachache, Hypotension Picrasma excelsa (Sw.) Planch. Palo Amarillo [35] diabetes [bark] Simaroubaceae Hepatotoxicity Castela tortuosa Liebm. Chaparro amargo Fever, amebas [37] [stem] Gastritis [whole aristolochiifolia Mill. Zarzaparilla Syphilis, psoriasis [19] plant] Dermatitis by rubbing or gastritis, ∗∗ Capsicum annuum L. Chile Analgesic hemorrhoids, and [35] colitis by oral administration [seeds, fruits] Nausea and Cestrum fasciculatum Hierba del perro Vomiting vomiting, dizziness [10] (Schltdl.) Miers [aerial parts] tachycardia, Headache, dyspnea, fever, Cestrum nocturnum L. Dama de noche [4] stomachache hallucinations [leaves] Narcotic, anorexic, ∗∗ Diabetes, asthma, cardiotoxicity, Datura inoxia Miller. Toloache [15] wound healing blurred vision [seeds] Solanaceae Dermatitis, ∗∗ Headache, wound vomiting, severe Solanum americanum Mill Quelite mora [29] healing diarrhea, paralysis [fruits] Dermatitis [whole Solanum elaeagnifolium Cav. Trompillo Rattlesnake bite [13] plant] Narcotic, Solanum mammosum L. Chichigua Diuretic, cough cardiotoxicity [35] [fruits] Solanum nigrescens M. Immobilization ∗∗ Hierba mora Fever, rheumatism [7] Martens & Galeotti [leaves and seeds] Diuretic, Dermatitis [aerial Solanum rostratum Dunal Duraznillo stomachache, [13] parts] diarrhea Nausea and Witheringia solanacea L’ H er´ . Merengena To purify blood vomiting [leaves [47] and seeds] Diuretic, Urera baccifera (L.) Gaudich. Dermatitis, edema ∗∗ Ortiga brava rheumatism, body [11] ex Wedd. [aerial parts] Urticaceae pain Diabetes, Skin burns [aerial Urtica mexicana Liebm. Ortiga [10] rheumatism parts] 14 Evidence-Based Complementary and Alternative Medicine

Table 1: Continued. Common name in Signs of toxicity Family Scientific name Medicinal use Reference Spanish [plant part] Nausea and To purify blood, Duranta repens L. Mohuite de huerto vomiting, seizures [4] fever [flowers] Hepatotoxicity, Stomachache, Verbenaceae ∗∗ Hierba de San nausea, and Lantana camara L. diarrhea, [52] Pedro vomiting [aerial rheumatism parts] Vertigo, Cough, diarrhea, Lippia dulcis Trevir. Hierbabuena dulce hypotension [aerial [18] stomachache parts] Rheumatism, ∗∗ Hepatotoxicity Larrea divaricata Cav. Chaparral tuberculosis, snake [56] [aerial parts] bite Hepatotoxicity, Zygophyllaceae nausea and Larrea tridentata (DC.) vomiting, ∗∗ Gobernadora Diabetes, diuretic [37] Coville abortifacient, gastritis [aerial parts] ∗∗ indicates plant with toxicological information obtained from preclinical or clinical studies.

4. Toxicology the ethanol extract of Pimenta dioica leaves [89], and the hydroalcoholic extract of Sanguinaria canadensis whole plant 4.1. In Vitro Studies. The Artemia salina (brine shrimp) bio- [90]. None of the plant extracts or compounds included in assay has been widely used for the analysis of acute tox- this review were considered highly toxic (LC50 < 10 𝜇g/ml). icity in vitro. Although there are no range values to con- sider an extract or compound as toxic in the brine shrimp test, vincristine, the positive control for toxicity, has a lethal 4.1.1. Cytotoxicity. Other plant extracts and their compounds have been tested in other in vitro models, including cytotoxic- concentration 50 (LC50)=0.91𝜇g/ml [76]. Considering this ity test in nontumorigenic cells, genotoxicity using the comet value, plant extracts or compounds with LC50 values 1000- fold higher than vincristine could be considered nontoxic. assay on lymphocytes, and the mutagenic test using lympho- The following plant extracts have been tested for their in cytes or Salmonella spp. The positive controls for cytotoxicity in nontumorigenic cells include cisplatin and Taxol. These vitro toxicology using the brine shrimp test and had LC50 values higher than 1000 𝜇g/ml. The ethyl acetate fraction of compounds have inhibitory concentration 50 (IC50)values ranging from 0.1 to 4 𝜇g/ml [91]. Some plants extracts have Solanum nigrescens aerial parts [77], the ethanol extract of > 𝜇 Ambrosia peruviana whole plant [78], the aqueous extract of been reported to lack cytotoxic effects (IC50 250 g/ml) Jatropha gossypifolia aerial parts [79], the methanol extract of in nontumorigenic cells. These include the ethanol extract Jatropha dioica leaves [80], the aqueous extract of Cnidoscolus of Phoradendron serotinum leaves tested on peripheral blood urens whole plant [79], the ethanol extract of Crescentia cujete mononuclear cells [91], the aqueous extract of Cnidoscolus fruits [81], the aqueous extract of Enterolobium cyclocarpum chayamansa leaves on baby hamster kidney (BHK) cells [92], bark [82], and the ethanol extract of Cordia dentata leaves and and the aqueous extract of Enterolobium cyclocarpum bark their fractions [83]. assayed on 3T3 murine preadipocytes [82]. Additionally, the The plant extract and compounds that could be con- ethanol extract of Equisetum hyemale aerial parts evaluated on rabbit corneal fibroblasts (SIRC) [93], the methanol sidered dangerous (LC50 = 100–1000 𝜇g/ml) include the following: methanol and hexane proportions derived from extract of Enterolobium cyclocarpum leaves evaluated on Vero a hexane extract of Gymnosperma glutinosum aerial parts cells (obtained from kidney epithelial cells extracted from the [84], the ethyl acetate extracts of Monstera deliciosa branches African green monkey (Cercopithecus aethiops) [88], and the [85], and icosandrin, a cyclic homoflavonoid isolated from diterpene ent-kaur-16-en-19-oic acid, obtained from Annona Phytolacca icosandra [86]. cherimola, tested on rat embryo primary striatal cultures The plant extract and compounds that could be con- [94]. On the other hand, the hydroalcoholic extract of Hura crepitans leaves had an IC50 =107.7𝜇g/ml in lung fibroblasts sidered toxic (LC50 =10–100𝜇g/ml) include the following: the ethyl acetate extracts of Monstera deliciosa leaves [85], [95]. the ethanol extract of Solanum americanum fruits [87], the ethanol extract of Scoparia dulcis aerial parts [76], the 4.1.2. Mutagenicity and Genotoxicity. Regarding mutagenic- methanol extract of Enterolobium cyclocarpum leaves [88], ity, parthenin, isolated from Parthenium hysterophorus, Evidence-Based Complementary and Alternative Medicine 15

lacked mutagenicity (0.19 to 19 𝜇M) but showed chromo- The following extracts have shown LD50 > 2000 mg/kg somal aberrations at concentrations of 10–60 𝜇M in blood p.o. in rats: aqueous extract of Pouteria sapota seeds [122], lymphocytes [96]. These results suggested genotoxic effects methanol extract of Martynia annua leaves [123], ethanol of parthenin. A methanol extract of Indigofera suffruticosa extract of Flourensia cernua leaves [124], aqueous extract of aerial parts (1.25–7.5 mg/plate) showed mutagenic activity Enterolobium cyclocarpum bark [82], ethanol and aqueous in a Salmonella microsome assay [97]. The acetone ex- extract C. pulcherrima aerial parts [125], aqueous extract tract of Heliopsis longipes roots (10–80 𝜇g/Petri dish) and its of Passiflora edulis leaves [126], hydroalcoholic extract of active compound affinin (6.25–50 𝜇g/Petri dish) were not Magnolia grandiflora seeds [127], and ethanol extract of Cres- mutagenic, as evaluated by the Ames test [98]. Lobeline centia cujete fruits[128].Thesamepatternwasalsoshown (5–10 mg/kg i.p.), an alkaloid isolated from Lobelia inflata, in methanol extracts of leaves of Amaranthus spinosus [129], had no genotoxic or mutagenic effects in the comet assay, and Rauvolfia tetraphylla [130], chloroform-methanol extract the micronucleus test in bone marrow, or the Salmonella/ of Cnidoscolus chayamansa leaves [131], aqueous extract of R. microsome mutagenic assay [99]. humilis fruits [132], a chloroform fraction from an ethanol extract of Tagetes erecta flowers [133], aqueous extract of For genotoxicity, the ethyl acetate/n-hexane extract of Karwinskia humboldtiana seeds [134], and hydroalcoholic Zinnia peruviana aerial parts tested using 5 and 20 mg/ml extract of Senna occidentalis aerial parts [135], as well as extracts showed genotoxic effects in PBMC compared to luteinandluteinester,obtainedfromTagetes erecta [136], and the positive control of copper sulfate (1%) [100]. A butanol ethanol extract of Jatropha gossypiifolia aerial parts [137], and fraction of Urera baccifera roots at a 1.8 mg/g concentration aqueous extract of Caladium bicolor [138]. of oxalic acid decreased leukocyte number significantly and Other plant extracts showed LD50 > 2000 mg/kg i.p. in increased cell death and DNA damage in primary cultures mice: hexane extract of Tilia mexicana inflorescences [139], of leukocytes in comparison to the control treatment [101]. aqueous extract of Tagetes lucida aerial parts [140], ethanol The methanolic extract of Psittacanthus calyculatus aerial extract of Mirabilis jalapa aerial parts [141], and aqueous parts (200 and 400 mg/kg i.p.) did not induce chromosomal extract of Urera baccifera leaves [142]. damage in peripheral blood erythrocytes obtained from mice Some plant extracts and plant compounds had LD50 val- after 72 h of exposure [102]. An ethanol extract of Heliopsis ues from 300 to 2000 mg/kg, which is considered dangerous longipes roots (3–100 mg/kg p.o.) did not produce geno- [104]. These plant extracts were intraperitoneally adminis- toxic or cytotoxic effects on peripheral blood mononuclear tered to mice: the ethanol extract of Tagetes lucida aerial parts cells obtained from mice 24–96 h after administration [103]. (LD50 = 970 mg/kg) [140], the aqueous extract of Caladium Parthenin, isolated from Parthenium hysterophorus,showed bicolor leaves (LD50 = 1778.28 mg/kg) [138], and the ethanol genotoxic effects at 4–31 mg/kg i.p. in micronuclei in mouse extract of Tagetes lucida aerial parts (LD50 = 970 mg/kg i.p.) peripheral blood after 48 and 72 h of treatment [96]. [140]. On the other hand, the ethanol extract of Phoradendron serotinum leaves had an LD50 =375mg/kgp.o.inmice[143], 4.2. In Vivo Acute Studies and sanguinarine, an alkaloid isolated from Sanguinaria canadensis,hadanLD50 = 1658 mg/kg p.o. in rats [144]. 4.2.1. Lethal Dose 50 (LD50). The guideline 423 of the Organi- Methanol extracts of Tilia mexicana inflorescences had 50LD zation for Economic Cooperation and Development (OECD) values of 375 mg/kg i.p. in mice [139]. establishesthatsubstanceswithanLD50 < 5 mg/kg are highly Other plant extracts and plant compounds had LD50 toxic, whereas LD50 values from 5 to 50 mg/kg are very toxic, values varying from 50 to 300 mg/kg, which is considered LD50 values from 50 to 300 mg/kg are toxic, LD50 values from toxic [104]. Ethanol extract of Phoradendron serotinum leaves 300 to 2000 mg/kg are dangerous, and LD50 values higher had an LD50 = 125 mg/kg i.p. in mice, [143], whereas capsaicin, than 2000 mg/kg are not dangerous [104]. themainactiveprincipleofCapsicum annum,hadanLD50 = Some plant extracts showed LD50 > 2000 mg/kg p.o. in 190 mg/kg p.o. [145]. The acetone extract of Heliopsis longipes mice:ethanolextractsofleavesofCasimiroa edulis [105] and roots had an LD50 =62.14mg/kgp.o.inmice,whereasits Cnidoscolus chayamansa [106], ethanol extracts of aerial parts active compound affinin had an LD50 = 113.13 mg/kg p.o. in of Moussonia deppeana [107], Equisetum hyemale [93], and mice [98]. The ethanol extract of Heliopsis longipes roots had Ruta chalepensis [108], as well as methanol extracts of leaves an LD50 =288mg/kgp.o.inmice[103]. of Chenopodium ambrosioides [109] and Rauvolfia tetraphylla The following plant extracts and compounds can be con- [110]. The same pattern was also shown in aqueous extract sidered very toxic (5–50 mg/kg) [104]: the free alkaloid frac- of Cuphea aequipetala aerial parts [111], ethanol extract of tion in hexane and methanol extracts from Erythrina ameri- Plumeria rubra flowers [112], aqueous extract of Larrea divar- cana seeds (LD50 = 38.54 to 40.37 mg/kg i.p.) in mice [146], icata leaves [113], ethanol extract of Caesalpinia pulcherrima Jatropha curcas oil (LD50 = 23.34 mg/kg p.o.) in mice [147], leaves and bark [114, 115]. aqueous extract of Euphorbia and 𝛼-solamargine, isolated from Solanum americanum,with prostrata whole plant [116], aqueous-methanol extract of an LD50 = 42 ± 2 mg/kgi.p.inrats[148].ThealkaloidN- Ceiba pentandra leaves [117], petroleum ether, chloroform, methylisocorydinium, obtained from Magnolia grandiflora and methanol extracts of Gelsemium sempervirens roots [118], trunkwood,hadanLD50 = 10 mg/kg i.p. in mice [149] and 𝛾- acetone extract of Capsicum annum fruits [119], and aqueous coniceine, isolated from Conium maculatum,hadanLD50 = and ethanol extract of Scoparia dulcis leaves and whole plant 12 mg/kg p.o in mice [150]. Parthenin, the toxic compound of [120, 121]. Parthenium hysterophorus,hadanLD50 = 42 mg/kg i.p. in rats 16 Evidence-Based Complementary and Alternative Medicine

[151]. Capsaicin had an LD50 = 8 mg/kg i.p. and 7.80 mg/kg The number of fetal resorptions was also increased, and the i.m in mice [152]. Sanguinarine, an alkaloid isolated from fetuses showed skeletal malformations [162]. Additionally, Sanguinaria canadensis, was toxic at 29 mg/kg i.v. in rats an aqueous extract of R. chalepensis leaves (0.8 and 1.6 g/kg [144]. p.o.) administered to mice from day 1 to day 14 post The following plant compounds had50 LD values < coitum caused perinatal changes in mice such as righting 5 mg/kg, which is considered highly toxic [104]. Capsaicin reflex, cliff avoidance, and swimming ability, among others had an LD50 = 0.56 mg/kg i.v. [152]. [163].

4.2.2. Biochemical and Hematological Parameters. Treatment 4.2.4. Dermal Tests. An aqueous extract of Pouteria sapota with plant extracts in short-term studies have effects on seeds lacked dermal irritation in rabbits and showed mild biochemical and hematological parameters, as well as the lev- reversible eye irritation in rabbits [122]. Jatropha multifida sap els of the hepatic enzymes alanine aminotransferase (ALT), did not induce skin lesions in rats after 14 days of treatment aspartate aminotransferase (AST), and alkaline phosphatase [164]. A diethyl ether extract of Jatropha multifida showed the (ALP). An aqueous extract of Larrea divaricata aerial parts presence of 16-hydroxyphorbol. This compound showed an (0.5–200 mg/kg i.p.) did not affect the levels of ALT in irritant dose 50 (ID50)of0.05𝜇g/ear [165]. mice after 2 days [153]. Aqueous extract of Karwinskia humboldtiana fruits (1250 mg/kg p.o.) administered to rats for 4.3. In Vivo Subacute and Chronic Studies 3 days increased the levels of hepatic enzymes compared to the untreated group [154]. An aqueous extract of Passiflora 4.3.1. Biochemical and Hematological Parameters. Some plant edulis (30 mg/kg p.o.) did not affect motor coordination in extracts and their active compounds have been tested for mice or change the biochemical measurements in serum after their effects on biochemical and hematological parameters in 4days[155].𝛼-Solamargine (15–35 mg/kg i.p.) did not affect rodents for at least 18 days of exposure. A histological study hematological parameters or the levels of hepatic enzymes has also been included in some reports. A hydroalcoholic in rats after 5 days [148], whereas an aqueous extract of extract of Senna occidentalis aerial parts (100–2500 mg/kg Karwinskia humboldtiana fruit (5000 mg/kg p.o.) in rats for p.o.) [135] and a hydroalcoholic extract of Sapindus saponaria 5daysinducedweightloss(15%)inrats,aswellastoxicity leaves (44.76 mg/kg p.o.) and fruits (45.0 mg/kg p.o.) [166] inthepancreas[156].AnaqueousextractofPassiflora edulis did not change the biochemical profile or hematological leaves (100–400 mg/kg p.o.) did not affect organ body weight parameters or alter body weight and organ weight for 30 or hematological parameters but decreased the levels of ALT days in rats. An ethanol extract of the pod of Plumeria rubra in rats after 7 days of treatment at all doses [126]. A methanol (50–200 mg/kg p.o) [167] and an aqueous-methanol extract extract of R. tetraphylla leaves (1000 mg/kg p.o.) decreased of Ceiba pentandra leaves (250 and 500 mg/kg p.o.) [117] did body weight change and food consumption and increased not alter hematological or biochemical parameters in rats and total bilirubin in rats after 7 days [157]. An aqueous extract mice, respectively, after 21 days [167]. A chloroform-methanol of K. humboldtiana (1000–2000 mg/kg p.o.) administered for extract of Cnidoscolus chayamansa leaves (1000 mg/kg p.o.) 7daysinratsinducedalterationsinmembranefluidityand [131] and an ethanol extract of Moussonia deppeana aerial ATPase activity in liver submitochondrial particles [158]. An parts (1000 mg/kg p.o.) [107] did not affect biochemical or ethanol extract of Euphorbia hirta leaves (60.4–483 mg/kg hematological parameters in mice after 28 days of daily i.p.) [159] and a chloroform fraction from an ethanol extract administration. In addition, histological examinations of the of Tagetes erecta flowers (200–400 mg/kg p.o.) [133] did not spleen, kidney, and liver showed no abnormalities. Capsaicin affect hematological or biochemical parameters in rats after (5–100 mg/kg p.o.) [168], obtained from Capsicum annum, 14 days. An aqueous extract of Euphorbia hirta whole plant and lutein and lutein ester (4–400 mg/kg p.o.) [136], obtained administered at a single dose of 2000 mg/kg p.o. significantly from Tagetes erecta, did not affect hematological or bio- decreased the levels of ALP and ALT after 14 days in broiler chemical parameters, growth, food consumption, or body chickens [160]. Lobeline (5–10 mg/kg i.p.) did not affect the weight in mice and rats, respectively, after 28 days. An aque- levels of AST, ALT, ALP, and LDH after 4 days of exposure ous extract of Rivina humilis fruits (2500 and 5000 mg/kg [99]. p.o.)administereddailyfor35daysshowednochangesin the hematological profile or in the relative organ weight, 4.2.3. Toxicity to Reproduction and Pregnancy. 𝛼-Solamar- whereas the same extract administered daily for 90 days at gine (15–35 mg/kg i.p.) did not affect the number of sperma- 0.5–2 g/100 g in a powdered diet did not affect hematological tozoa or the weight of the testicles and epididymis of male parameters, biochemical determinations, or the levels of rats after 24 h of treatment [148]. Jervine (70–300 mg/kg p.o.), hepatic enzymes [132]. a steroidal alkaloid found in Veratrum californicum,admin- In contrast, some plant extracts have altered biochemical isteredondays8–10ofgestationinducedmalformations and/or hematological parameters. An aqueous extract of in the offspring, including isolated cleft palate, mandibular Abrus precatorius leaves (400–1600 mg/kg p.o.) was adminis- micrognathia, and limb malformations in C57BL/6J and tered to rats for 18 days. Only the highest dose (1600 mg/kg A/J mice [161]. The administration of an aqueous extract p.o.) decreased levels of hematological parameters and of Ruta chalepensis leaves (10 mg/kg p.o.) to pregnant rats increased the levels of hepatic enzymes [169]. An aqueous from day 9 to day 17 of gestation decreased the uterine extract of Scoparia dulcis leaves (250–500 mg/kg p.o.) showed weight, the number of live fetuses, and the fetal weight. mild vascular and portal congestion in the heart and the Evidence-Based Complementary and Alternative Medicine 17 liver, respectively, of rats treated daily with this extract Those cases that report hepatic damage were also eval- for 30 days. Nevertheless, there were effects in the lungs uated using the method proposed by the Council for Inter- and testis [120]. A methanol extract of Rauvolfia tetraphylla national Organizations of Medical Sciences/Roussel Uclaf leaves did not affect hematological parameters. However, a Causality Assessment Method (CIOMS/RUCAM) [178], significant decrease in the total bilirubin and glucose levels which is an organospecific instrument designed for the was observed in the mice treated at 100 and 300 mg/kg, with a assessment of hepatotoxicity. This method evaluates the tem- significant increase in triglycerides at doses of 10–300 mg/kg poral relationship between the consumption of a substance after 28 days in mice [130]. An ethanol extract of the aerial (drug or natural remedy) and the appearance of hepatic parts from Jatropha gossypifolia (135 mg/kg p.o. or higher damage, the absence or presence of risk factors, the exclusion doses) reduced the activity in the central nervous system of alternative causes of liver injury, among others. The sum − and showed hepatotoxicity, pulmonary damage, and digestive of the scores leads to a final score between 8 and 14 points, disturbances in rats over 13 weeks of treatment [170]. The which results in the following categories: highly probable lethality was 46.6% and 13.3% among male and female or definite, probable, possible, or excluded. The amount of information of each clinical case considered for this review rats under the highest tested dose (405 mg/kg), respectively was classified as enough (number of criteria: 5-6), regular [170]. (number of criteria: 3-4), and poor (number of criteria: 1-2). Thefollowingcriteriawereusedtoevaluatetheamountof 4.3.2. Toxicity during Reproduction and Pregnancy. Yao et al. information: (1) clear information regarding the intake and [171] reported that an aqueous extract of Hydrastis canaden- timeelapsedfortheonsetofsymptoms,(2)informationofthe sis (1.86 g/kg p.o.) containing 9.6 mg/ml of berberine and dose ingested, (3) explanation and clinical management of the 8.4 mg/ml of hydrastine did not affect fetal development in intoxication, (4) information for the exclusion of other causes pregnant rats over 20 days of treatment. A Prosopis juliflora that might induce the toxic effect, (5) information of the seedcase added at 70% to the diet of pregnant rats resulted withdrawal of the plant substance, and (6) time of recovery to be teratogenic (13-fold) compared to the untreated group from the toxicity or death of the patient. [172]. Aqueous and ethanol extracts of Plumeria rubra pods The toxicity presented in clinical cases was mainly due (200 mg/kg p.o.) had 51% and 100% abortifacient activity, to the accidental consumption of toxic medicinal plants, respectively, in female albino rats from day 11 to day 15 especially by children. In all the cases, the toxic effects of pregnancy [173]. The hydroalcoholic extract of Lantana occurred after the administration of the plant. The symptoms camara leaves (1000–7000 mg/kg p.o.) administered during of toxicity were confirmed using objective evidence. None premating, mating, pregnancy, and lactation (56 days in of the reports provided information about the presence of total) in rats did not affect mating, pregnancy, delivery, similar toxic effects compared to a previous experience. and live birth. Nevertheless, the two highest doses tested Improvement of symptoms occurred in some cases (i.e., [58, (3000 and 7000 mg/kg p.o.) produced an increase in the 62–64, 69, 71, 72]). The information about the number of resorption rate and parallel increases in the postimplantation ingestion with the plant is only reported in some cases (i.e., loss index, as well as embryotoxicity characterized by skeletal [43, 57, 59, 60, 65, 67, 70]). abnormalities [174]. 4.4.1. Case Series. Krenzelok et el. [179] gathered information 4.3.3. Carcinogenicity. Only one plant extract has been tested about Euphorbia pulcherrima exposure during an 8-year period in the United States of America. The results showed for its carcinogenic effects. Rats (treated with doses ranging that children accounted for 93.3% of cases of exposure, which 136–1175 mg/kg p.o.) and mice (treated with doses ranging were accidental (98.9% of cases) and by ingestion (94.5% 375–3275 mg/kg) received an aqueous extract of Hydrastis of cases). No deaths were reported. However, this study did canadensis root for 2 years (106 weeks). At the end of the treat- notreportthesymptomatology.ThetoxicityofCimicifuga ment, the doses of 1175 mg/kg in rats and the doses varying racemosa has been extensively studied. The reviews of Borrelli from 1120 to 3275 mg/kg in mice showed hepatocarcinoma and Ernst [180] and Teschke et al. [181] can be consulted for [175]. more information regarding the adverse effects of Cimicifuga racemosa in other clinical cases. The prevalence of allergy 4.4. Clinical Cases. The toxicity of sixteen species plants has to Myroxylon pereirae resin has been reported in many been reported in clinical cases. Fourteen of the sixteen plants countries, ranging from 5.4 to 11.8% (i.e., [49, 182–185]). From are enlisted in Table 2. The other two plants are described in a total of 27815 patients recorded over 5 years in Croatia, Section4.4.1.TheNaranjoalgorithm[176],whichconsistsof 8.4% were positive to contact dermatitis upon exposure to 10 questions that address the factors considered to determine Myroxylon pereirae bark [186]. In another case, the prevalence the causal relationship in case reports, was used to assess of toxicity by medicinal plants was also reported. Jatropha causality. A score is obtained (maximum 13) and the results curcas, Andira inermis,andCanella winterana were the third, are classified as doubtful or unlikely (0), possible (from 1 the fourth, and the fifth most cited plant species, respectively, to 4), probable (from 5 to 8), and clear or definite (socre associated with cases of toxicity in from 1998–2007 [36]. > 9). The event must be definitive from a pharmacological Eddleston et al. [187] reported 351 patients with a history or phenomenological point of view, using, if necessary, a of T. peruviana consumption for 2 years. No deaths were conclusive procedure of reexposure [177]. reported. 18 Evidence-Based Complementary and Alternative Medicine [60] [61] [43] Reference s toxic. ND [57] excluded due to lead (postmortem) (postmortem) poisoning and Encephalopathy Alternate causes Thalassemia and Thalassemia and sickle cell disease sickle cell disease organophosphates (days) (6 hours) Outcome Recovered Regular Fatal (4) Regular Fatal (11) Regular Recovered (6) ND [58] Regular Recovered (1) ND [59] Enough Fatal (3) Enough Recovered (5) ND Enough Recovered (5) ND Amount of information ND Regular probable probable probable probable probable Probable Probable Naranjo (5): Naranjo (5): Naranjo (5): Naranjo (6): Naranjo (6): Naranjo (6): Naranjo (6): Evaluation of causality (score) ND ND ND apnea Hepatic Hepatic Clinical enzymes enzymes Seizures, elevation elevation Difficulty breathing periods of al cases of medicinal plants from Mexico and Central America considered a complications Fever (40%) Diarrhea (50%) Vomiting (95%) Headache (40%) (ND) (ND) hours) dysfunction Toxic effects Multiple organ syndrome (ND) Central nervous Central nervous the toxic effects) Epidemic dropsy (onset, in days, of Gastroenteritis (1) Gastroenteritis (1) system depression system depression (3 (20) 1-2 h and swelling diarrhea, and diarrhea, and of breath (20) First symptoms speaking (0.5 h) depression (3 h) Abdominal pain, Abdominal pain, Vomiting, watery Vomiting, watery (onset, in days, of Headache, blurred Drowsiness (0.5 h) loos of movements Vomiting and CNS the first symptoms) fever, and shortness vision, and difficulty abdominal pain (1 h) abdominal pain (1 h) throughout the body Oral: Oral: Oral: oil ND Oral: oil 1–4 seeds indicated > 10 fruits ascaridol) plant), ND Plant, way of Chenopodium consumption if 80 ml (1,560 mg consumed, time of Conium maculatum Argemone mexicana Conium maculatum, and part of the plant administration, dose (piperidina 850 Ug/g Jatropha curcas, ambrosioides, Jatropha multifida Table 2: Evaluation of causality and exclusion of alternate causes in clinic 10, M, India Information of the patient (age, gender, country of residence) 9, M, Israel 20 children; 8–13 years old, India 4, M, United States of America 19,F,Turkey 5, M, India 2, F, Mexico 8, M, Israel Evidence-Based Complementary and Alternative Medicine 19 [63] [65] [62] [67] Reference ND ND ND [66] ND [64] ND factor normal excluded discarded antibodies Poison ivy [68] serology of Antinuclear anesthesia not or vascular risk Hepatic disease, Alternate causes Previous cesarean negative hepatitis, No cardiac history (1) (14) (90) (90) (90) (120) (ND) (days) Outcome Recovered Recovered Recovered Recovered Recovered Recovered Recovered Poor Poor ND Regular Regular Regular Regular Recovered (3) Regular Recovered (2) ND Enough Enough Amount of information ND Regular Possible Possible Possible Possible probable probable probable probable Probable Probable Naranjo (5): Naranjo (3): Naranjo (5): Naranjo (3): Naranjo (3): Naranjo (5): Naranjo (7): Naranjo (4): Naranjo (6): RUCAM (6) Evaluation of causality (score) (Hepatocellular) ND ND ND ND Clinical weakness abdominal respiratory and muscle neuropathy toxicity and bradycardia bradycardia diaphoresis, Tachycardia, Neurological Hypokalemia complications complications pain, vomiting and peripheral Hyperkalemia, Table 2: Continued. < 1) Blebs (2%) Papules (4%) Vesicles (60%) Erythema (95%) ( < 1) (42) (90) block (1) block (1) peripheral dysfunction dysfunction Toxic effects hepatitis (21) Autoimmune syndrome ( Multiple organ Multiple organ syndrome (ND) neuropathy ( < 1) Atrioventricular Atrioventricular the toxic effects) Nicotinic toxicity (onset, in days, of Hypokalemia and Cutaneous vasculitis Cutaneous vasculitis ND ND ND ND ND (14) Ulcers (ND) diarrhea, and First symptoms Vomiting, watery (onset, in days, of her left foot (ND) Painful nodules on the first symptoms) Lethargy and fatigue abdominal pain (7 h) ND 1–4 ND = 1.88 g) indicated Oral: seeds Oral: leaves Plant, way of Caulophyllum Oral: capsules Oral: capsules Oral: infusion consumption if resin in tincture thalictroides, consumed, time of Thevetia peruviana Topical; 25% of the Topical; 20% of the Cinchona pubescens Cinchona pubescens more specifications) and part of the plant Cimicifuga racemosa administration, dose Cimicifuga racemosa, Cimicifuga racemosa, Podophyllum peltatum (80 mg/day/2 months) (80 mg/day/4 months) Podophyllum peltatum, resin in tincture (7.5ml Oral: capsules (without Metopium brownie, 54,F,United States of America Information of the patient (age, gender, country of residence) 64,F,United States of America 57, F, United States of America 16, F, United States of America 18, F, United Kingdom 21, F, United States of America 40, M 20 patients: 9–50 years old, Mexico 75, F 25, F 20 Evidence-Based Complementary and Alternative Medicine [71] [72] [70] [69] Reference ND, abuse) excluded nephritis, substances serology of glomerular and dengue Hepatic disease, Alternate causes poisoning, acute (cytomegalovirus viral myocarditis, history of alcohol intentional intake intake, and intake Organophosphate negative hepatitis, of other unknown positive, ingestion ofotherplantsand Methamphetamine (4) (21) (days) Outcome Recovered Recovered Regular ND Enough Enough Enough Recovered (3) Enough Fatal (4) Amount of information Possible Possible Possible probable Probable Probable Naranjo (5): Naranjo (5): Naranjo (5): Naranjo (4): Naranjo (4): RUCAM (4): Evaluation of causality (score) (Hepatocellular) ND ND and failure disease Clinical Early renal respiratory Seizures and hypokalemia parenchymal complications hyponatremia, Hepatic failure, Table 2: Continued. ( < 1) (ND) Idiopathic Idiopathic intracranial intracranial intoxication Toxic effects associated with Anticholinergic Hepatic damage hypertension (1) the toxic effects) hypertension (6) hypertension (4) (onset, in days, of Pulmonary edema (ND) diarrhea, and diarrhea, and First symptoms abdominal pain Vomiting, watery Vomiting, watery (onset, in days, of Incoherences and abdominal pain (5) hallucination (ND) the first symptoms) Gastrointestinal (4) Gastrointestinal (20) Oral: Oral: Oral: Oral: ,Oral: seeds 1 seed 7 seeds 10 seeds indicated 500 capsules Plant, way of consumption if consumed, time of Datura inoxia and part of the plant administration, dose (3–7/day/10 months) Abrus precatorius Larrea tridentata, Abrus precatorius, Abrus precatorius, Information of the patient (age, gender, country of residence) 27, M, United States of America 13, M, Siri Lanka 17,F,India 18, M, United States of America 28,F,India Age is given in years old; ND, not described; F, female; M, male. Evidence-Based Complementary and Alternative Medicine 21

5. General Considerations misidentification of medicinal plants, and (c) adulteration of medicinal plants. Most of the acute symptoms reported The identification of the compounds responsible for the in this review appear in the first 24 h after exposure. toxicity has been reported only in some cases. Urushiol might Nevertheless, more studies, including subacute and chronic be the compound responsible for the dermatitis reactions assays, as well as the quantitation of hepatic enzymes, should to Metopium brownei [188], whereas sanguinarine is the be performed. In other cases, such as the intoxication of compound associated with the toxicity of Argemone mexi- Crotalaria sagittalis,thetoxicsymptomsappear2to6 cana. Eddleston et al. [189] reported six fatalities in patients months after the exposure [4]. However, chronic poisoning who ingested between 1 and 10 seeds of T. peruviana.These induced by medicinal plants is not easily detected since fatalities occurred due to high concentrations of cardiac the symptoms are multiple and variable and a diagnosis glycosides (neriifolin, thevetin A, thevetin B, and olean- cannot be made. Many poisonings caused by medicinal drin) in seeds. Three toxins (T-544, T-514, and T-496) have plants are classified as of unknown origin because most of been reported in Karwinskia humboldtiana [190]. Manihot the patients deny the consumption of herbal products. For esculenta, an important dietary staple, is toxic because of instance, the clinical picture of intoxication with Karwinskia the presence of cyanogenic compounds. Linamarin, the humboldtiana might be confused with poliomyelitis [190]. predominant cyanogenic glycoside in Manihot esculenta,can In addition, in most of the cases, the plants are not taxo- be accumulated in a range of concentrations between 100 nomically identified [36]. The misidentification of medici- and 500 mg/kg in roots and leaves. The content of HCN in nal plants represents a serious problem for human health. Manihot esculenta has been reported 0.1–1 mg/g fresh weight The adulteration of medicinal plants sold as food products in the leaves [191]. Several intoxications have been described should be considered as a risk of intoxication by medicinal in humans. The clinical pattern consists of neuropathy and plants. hyperthyroidism [192]. Another aspect to consider for further studies is the The mechanism of toxicity is also unknown in many evaluation of mixtures of medicinal plants and the combi- cases. The mechanism of toxicity of Argemone mexicana oil nation of medicinal plants with allopathic medications. It might be explained by the inhibitory effects of sanguinarine is thought that the combination of medicinal plants might on Na+/K+ATPase, induction of cell membrane damage by result in higher beneficial effects compared to those found reactive oxygen species and lipid peroxidation, and inhibition with single preparations. Nevertheless, it might be the case of DNA polymerase activity, among other effects [193]. that two toxic plants are combined and their toxic effects Larrea tridentata and nordihydroguaiaretic acid, its active might result in a synergistic action. The self-medication of compound, generate acute hepatotoxicity by the inhibition of drugs along with the consumption of medicinal plants is cyclooxygenase and cytochrome P-450 [194]. a common practice among patients with chronic diseases Special attention should be given in medicinal plants [195], which can be considered as an alternative cause of such as Argemone mexicana, Chenopodium ambrosioides,and intoxication. In the clinical record, it is not indicated whether Thevetia peruviana. Effects in humans have been reported the patient consumes medicinal plants. The interaction of due the consumption of these medicinal plants. Other plant herbal extracts and drugs remains to be studied. There species, including Abrus precatorius, Capsicum annum, are few documented cases that report the toxicity of the Conium maculatum, Erythrina Americana, Heliopsis longipes, combination of plant extracts and drugs. For instance, the Hydrastis canadensis, Jatropha curcas, Jatropha gossypifolia, combination of Picrasma excelsa coumarins are reported to Karwinskia humboldtiana, Larrea tridentata, Magnolia gran- potentiate the activity of warfarin [196]. The toxicity of mix- diflora, Parthenium hysterophorus, Phoradendron serotinum, tures of medicinal plants and the combination of medicinal Plumeria rubra, Prosopis juliflora, Ruta chalepensis, San- plants with allopathic medication requires further investiga- guinaria canadensis, Solanum americanum,andVeratrum tion. californicum, have shown effects considered highly toxic, including hepatotoxicity, teratogenic, and cardiotoxicity, or 6. Conclusions with high toxicity in acute studies. Therefore, a total of 22 plants of 216 cited in this review should be extensively stud- There is limited information about the toxicity of medicinal ied in terms of their toxicity. Regarding the hepatotoxicity plants used in Mexico, Central America, and the Caribbean. induced by medicinal plants, Valdivia-Correa [39] reported The molecular mechanisms by which medicinal plants induce 15 medicinal plants commonly used in Mexican traditional toxic effects should also be addressed. In many cases, intox- medicine that induce hepatotoxicity. Five (Equisetum hye- ication by medicinal plants might be confused with other male, Tilia mexicana, Passiflora edulis,andScoparia dulcis)of diseases. The detection of intoxication with medicinal plants these fifteen medicinal are considered as toxic, according to couldbedifficultbecausethesymptomsmightbeconfused our bibliographic research. The induction of hepatotoxicity with other diseases. induced by herbal products represents a serious problem in The prevention of poisoning in humans can be avoided if Mexico since the symptoms and signs might be confused the chemical composition of medicinal plants is known. with other diseases, and the diagnosis can be incorrect [39]. Conflicts of Interest Some aspects that influence the toxicity of medicinal plants reported in this study are: (a) time of exposure, (b) The authors declare that there are no conflicts of interest. 22 Evidence-Based Complementary and Alternative Medicine

References [19] A. DerMarderosian and J. A. Beutler, “The Review of Natural Products: the most complete source of natural product infor- [1] UICN, OMS, and WWF, “Guidelines on the conservation of mation,” in editorial Facts and Comparisons,p.1672,StLouis, medicinal plants World Health Organization (OMS),” in Union´ United States of America, editorial Facts and Comparisons, Internacional para la Conservacion´ de la Naturaleza (UICN) and 2002. WorldWildlifeFund(WWF),Gland,Switzerland,1993. [20] D. W. Nellis, “Poisonous plants and animals of Florida and the [2] G. A. Taddei-Bringas, M. A. Santillana-Macedo, J. A. Romero- Caribbean,” in USA,p.321,PineapplePress,Sarasota,1997. Cancio, and M. B. Romero-Tellez,´ “Acceptance and use of ther- [21] L. Gonzalez-Ch´ evez,´ P.Hersch-Martinez, and A. Juarez-Miran-´ apeutic medical plants in family medical care,” Salud Publica´ de da, Plantas medicinales de Copalilloy Temalac, Guerrero,Insti- Mexico´ ,vol.41,no.3,pp.216–220,1999. tuto Nacional de Antropolog´ıa e Historia, Consejo Nacional de [3] Botanical and plant derived drugs, “Global markets. BCC Re- Ciencia y Tecnolog´ıa, Mexico city, Mexico, 2000. search Report BIO022G,”http://www.bccresearch.com/market- [22] P. Giovannini and M. Heinrich, “Xki yoma’ (our medicine) and research/biotechnology/botanical-plant-derived-drugs-report- xki tienda (patent medicine)-Interface between traditional and bio022g.html. modern medicine among the Mazatecs of , Mexico,” [4] A. Aguilar-Contreras and C. Zollas, Plantas toxicas´ de Mexico.´ Journal of Ethnopharmacology,vol.121,no.3,pp.383–399,2009. InstitutoMexicanodelSeguroSocial,Mexicocity,Mexico,1982. [23] S. Blair-Trujillo and B. Madrigal, “Plantas antimalaricas de [5]M.H.Royo-Marquez´ and A. Melgoza-Castillo, “Listado flor´ıs- Tucumaco, costa pac´ıfica Colombiana,”in Editorial Universidad tico del campo experimental la campana y usos de su flora,” de Antioquia,p.348,Medellin,Colombia,2005. Tecnica´ Pecuaria Mexicana,vol.39,no.2,pp.105–125,2001. [24] P. J. Salinas, “Plantas toxicas´ comunes en el estado de Merida, [6]M.E.MitreandN.Camacho,Plantas Medicinales de la Cuenca Venezuela. Segunda parte. Adoxaceae, Asteraceae, Caesalpin- Hidrografica´ del Canal de Panama´,vol.6,EditoraSibauste, aceae, Chenopodiaceae, Combretaceae, Cruciferaceae, Cycad- Panama,´ Panama, 2013. aceae, Ericaceae, Euphorbiaceae, Fabiaceae, Lamiaceae, Mal- vaceae, Moraceae, Myrtaceae, Papaveraceaea,” Revista.Facultad [7] S. Castaneda-D˜ ´ıaz, Uso de la vegetacion´ forestal fanerogamica de Medicina,vol.21,no.1,pp.26–46,2012. de San Miguel Pipillola, Tlaxcala, Mexico´ [Bachelor thesis], Uni- [25] L. O. Loreno-Medina, J. M. Rodr´ıguez-Chavez,´ and M. G. versidad Autonoma´ Chapingo, Texcoco, Estado de Mexico,´ Ramos-Espinosa, “Aprovechamiento de recursos vegetales en Mexico,´ 2013. una localidad de la reserva de la biosfera mariposa monarca, [8] J. S. Flores, G. C. O. Canto-Aviles, and A. G. Flores-Serrano, Michoacan,´ Mexico,”´ Etnobiolog´ıa,vol.2,no.1,pp.33–60,2002. “Plantas de la flora yucatense que provocan toxicidad enel [26] J. Adame and H. Adame, “Plantas curativas del noreste mex- humano,” Revista Biomedica,vol.12,no.2,pp.86–96,2001. icano,” in Ediciones Castillo, p. 347, Monterrey Nuevo Leon, [9]L.C.Navarro-Perez´ and S. Avendano-Reyes,˜ “Flora util´ del Mexico,´ 2000. municipio de Astancinga, , Mexico,” Polibotanica,vol. [27] J. Gonzalez-Rodrigo´ and J. Gonzalez-Rodrigo,´ Editorial Univer- 14, pp. 67–84, 2002. sidad Iberoamericana,vol.3,Mexico´ City, Mexico,´ 1993. [10] C. Gutierrez-B´ aez,´ Plantas utiles´ de Chiconquiaco, Veracruz,vol. [28] J. C. R´ıos, E. Par´ıs, and G. Repetto, “Intoxicaciones por plantas 19, Universidad Veracruzana, La Ciencia y el Hombre, 1995. medicinales,”in Toxicolog´ıa Alimentaria,A.M.Camean´ and M. [11] L. S. Nelson and M. J. Shih, Handbook of poisonous and injurious Repetto, Eds., pp. 212–222, Madrid, Spain, 2012. plants, New York Botanical Garden, Springer-Verlag, New York, [29] G. Gutierrez,´ M. E. Siqueiros-Delgado, H. E. Rodr´ıguez- NY, USA, 2007. Chavez,´ M. De la, and E. Cerda-Lemus, “Comision´ Nacional [12] A. M. Fernandez-Brewer,´ V. Juarez-Jaimes,´ and L. Cortes-´ para el Conocimiento y Uso de la Biodiversidad (CONABIO)/ Zarraga,´ “Usos de las especies del genero´ Asclepias L. (Apoc- Instituto de Ecolog´ıa del Estado de Guanajuato,” in en Guana- ynaceae, aclepiadoideae), informacion´ del herbario nacional de juato: Estudio de Estado,A.Cruz-Angon,E.D.Melgarejo,A.V.´ Mexico,´ MEXU,” Polibotanica,vol.25,pp.155–171,2008. Contreras-Ruiz Esparza, and M. A. Gonzalez-Guti´ errez,´ Eds., pp. 262–265, Mexico, 2012. [13] O. Gonzalez-Costilla,´ Estudio etnobotanico del municipio de Matehuala, San Luis Potos´ı, Mexico,´ Universidad Autonoma´ de [30] M. Gonzalez-Elizondo,´ I. L. Lopez-Enr´ ´ıquez, M. S. Gonzalez-´ [M.sc. thesis], Universidad Autonoma´ de Nuevo Leon,´ Mexico,´ Elizondo, and J. A. Tena-Flores, Plantas Medicinales del Estado 1991. de Durango y Zonas Aledanas,˜ Centro Interdisciplinario de Inves- tigacion´ para el Desarrollo Integral Regional Unidad Durango, [14] G. Garc´ıa-Regalado, Plantas medicinales de Aguascalientes, Uni- Instituto Politecnico Nacional, Mexico,´ 2004. versidad Autonoma´ de Aguascalientes, Aguascalientes, Aguas- calientes., Mexico,´ 2014. [31] G. Mendoza-Castelan,´ Manual de usos terapeuticos´ y dosifi- cacion´ de flores medicinales de Mexico´ , Universidad Autonoma´ [15] M. Mart´ınez, Las plantas medicinales de Mexico´ ,EditorialBotas, Chapingo, Guerrero, Mexico,´ 2002. Mexico´ city, Mexico,´ 1996. [32] E. Linares, R. A. Bye, and B. Flores, Plantas Medicinales de [16] B. Juscafresa, “Gu´ıa de la flora medicinal:oxica, t´ aromatica´ y Mexico.´ Usos y remedios tradicionales, Instituto de Biolog´ıa. Uni- condimenticia,” in Editorial Aedos,vol.851,p.542,Barcelona, versidad Nacional Autonoma´ de Mexico.´ Mexico´ city,Plantas Espana,˜ 1995. Medicinales de Usos y remedios tradicionales, Mexico,´ 1999. [17] Y. A. Gonzalez,´ M. Pena,J.P˜ erez´ Agreda, and M. D´ıaz, “Intox- [33] M. A.´ Bello-Gonzalez,´ S. Hernandez-Mu´ noz,˜ M. B. Lara- icacion´ por la administracion´ de tabletas de Thevetia peru- Chavez,´ and R. Salgado-Garciglia, “Plantas utiles´ de la comu- vianacomo tratamiento para bajar de peso: presentacion´ de un nidad ind´ıgena Nuevo San Juan Parangaricutiro, Michoacan,´ caso,” Revista de Toxicolog´ıa, vol. 20, no. 3, pp. 221–223, 2003. Mexico´ ,” Polibotanica´ ,vol.0,no.39,2015. [18] F. Lagunes-Gutierrez, Vademecum de plantas medicinales del [34] E. Nunez-Melendez,˜ “Plantas venenosas de Puerto Rico y las municipio de puente nacional, Veracruz, Universidad Ver- que producen dermatitis,” in Editorial de la Universidad de acruzana, Mexico,´ 2013. Puerto Rico,p.321,R´ıo Piedras, Puerto Rico, 1996. Evidence-Based Complementary and Alternative Medicine 23

[35] R. Sosa-Gomez,´ El poder medicinal de las plantas, Ediciones [52] V. Leon-Jim´ enez,´ Elaboracion´ de una base de datos de plantas GEMA, Asociacion´ Publicadora Interamericana, Miami, Fl, utilizadas en la medicina tradicional de Mexico´ [Bachelor the- USA, 2012. sis], Universidad Autonoma´ del Estado de Hidalgo, Pachuca, [36] B. Mac´ıas-Peacok, M. F. Sußrez-Crespo, A. Berenguer-Rivas et Hidalgo, Mexico, 2005. al., “Intoxicaciones por plantas toxicas´ atendidas desde un ser- [53] M. V. Bermudez-de´ Rocha, F. E. Lozano-Melendez,´ V. A. vicio de informacion´ toxicologica,”´ RevistaCubanadePlantas Tamez-Rodr´ıguez, G. D´ıaz-Cuello, and A. Pinedo-L˜ opez,´ “Fre- Medicinales,vol.14,no.2,p.1,2009. cuencia de intoxicacion´ con Karwinskia humboldtiana en [37] G. Mendoza-Castelan,´ Manual de usos terapeuticos´ y dosifi- Mexico,”´ Salud Publica de Mexico´ ,vol.37,no.1,pp.57–62,1995. cacion´ de maderas medicinales de Mexico´ , Universidad Autono- [54] M. E. Arreola-Nava, J. L. Vazquez-Castellanos,´ and M. E. ma Chapingo, Guerrero, Mexico,´ 2003. Gonzalez-Casta´ neda,˜ “Geographical factors in the epidemiol- [38] V.A. Argueta, A. L. M. Cano, and M. E. Rodarte, Flora Medicinal ogy of intoxication by Karwinskia (tullidora),” Cadernos Saude´ Ind´ıgena de Mexico´ , Instituto Nacional Indigenista, Mexico´ city, Publica´ ,vol.16,no.1,pp.255–260,2000. Mexico,´ 1994. [55] J. Waizel-Bucay and I. Martinez-Rico, “Algunas plantas usadas [39] B. Valdivia-Correa, C. Gomez-Guti´ errez,´ M. Uribe, and N. en Mexico´ en padecimiento periodontales,” Revista de la Aso- Mendez-S´ anchez,´ “Herbal medicine in Mexico: a cause of hep- ciacion´ Dental Mexicana, vol. 68, no. 2, pp. 73–88, 2011. atotoxicity. A critical review,” International Journal of Molecular [56] L. Rodriguez-Fragoso, J. Reyes-Esparza, S. W. Burchiel, D. Sciences,vol.17,no.2,article235,2016. Herrera-Ruiz, and E. Torres, “Risks and benefits of commonly used herbal medicines in Mexico,” Toxicology and Applied Phar- [40] S. Nogue-Xarau,´ P.Sanz-Gallen,´ and C. Blanche-Verg´ es,´ “Intox- macology,vol.227,no.1,pp.125–135,2008. icaciones por plantas (I),” Medicina Integral,vol.36,no.10,pp. 371–379, 2000. [57] M.L.Kulkarni,H.Sreekar,K.S.Keshavamurthy,andN.Shenoy, “Jatropha curcas - Poisoning,” The Indian Journal of Pediatrics, [41] K. Mej´ıa and F. Rengifo, “Plantas medicinales de uso popular vol.72,no.1,pp.75-76,2005. en la Amazonia Peruana,” in Agencia Espanola˜ de cooperacion´ internacional (AECI) & Instituto de investigaciones de la ama- [58] B. S. Frank, W. B. Michelson, K. E. Panter, and D. R. Gardner, zon´ıa peruana (IIAP), p. 286, Lima, Peru,´ 2000. “Ingestion of poison hemlock (Conium maculatum),” Western Journal of Medicine,vol.163,no.6,pp.573-574,1995. [42] D. God´ınez-Carballo and G. Volpato, “Plantas medicinales que [59] E. Biberci, Y. Altuntas, A. C¸ obanoglu, and A. Alpinar, “Acute se venden en el mercado El R´ıo, Camaguey,¨ Cuba,” Revista respiratory arrest following hemlock (Conium maculatum) Mexicana de Biodiversidad,vol.79,no.1,pp.243–259,2008. intoxication [1],” JournalofToxicology-ClinicalToxicology,vol. [43] Y. Levin, Y. Sherer, H. Bibi, M. Schlesinger, and E. Hay, “Rare 40,no.4,pp.517-518,2002. Jatropha multifida intoxication in two children,” The Journal of [60] S. K. Verma, G. Dev, A. K. Tyagi, S. Goomber, and G. V. Jain, Emergency Medicine,vol.19,no.2,pp.173–175,2000. “Argemone mexicana poisoning: autopsy findings of two cases,” [44] C. N. Arroyo, “Plantas toxicas´ del estado de Aguascalientes, Forensic Science International,vol.115,no.1-2,pp.135–141,2001. Taller de Investigacion,”´ in Aguascalientes: Universidad Auton-´ [61] M. A. Montoya-Cabrera, P. Escalante-Galindo, M. Meckes- oma de Aguascalientes, Mexico, 2007. Fischer, G. Sanchez-Vaca, E. Flores-Alvarez, and M. Reynoso- [45] A. Herrera, Farmacopea Latinoamericana,Mexico´ city, Mexico, Garcia, “Envenenamiento mortal causado por el aceite de 1921. epazote, Chenopodium graveolens,” Gaceta Medica de Mexic´ o, [46] P. J. Cambar, “”Algunos estudios farmacologicos´ de las plantas vol. 132, pp. 433–437, 1996. medicinales de Honduras,” RevistaMedicaHondurena˜ ,vol.53, [62]A.Ingraffea,K.Donohue,C.Wilkel,andV.Falanga,“Cuta- pp. 190–196, 1985. neous vasculitis in two patients taking an herbal supplement [47] A. Fierro-Alvarez, A. Perez-Cardona,´ C. Guerrero-Borda et containing black cohosh,” Journal of the American Academy of al., “Plantas silvestres que se comen en Ixhuatlan´ del Cafe,´ Dermatology, vol. 56, no. 5, pp. S124–S126, 2007. Veracruz,” in Editoriales Instituto Nacional de Antropolog´ıa e [63] S. M. Cohen, A. M. O’Connor, J. Hart, N. H. Merel, and H. S. Te, Historia, Consejo Nacional de Ciencia y Tecnolog´ıa,p.47,Mexico “Autoimmune hepatitis associated with the use of black cohosh: city, Mexico, 2000. Acasestudy,”Menopause, vol. 11, no. 5, pp. 575–577, 2004. [48] A. Casas, “Silvicultura y domesticacion´ de plantas en Mesoa- [64]G.E.Slater,B.H.Rumack,andR.G.Peterson,“Podophyllin merica,”in´ Plantas, Cultura y Sociedad: Estudio sobre la Relacion´ poisoning: Systemic toxicity following cutaneous application,” entre Seres Humanos y Plantas en los Albores del Siglo XX, Obstetrics & Gynecology,vol.52,no.1,pp.94–96,1978. B. Rendon-Aguilar, S. Rebollar-Dom´ınguez, J. Caballero-Nieto, [65] M. J. Chamberlain, A. L. Reynolds, and W. B. Yeoman, “Med- and M. A. Mart´ınez-Alfaro, Eds., pp. 123–159, Universidad ical Memoranda. Toxic Effect of Podophyllum Application in Autonoma Metropolitana unidad Iztapalapa, Mexico city, Mex- Pregnancy,” British Medical Journal,vol.3,no.5823,pp.391-392, ico, 2001. 1972. [49] P. Avalos-Peralta, B. Garc´ıa-Bravo, and F. M. Camacho, “Sensi- [66] R. B. Rao and R. S. Hoffman, “Nicotinic toxicity from tincture tivity to Myroxylon pereirae resin (balsam of Peru). A study of of blue cohosh (Caulophyllum thalictroides) used as an abor- 50 cases,” Contact Dermatitis,vol.52,no.6,pp.304–306,2005. tifacient,” Veterinary and Human Toxicology,vol.44,no.4,pp. [50] F. Garc´ıa-Fajardo, L. Gonzalez-Ch´ evez,´ P. Hersch-Mart´ınez, 221-222, 2002. and A. Perez-Cardona,´ “Plantas medicinales de Ixhuatlan´ del [67] P. Durasnel, L. Vanhuffel, R. Blonde´ et al., “Severe poisoning by Cafe,´ Veracruz,” in Editorial Instituto Nacional de Antropolog´ıa plants used for traditional medicine in Mayotte,” Bulletin de la e Historia (INAH) y Consejo Nacional de Ciencia y Tecnolog´ıa Societ´ edePathologieExotique´ ,vol.107,no.5,pp.306–311,2014. (CONACyT), vol. 43, Mexico city, Mexico, 2000. [68] M. R. Quintanilla and R. Arenas, “Dermatitis por contacto a [51] J. D. Guin, R. H. Schosser, and E. W. Rosenberg, “Magnolia Metopium brownei (Chechem). Observaciones cl𝜑nicas de 20 grandiflora dermatitis,” Dermatologic Clinics,vol.8,no.1,pp. casos en ,” Dermatolog´ıa Cosmetica,´ Medica y 81–84, 1990. Quirurgica´ ,vol.7,no.4,pp.226–233,2009. 24 Evidence-Based Complementary and Alternative Medicine

[69] K. L. Grant, L. V. Boyer, and B. E. Erdman, “Chaparral-induced [85]C.H.Tokarnia,A.G.Armien,P.V.Peixoto,J.D.Barbosa,M.´ hepatotoxicity,” Integrative Medicine A Clinicican’s Journal,vol. De Farias Brito, and J. Dobereiner,¨ “Experiments on the toxicity 1, no. 2, pp. 83–87, 1998. of some ornamental plants in cattle,” Pesquisa Veterinaria´ [70] C. Fernando, “Poisoning due to Abrus precatorius (jequirity Brasileira,vol.16,no.1,pp.5–20,1996. bean),” Anaesthesia,vol.56,no.12,pp.1178–1180,2001. [86] E. Galarraga Montes and J. M. Amaro-Luis, “Icosandrin, a [71] D. Subrahmanyan, J. Mathew, and M. Raj, “An unusual mani- novel peltogynoid from the fruits of Phytolacca icosandra festation of Abrus precatorius poisoning: A report of two cases,” (Phytolaccaceae),” Natural Product Research (Formerly Natural Clinical Toxicology,vol.46,no.2,pp.173–175,2008. Product Letters),vol.30,no.1,pp.89–94,2016. [72] L. J. DeFrates, J. D. Hoehns, E. L. Sakornbut, D. G. Glascock, [87] G. Lopes, T. M. S. Da Silva, and A. Echevarria, “Toxicity from and A. R. Tew, “Antimuscarinic intoxication resulting from the crude extracts and glycoalkaloid fractions of Solanum spp. ingestion of moonflower seeds,” Annals of Pharmacotherapy, Against Artemia salina and Biomphalaria glabrata,” Revista vol.39,no.1,pp.173–176,2005. Virtual de Qu´ımica,vol.8,no.1,pp.141–156,2016. [73] Missouri Botanical Garden, “Tropicos,” 2017, http://www [88] A. Sowemimo, L. Venables, M. Odedeji, T. Koekemoer, M. Van .tropicos.org. De Venter, and L. Hongbing, “Antiproliferative mechanism of [74] A. D. Ologhobo, B. L. Fetuga, and O. O. Tewe, “The cyanogenic the methanolic extract of Enterolobium cyclocarpum (Jacq.) glycoside contents of raw and processed limabean varieties,” Griseb. (Fabaceae),” Journal of Ethnopharmacology,vol.159,pp. Food Chemistry,vol.13,no.2,pp.117–128,1984. 257–261, 2015. [75] P. Cressey, D. Saunders, and J. Goodman, “Cyanogenic gly- [89] A. Lagarto Parra, R. Silva Yhebra, I. Guerra Sardinas,˜ and L. cosides in plant-based foods available in New Zealand,” Food Iglesias Buela, “Comparative study of the assay of Artemia salina Additives and Contaminants - Part A Chemistry, Analysis, Con- L. and the estimate of the medium lethal dose (LD50 value) trol, Exposure and Risk Assessment,vol.30,no.11,pp.1946–1953, in mice, to determine oral acute toxicity of plant extracts,” 2013. Phytomedicine,vol.8,no.5,pp.395–400,2001. [76] A. H. Md. Zulfiker, M. Siddiqua, L. Nahar et al., “In vitro [90] M. A. Karim, A. A. Sidddiqui, G. H. Rizwani, M. F. Khan, and antibacterial, antifungal and cytotoxic activity of Scoparia M. Ahmed, “Toxicity of Sanguinaria canadensis as compared to dulcis L,” International Journal of Pharmacy and Pharmaceutical Aloe vera against brine shrimp (Artemia salina) using the probit Sciences,vol.3,no.2,pp.198–203,2011. methodology,” Journal of Pharmacy and Nutrition Sciences,vol. [77]P.G.Susana,R.C.Aarland,M.G.C.Lara,M.E.Jimenez´ 5, no. 1, pp. 1–4, 2015. Lara, and M. E. Jose´ Alberto, “Toxicity analysis, phytochemical [91] M. C. Jacobo-Salcedo, A. J. Alonso-Castro, L. A. Salazar-Olivo and pharmacological study of the plant known as Mora herb, et al., “Antimicrobial and cytotoxic effects of Mexican medicinal collected at the environmental education center of yautlica plants,” Natural Product Communications,vol.6,no.12,pp. (CEA-Yautlica),” Asian Journal of Plant Sciences,vol.12,no.4, 1925–1928, 2011. pp. 159–164, 2013. [92] F. M. Torrico, J. Gambay, A. I. Suarez,´ R. S. Compagnone, and [78] R. W. Bussmann, G. Malca, A. Glenn et al., “Toxicity of medic- A. I. Suarez,´ “Estudio toxicologico´ de Cnidoscolus chayamansa inal plants used in traditional medicine in Northern Peru,” Mc Vaugh,” RevistadelaFacultaddeFarmacia,vol.66,no.2, Journal of Ethnopharmacology,vol.137,no.1,pp.121–140,2011. pp.58–66,2003. [79] F. G. Coe, D. M. Parikh, and C. A. Johnson, “Alkaloid presence [93] G. M. de Queiroz, T. M. de Souza-Moreira, H. R. N. Salgado and brine shrimp (Artemia salina) bioassay of medicinal species et al., “Antimicrobial activity and toxicity in vitro and in vivo of of eastern Nicaragua,” Pharmaceutical Biology,vol.48,no.4,pp. Equisetum hyemale extracts,” Revista de Cienciasˆ Farmaceuticasˆ 439–445, 2010. Basica´ e Aplicada,vol.35,no.4,pp.559–563,2014. [80] S.-G. Luis-Benjam´ın, C.-M. Irais, B.-R. Claudia-Guadalupe et [94] R. Guillope,´ M. Escobar-Khondiker, V. Guerineau,´ O. Lapre-´ al., “Antimicrobial activity and toxicity of plants from northern vote, G. U. Hoglinger,¨ and P. Champy, “Kaurenoic acid from Mexico,” Indian Journal of Traditional Knowledge,vol.16,no.2, pulp of Annona cherimolia in regard to annonaceae-induced pp. 203–207, 2017. parkinsonism,” Phytotherapy Research, vol. 25, no. 12, pp. 1861– [81] J. E. Espitia-Baena, H. D. R. Duran-Sandoval, J. Fandino-˜ 1864, 2011. Franky, F. D´ıaz-Castillo, and H. A. Gomez-Estrada,´ “Chemistry [95] A. F. Valdes,´ J. Mendiola, D. Acuna,Y.caballero,R.Scull,andY.˜ and biology of ethanol extract from the epicarp of Crescentia Gutierrez,´ “Antimalarial activity and cytotoxicity of hydroalco- cujete L. (totumo),” Revista Cubana de Plantas Medicinales,vol. holic extracts from six plant species used in Cuban traditional 16, no. 4, pp. 337–346, 2011. medicine,” RevistaCubanadeMedicinaTropical,vol.63,no.1, [82] D. Raya-Gonzalez,´ J. Chavez´ Duran, S. E. Urrutia Hernandez´ et pp. 52–57, 2011. al., “Toxicological study of an aqueous extract from Enterolo- [96]A.Ramos,R.Rivero,A.Visozo,J.Piloto,andA.Garc´ıa, bium cyclocarpum (Jacq.) Griseb. duramen,” RevistaCubanade “Parthenin, a sesquiterpene lactone of Parthenium hysteropho- Plantas Medicinales,vol.13,no.3,pp.1–8,2008. rus L. is a high toxicity clastogen,” Mutation Research,vol.514, [83] J. E. Espitia-Baena, S. M. Robledo-Restrepo, B. S. Cuadrado- no. 1-2, pp. 19–27, 2002. Cano, H. R. Duran-Sandoval, and H. A. Gomez-Estrada,´ “Per- [97] E. A. Varanda, T. R. Calvo, C. R. P. Cardoso et al., “Mutagenic fil fitoqu´ımico, actividad anti-Leishmania, hemol´ıtica y toxi- activity of Indigofera truxillensis and I. suffruticosa aerial parts,” cologica´ de Cordia dentata Poir. y Heliotropium indicum L,” Evidence-Based Complementary and Alternative Medicine,vol. RevistaCubanadePlantasMedicinales,vol.19,no.3,pp.208– 2011, Article ID 323276, 2011. 224, 2014. [98] M. Deciga-Campos,´ M. Arriaga-Alba, R. Ventura-Mart´ınez, B. [84] M. Canales, T. Hernandez,´ R. Serrano et al., “Antimicrobial Aguilar-Guadarrama, and M. Y. Rios, “Pharmacological and and general toxicity activities of Gymnosperma glutinosum: A toxicological profile of extract from Heliopsis longipes and comparative study,” Journal of Ethnopharmacology,vol.110,no. affinin,” Drug Development Research,vol.73,no.3,pp.130–137, 2, pp. 343–347, 2007. 2012. Evidence-Based Complementary and Alternative Medicine 25

[99] L. D. Da Costa E Silva, L. C. L. V.Rodrigues, V.R. Dos Santos et [113] C. Anesini, J. Boccio, G. Cremaschi et al., “In vivo antitumoural al., “Evaluation of mutagenic and genotoxic activities of lobeline activity and acute toxicity study of Larrea divaricata Cav. and its modulation on genomic instability induced by ethanol,” extract,” Phytotherapy Research,vol.11,no.7,pp.521–523,1997. Life Sciences,vol.103,no.2,pp.73–78,2014. [114] D. Kumar, J. Singh, A. Baghotia, and S. Kumar, “Anticonvulsant [100] C.M.Mattana,M.A.Cangiano,S.E.Satorres,L.E.Alcaraz,´ and effect of the ethanol extract of Caesalpinia pulcherrima (L.) Sw., A. L. Laciar, “Potential genotoxicity of zinnia peruviana extract,” Fabaceae, leaves,” Revista Brasileira de Farmacognosia,vol.20, Pharmacologyonline,vol.2016,no.2,pp.72–80,2016. no.5,pp.751–755,2010. [101] A. L. Gindri, L. B. De Souza, R. C. Cruz, A. A. Boligon, M. [115] S. Kumar, J. Singh, A. Baghotia et al., “Antifertility potential of M. Machado, and M. L. Athayde, “Genotoxic evaluation, sec- the ethanolic extract of Caesalpinia pulcherrima Linn. leaves,” ondary metabolites and antioxidant capacity of leaves and Asian Pacific Journal of Reproduction,vol.2,no.2,pp.90–92, roots of Urera baccifera Gaudich (Urticaceae),” Natural Product 2013. Research (Formerly Natural Product Letters),vol.28,no.23,pp. [116] F. Kengni, D. Tala, M. Djimeli et al., “In vitro antimicrobial 2214–2216, 2014. activity of Harungana madagascriensis and Euphorbia prostrata extracts against some pathogenic Salmonella sp,” International [102] J.G.Avila-Acevedo,A.M.Garc´ıa-Bores,F.Mart´ınez-Ram´ırez et Journal of Biological and Chemical Sciences, vol. 7, no. 3, p. 1106, al., “Antihyperglycemic effect and genotoxicity of Psittacanthus 2013. calyculatus extract in streptozotocin-induced diabetic rats,” Boletin Latinoamericano y del Caribe de Plantas Medicinales y [117] S. Sarkiyayi, S. Ibrahim, and M. S. Abubakar, “Toxicological Aromaticas,vol.11,no.4,pp.345–353,2012. studies of Ceiba pentandra Linn,” African Journal of Biochem- istry Research,vol.3,no.7,pp.279–281,2009. [103] R. Carino-Cort˜ es,´ J. A. Gayosso-De-Lucio, M. I. Ortiz et al., [118]V.Dutt,V.J.Dhar,andA.Sharma,“Antianxietyactivityof “Antinociceptive, genotoxic and histopathological study of He- Gelsemium sempervirens,” Pharmaceutical Biology,vol.48,no. liopsis longipes S.F. Blake in mice,” Journal of Ethnopharmacol- 10, pp. 1091–1096, 2010. ogy,vol.130,no.2,pp.216–221,2010. [119] M. Hernandez-Ortega,´ A. Ortiz-Moreno, M. D. Hernandez-´ [104] Organization for Economic Cooperation and Development, Navarro, G. Chamorro-Cevallos, L. Dorantes-Alvarez, and Guideline for Testing of Chemicals, Test guideline 423: acute oral H. Necoechea-Mondragon,´ “Antioxidant, antinociceptive, and toxicity, acute toxic class methods, 2012. anti-inflammatory effects of carotenoids extracted from dried [105]A.S.Awaad,N.A.Al-Jaber,G.A.Solimanetal.,“Newbio- pepper (Capsicum annuum L.),” Journal of Biomedicine and logical activities of Casimiroa edulis leaf extract and isolated Biotechnology,vol.2012,ArticleID524019,2012. compounds,” Phytotherapy Research,vol.26,no.3,pp.452–457, [120]T.A.Abere,C.J.Okoye,F.O.Agoreyoetal.,“Antisickling 2012. and toxicological evaluation of the leaves of Scoparia dulcis [106] R. V.Garc´ıa-Rodr´ıguez, G. A. Gutierrez-Rebolledo,´ E. Mendez-´ Linn (Scrophulariaceae),” BMC Complementary and Alternative Bolaina et al., “Cnidoscolus chayamansa Mc Vaugh, an impor- Medicine,vol.15,article414,2015. tant antioxidant, anti-inflammatory and cardioprotective plant [121] M. Moniruzzaman, M. Atikur Rahman, and A. Ferdous, “Eval- used in Mexico,” JournalofEthnopharmacology,vol.151,no.2, uation of sedative and hypnotic activity of ethanolic extract pp. 937–943, 2014. of Scoparia dulcis Linn.,” Evidence-Based Complementary and [107] G. A. Gutierrez-Rebolledo,´ L. Garduno-Siciliano,˜ R. V. Garc´ıa- Alternative Medicine,vol.2015,ArticleID873954,6pages,2015. Rodr´ıguez et al., “Anti-inflammatory and toxicological eval- [122]C.M.S.Dutok,C.A.Berenguer-Rivas,E.Rodr´ıguez-Leblanch uation of Moussonia deppeana (Schldl. & Cham) Hanst and et al., “Acute toxicity and dermal and eye irritation of the Verbascoside as a main active metabolite,” Journal of Ethnophar- aqueous and hydroalcoholic extracts of the seeds of “zapote” macology, vol. 187, pp. 269–280, 2016. pouteria mammosa (L.) cronquist,” The Scientific World Journal, vol. 2015, Article ID 642906, 2015. [108] A. H. Shah, S. Qureshi, and A. M. Ageel, “Toxicity studies in [123] B. Harish-Babu, S. Mohana-Lakshmi, and A. Saravana-Kumar, mice of ethanol extracts of Foeniculum vulgare fruit and Ruta “Studies on phytochemical and anticonvulsant property of chalepensis aerial parts,” Journal of Ethnopharmacology,vol.34, Martyniya annua Linn,” vol. 1, pp. 82–86, 2010. no. 2-3, pp. 167–172, 1991. [124]C.D.Zavala,M.L.CarrilloI,B.AlvaradoS,andA.O.Sanchez´ [109] O. A. Olajide, S. O. Awe, and J. M. Makinde, “Pharmacological Ch, “Evaluation of the acute toxicity of an alcoholic extract screening of the methanolic extract of Chenopodium ambro- from tarbush leaves (Flourensia cernua),” RevistaMexicanade sioides,” Fitoterapia, vol. 68, no. 6, pp. 529–532, 1997. Ciencias Farmaceuticas,vol.41,no.3,pp.50–54,2010. [110] S. R. Tamboli and R. S. Pandit, “Acute toxicity evaluation of [125] V. Sharma and G. Rajani, “Evaluation of Caesalpinia pul- Rauvolfia tetraphylla leaf extract in rat by up and down method,” cherrima Linn. for anti-inflammatory and antiulcer activities,” International Journal of Pharmaceutical and Clinical Research, Indian Journal of Pharmacology, vol. 43, no. 2, pp. 168–171, 2011. vol. 6, no. 4, pp. 316–319, 2014. [126]K.Devaki,U.Beulah,G.Akila,andV.K.Gopalakrishnan, [111] J. F. Palacios-Espinosa, O. Arroyo-Garc´ıa, G. Garc´ıa-Valencia, “Effect of aqueous extract of Passiflora edulis on biochemical E. Linares, R. Bye, and I. Romero, “Evidence of the anti- and hematological parameters of Wistar Albino rats,” Toxicology Helicobacter pylori, gastroprotective and anti-inflammatory International,vol.19,no.1,pp.63–67,2012. activities of Cuphea aequipetala infusion,” Journal of Ethnophar- [127]B.E.Bastidas-Ram´ırez, N. Navarro-Ru´ız, J. D. Quezada- macology,vol.151,no.2,pp.990–998,2014. Arellano, B. Ru´ız-Madrigal, M. T. Villanueeva-Michel, and P. [112]K.Sirisha,Y.Rajendra,P.Gomathi,K.Soujanya,andN.Yas- Garzon,´ “Anticonvulsant effects of Magnolia grandiflora L. in meen, “Antioxidant and anti-inflammatory activities of flowers the rat,” Journal of Ethnopharmacology,vol.61,no.2,pp.143– of plumeria rubra l. f. rubra and plumeria rubra f. lutea: A com- 152, 1998. parative study,” Research Journal of Pharmaceutical, Biological [128] C. S. Shastry, M. Bhalodia Maulik, and B. J. Aswathanarayana, and Chemical Sciences,vol.4,no.4,pp.743–756,2013. “Antivenom activity of ethanolic extract of Crescentia cujete 26 Evidence-Based Complementary and Alternative Medicine

fruit,” International Journal of Phytomedicine,vol.4,no.1,pp. in Sprague-Dawley rats,” Revista de Biolog´ıa Tropical,vol.47,no. 108–114, 2012. 4, pp. 723–727, 1999. [129]B.S.Kumar,K.Lakshman,R.Nandeeshetal.,“Invitro [143]A.J.Alonso-Castro,M.D.C.Juarez-V´ azquez,´ F. Dom´ınguez et alpha-amylase inhibition and in vivo antioxidant potential of al., “The antitumoral effect of the American mistletoe Phoraden- Amaranthus spinosus in alloxan-induced oxidative stress in dron serotinum (Raf.) M.C. Johnst. (Viscaceae) is associated diabetic rats,” Saudi Journal of Biological Sciences,vol.18,no.1, with the release of immunity-related cytokines,” Journal of pp. 1–5, 2011. Ethnopharmacology, vol. 142, no. 3, pp. 857–864, 2012. [130] S. Gupta, V. K. Khanna, A. Maurya et al., “Bioactivity guided [144]P.J.Becci,H.Schwartz,H.H.Barnes,andG.L.Southard, isolation of antipsychotic constituents from the leaves of Rau- “Short-term toxicity studies of sangu1nar1ne and of two alkaloid wolfia tetraphylla L.,” Fitoterapia,vol.83,no.6,pp.1092–1099, extracts of Sanguinaria Canadensis L,” Journal of Toxicology and 2012. Environmental Health,vol.20,no.1-2,pp.199–208,1987. [131] M. Z. Perez-Gonz´ alez,G.A.Guti´ errez-Rebolledo,´ L. Yepez-´ [145] Muralidhara and K. Narasimhamurthy, “Non-mutagenicity of Mulia, I. S. Rojas-Tome,´ J. Luna-Herrera, and M. A. Jimenez-´ capsaicin in Albino mice,” Food and Chemical Toxicology,vol. Arellanes, “Antiprotozoal, antimycobacterial, and anti-inflam- 26, no. 11-12, pp. 955–958, 1988. matory evaluation of Cnidoscolus chayamansa (Mc Vaugh) [146] M. E. Gar´ın-Aguilar, J. E. Ram´ırezLuna,M.Soto-Hernandez,´ extract and the isolated compounds,” Biomedicine & Pharma- G. Valencia del Toro, and M. Mart´ınez Vazquez,´ “Effect of crude cotherapy,vol.89,pp.89–97,2017. extracts of Erythrina americana Mill. on aggressive behavior in [132] M. I. Khan, K. M. Denny Joseph, Muralidhara, H. P. Ramesh, rats,” Journal of Ethnopharmacology,vol.69,no.2,pp.189–196, P. Giridhar, and G. A. Ravishankar, “Acute, subacute and 2000. subchronic safety assessment of betalains rich Rivina humilis L. [147]C.-Y.Li,R.K.Devappa,J.-X.Liu,J.-M.Lv,H.P.S.Makkar,and berry juice in rats,” Food and Chemical Toxicology,vol.49,no. K. Becker, “Toxicity of Jatropha curcas phorbol esters in mice,” 12, pp. 3154–3157, 2011. Food and Chemical Toxicology,vol.48,no.2,pp.620–625,2010. [133]F.Nikkon,M.R.Habib,Z.A.Saud,andM.R.Karim,“Tagetes [148] L.A.Chami,R.Mendez,´ B. Chataing, J. O’Callaghan, A. Usubil- erecta Linn. and its mosquitocidal potency against Culex laga, and L. LaCruz, “Toxicological effects of 𝛼-solamargine in quinquefasciatus,” Asian Pacific Journal of Tropical Biomedicine, experimental animals,” Phytotherapy Research,vol.17,no.3,pp. vol. 1, no. 3, pp. 186–188, 2011. 254–258, 2003. [134] F. Jaramillo-Juarez,´ M. L. Rodr´ıguez-Vazquez,´ J. Munoz-˜ [149]K.V.RaoandT.L.Davis,“ConstituentsofMagnoliagran- Mart´ınez et al., “The ATP levels in kidneys and blood are diflora. III. Toxic principle of the wood,” JournalofNatural mainly decreased by acute ingestion of tullidora (Karwinskia Products,vol.45,no.3,pp.283–287,1982. humboldtiana),” Toxicon,vol.46,no.1,pp.99–103,2005. [150] W. C. Bowman and I. S. Sanghvi, “Pharmacological actions of [135] M. G. B. Silva, T. P. Aragao,C.F.B.Vasconcelosetal.,“Acute˜ hemlock (Conium maculatum) alkaloids,” Journal of Pharmacy and subacute toxicity of Cassia occidentalis L. stem and leaf in and Pharmacology,vol.15,no.1,pp.1–25,1963. Wistar rats,” Journal of Ethnopharmacology,vol.136,no.2,pp. [151] T. R. Narasimhan, B. S. K. Murthy, N. Harindranath, and P.V.S. 341–346, 2011. Rao, “Characterization of a toxin from Parthenium hysteropho- [136] K. B. Harikumar, C. V. Nimita, K. C. Preethi, R. Kuttan, M. L. rus and its mode of excretion in animals,” Journal of Biosciences, Shankaranarayana, and J. Deshpande, “Toxicity profile of lutein vol. 6, no. 5, pp. 729–738, 1984. and lutein ester isolated from marigold flowers (Tagetes erecta),” [152] T. Glinsukon, V.Stitmunnaithum, C. Toskulkao, T. Buranawuti, International Journal of Toxicology,vol.27,no.1,pp.1–9,2008. and V.Tangkrisanavinont, “Acute toxicity of capsaicin in several [137] S. R. Mariz, M. S. T. Araujo,´ G. S. Cerqueira et al., “Histopatho- animal species,” Toxicon,vol.18,no.2,pp.215–220,1980. logical evaluation in rats after acute treatment with the ethanol [153]R.Davicino,A.Mattar,Y.Casali,C.Porporatto,S.G.Correa, extract from aerial parts of Jatropha gossypiifolia L.,” Revista and B. Micalizzi, “In vivo immunomodulatory effects of aque- Brasileira de Farmacognosia,vol.18,no.2,pp.213–216,2008. ousextractsofLarreadivaricataCav.,”Immunopharmacology [138]O.A.Salako,A.J.Akindele,O.M.Shitta,O.O.Elegunde,and and Immunotoxicology,vol.29,no.3-4,pp.351–366,2007. O. O. Adeyemi, “Antidiarrhoeal activity of aqueous leaf extract [154] F.Jaramillo, V.M. L. Rodr´ıguez, C. M. G. Castillo et al., “Hepatic of Caladium bicolor (Araceae) and its possible mechanisms of and blood coagulation damage produced by administration of action,” Journal of Ethnopharmacology,vol.176,pp.225–231, ripe fruit from the tullidora plant (Karwinskia humboldtiana) 2015. in the rat,” Revista Mexicana de Ciencias Farmaceuticas,vol.40, [139] E. Aguirre-Hernandez,´ A. L. Mart´ınez,M.E.Gonzalez-Trujano,´ no. 1, pp. 28–34, 2009. J. Moreno, H. Vibrans, and M. Soto-Hernandez,´ “Pharmaco- [155]E.Maluf,H.M.T.Barros,M.L.Frochtengarten,R.Benti, logical evaluation of the anxiolytic and sedative effects of Tilia and J. R. Leite, “Assessment of the hypnotic/sedative effects americana L. var. mexicana in mice,” Journal of Ethnopharma- and toxicity of Passiflora edulis aqueous extract in rodents and cology,vol.109,no.1,pp.140–145,2007. humans,” Phytotherapy Research,vol.5,no.6,pp.262–266,1991. [140] G. Perez-Ortega,´ M. E. Gonzalez-Trujano,´ G. E. Angeles-L´ opez,´ [156] K. Carcano-Diaz, A. Garcia-Garcia, J. C. Segoviano-Ramirez, F. Brindis, H. Vibrans, and R. Reyes-Chilpa, “Tagetes lucida H. Rodriguez-Rocha, M. D. J. Loera-Arias, and J. Garcia-Juarez, Cav.: Ethnobotany, phytochemistry and pharmacology of its “Damage to pancreatic acinar cells and preservation of islets of tranquilizing properties,” Journal of Ethnopharmacology,vol. langerhans in a rat model of acute pancreatitis induced by kar- 181,pp.221–228,2016. winskiahumboldtiana(Buckthorn),”Histology and Histopathol- [141] M. Singh, V. Kumar, I. Singh, V. Gauttam, and A. Kalia, “Anti- ogy,vol.31,no.9,pp.1001–1010,2016. inflammatory activity of aqueous extract of Mirabilis jalapa [157] S. R. Tamboli and R. S. Pandit, “Subacute toxicity evaluation of Linn. leaves,” Pharmacognosy Research,vol.2,no.6,p.364,2010. RauvolfiatetraphyllamethanolicleafextractinSpraguedawley [142] B. Badilla, G. Mora, and L. J. Poveda, “Anti-inflammatory rat,” International Journal of Pharmaceutical Sciences Review activity of aqueous extracts of five Costa Rican medicinal plants and Research,vol.34,no.1,articleno.24,pp.152–157,2015. Evidence-Based Complementary and Alternative Medicine 27

[158] M. Cid-Hernandez,´ A. C. Ram´ırez-Anguiano, G. G. Ortiz [174]F.B.Mello,D.Jacobus,K.Carvalho,andJ.R.B.Mello,“Effects et al., “Mitochondrial atpase activity and membrane fluidity of Lantana camara (Verbenaceae) on general reproductive changes in rat liver in response to intoxication with buckthorn performance and teratology in rats,” Toxicon,vol.45,no.4,pp. (karwinskia humboldtiana),” Biological Research,vol.48,2015. 459–466, 2005. [159] J. N. Ogbulie, C. C. Ogueke, I. C. Okoli, and B. N. Anyanwu, [175] National Toxicology Program, Toxicology and carcinogenesis “Antibacterial activities and toxicological potentials of crude studies of goldenseal root powder (Hydrastis Canadensis)in ethanolic extracts of Euphorbia hirta,” African Journal of F344/N rats and B6C3F1 mice (feed studies),vol.562,National Biotechnology,vol.6,no.13,pp.1544–1548,2007. Toxicology Program Technical Report Series, 2010. [160]S.R.Hashemi,I.Zulkifli,H.Davoodi,Z.Zunita,andM. [176]C.A.Naranjo,U.Busto,andE.M.Sellers,“Amethodfor Ebrahimi, “Growth performance, intestinal microflora, plasma estimating the probability of adverse drug reactions,” Clinical fatty acid profile in broiler chickens fed herbal plant (Euphorbia Pharmacology & Therapeutics,vol.30,no.2,pp.239–245,1981. hirta) and mix of acidifiers,” Animal Feed Science and Technol- [177] Mexican Official Norm NOM-220-SSA1-2016, Pharmacovigi- ogy,vol.178,no.3-4,pp.167–174,2012. lance Installation and Operation, Secretary of Health, Mexico [161]M.L.Omnell,F.R.P.Sim,R.F.Keeler,L.C.Harne,andK.S. City, Mexico, 2013. Brown, “Expression of Veratrum alkaloid teratogenicity in the [178] G. Danan and C. Benichou, “Causality assessment of adverse mouse,” Teratology,vol.42,no.2,pp.105–119,1990. reactions to drugs—I: a novel method based on the conclu- [162] J. Gonzales, V. Benavides, R. Rojas, and J. Pino, “Efecto sions of international consensus meetings: application to drug- embriotoxico´ y teratogenico´ de Ruta chalepensis L. ruda, en induced liver injuries,” Journal of Clinical Epidemiology,vol.46, raton´ (Mus musculus),” Revista Peruana de Biolog´ıa,vol.13,no. no. 11, pp. 1323–1330, 1993. 3, 2013. [179]E.P.Krenzelok,T.D.Jacobsen,andJ.M.Aronis,“Poinsettia [163] R. Zeichen de Sa, A. Rey, E. Arganaraz,˜ and E. Bindstein, “Peri- exposureshavegoodoutcomes—Justaswethought,”The natal toxicology of Ruta chalepensis (Rutaceae) in mice,” Journal American Journal of Emergency Medicine,vol.14,no.7,pp.671– of Ethnopharmacology,vol.69,no.2,pp.93–98,2000. 674, 1996. [164]D.T.Victorien,K.JeanRobert,D.T.Jacquesetal.,“Hemostatic [180] F. Borrelli and E. Ernst, “Black cohosh (Cimicifuga racemosa): activity screening and skin toxicity of sap of Jatropha multifida a systematic review of adverse events,” American Journal of L. (Euphorbiaceae) used in traditional medicine (Benin),” Asian Obstetrics & Gynecology,vol.199,no.5,pp.455–466,2008. PacificJournalofTropicalDisease,vol.2,no.2,pp.S927–S932, [181] R. Teschke, A. Schwarzenboeck, W. Schmidt-Taenzer, A. Wolff, 2012. and K. Hennermann, “Herb induced liver injury presumably [165]W.Adolf,H.J.Opferkuch,andE.Hecker,“Irritantphorbol caused by black cohosh: a survey of initially purported cases and derivatives from four Jatropha species,” Phytochemistry,vol.23, herbal quality specifications,” Annals of Hepatology,vol.10,no. no. 1, pp. 129–132, 1984. 3,pp.249–259,2011. [166] A. L. Meyer Albiero, J. A. Aboin Sertie,´ and E. M. Bacchi, [182] A. Schnuch, H. Lessmann, J. Geier, P. J. Frosch, and W. Uter, “Antiulcer activity of Sapindus saponaria L. in the rat,” Journal “Contact allergy to fragrances: Frequencies of sensitization of Ethnopharmacology,vol.82,no.1,pp.41–44,2002. from 1996 to 2002. Results of the IVDK,” Contact Dermatitis, [167]D.Dabhadkar,V.Zade,S.Dawada,M.Dhore,andM.Kodape, vol.50,no.2,pp.65–76,2004. “Effect of alcoholic pod extract of Plumeria rubra on bio- [183] J.G.MarksJr.,D.V.Belsito,V.A.DeLeoetal.,“NorthAmerican chemical and haematologicalparameters of female albino rats,” contact dermatitis group patch-test results, 1996-1998 [8],” International Journal of Pharmaceutical Sciences Review and JAMA Dermatology,vol.136,no.2,pp.272-273,2000. Research,vol.19,no.1,pp.69–74,2013. [184] S. Wohrl,W.Hemmer,M.Focke,M.G¨ otz,¨ and R. Jarisch, “The [168]J.-J.Jang,D.E.Devor,D.L.Logsdon,andJ.M.Ward,“A4-week significance of fragrance mix, balsam of Peru, colophony and feeding study of ground red chilli (Capsicum annuum) in male propolis as screening tools in the detection of fragrance allergy,” B6C3F1 mice,” Food and Chemical Toxicology,vol.30,no.9,pp. British Journal of Dermatology,vol.145,no.2,pp.268–273,2001. 783–787, 1992. [185] A. Trattner and M. David, “Patch testing with fine fragrances: [169] A. A. Adedapo, O. A. Omoloye, and O. G. Ohore, “Studies on the Comparisonwithfragrancemix,balsamofPeruandafragrance toxicity of an aqueous extract of the leaves of Abrus precatorius series,” Contact Dermatitis,vol.49,no.6,pp.287–289,2003. in rats,” Onderstepoort Journal of Veterinary Research,vol.74, [186] P. Turic,´ J. Lipozenciˇ c,´ V. Milavec-Puretic,´ and S. M. Kuliˇsic,´ no. 1, pp. 31–36, 2007. “ContactallergycausedbyfragrancemixandMyroxylon [170] S.R.Mariz,G.S.Cerqueira,W.C.Araujo´ et al., “Chronic toxico- pereirae(balsamofPeru)-Aretrospectivestudy,”Collegium logic study of the ethanolic extract of the aerial parts of Jatropha Antropologicum,vol.35,no.1,pp.83–87,2011. gossypiifolia in rats,” Revista Brasileira de Farmacognosia,vol. [187]M.Eddleston,S.Attapattu,S.A.M.Kularatneetal.,“Acuteyel- 22,no.3,pp.663–668,2012. low oleander (Thevetia peruviana) poisoning: Cardiac arrhyth- [171] M. Yao, H. E. Ritchie, and P.D. Brown-Woodman, “Areproduc- mias, electrolyte disturbances, and serum cardiac glycoside tive screening test of goldenseal,” Birth Defects Research Part B concentrations on presentation to hospital,” Heart,vol.83,no. -DevelopmentalandReproductiveToxicology,vol.74,no.5,pp. 3,pp.301–306,2000. 399–404, 2005. [188] J. F. Rivero-Cruz, D. Chavez, B. Hernandez Bautista, A. L. [172]M.A.Medeiros,F.Riet-Correa,F.P.M.Dantas,J.R.S.Santos, Anaya, and R. Mata, “Separation and characterization of Me- andR.M.T.Medeiros,“Efeitosteratogenicosˆ de prosopis topium brownei urushiol components,” Phytochemistry,vol.45, juliflora em ratos ealis an´ e da toxicidad e das vagens,” Pesquisa no.5,pp.1003–1008,1997. Veterinaria Brasileira, vol. 34, no. 11, pp. 1089–1093, 2014. [189] M.Eddleston,C.A.Ariaratnam,W.P.Meyeretal.,“Epidemicof [173] D. Dabhadkar and V. Zade, “Abortifacient activity of Plumeria self-poisoning with seeds of the yellow oleander (Thevetia rubra (Linn) pod extract in female albino rats,” Indian Journal peruviana) in northern Sri Lanka,” Tropical Medicine & Inter- of Experimental Biology (IJEB), vol. 50, no. 10, pp. 702–707, 2012. national Health,vol.4,no.4,pp.266–273,1999. 28 Evidence-Based Complementary and Alternative Medicine

[190] M. Guerrero, A. Pineyro,˜ and N. Waksman, “Extraction and quantification of toxins from Karwinskia humboldtiana (Tul- lidora),” Toxicon,vol.25,no.5,pp.565–568,1987. [191] P.A. Lancaster and J. E. Brooks, “Cassava leaves as human food,” Economic Botany,vol.37,no.3,pp.331–348,1983. [192] J. M. McMahon, W. L. White, and R. T. Sayre, “Cyanogenesis in cassava (Manihot esculenta Crantz),” Journal of Experimental Botany, vol. 46, no. 288, pp. 731–741, 1995. [193] S. Husain, R. Narsimha, and R. N. Rao, “Separation, identifica- tion and determination of sanguinarine in argemone and other adulterated edible oils by reversed-phase high-performance liquid chromatography,” Journal of Chromatography A,vol.863, no. 1, pp. 123–126, 1999. [194]F.StickelandD.Shouval,“Hepatotoxicityofherbalanddietary supplements: an update,” Archives of Toxicology,vol.89,no.6, pp.851–865,2015. [195] S. R. Lin, L. P. Cai, and D. Y. Lin, “Effects of electroacupuncture of “Zusanli” (ST 36) on gastric mucosal blood flow, NO and ET contents in gastric mucosal injury rats,” Acupuncture Research, vol.31,no.2,pp.110–112,2006. [196] S. P. Myers, “Interactions between complementary medicines and warfarin,” Australian Prescriber,vol.25,no.3,pp.54–56, 2002. M EDIATORSof INFLAMMATION

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