# Medicinal Plants from North and Central America and the Caribbean Considered Toxic for Humans: The Other Side of the Coin

Authors: Angel Josabad Alonso-Castro; Fabiola Domínguez; Alan Joel Ruiz-Padilla; Nimsi Campos-Xolalpa; Juan Ramón Zapata-Morales; Candy Carranza-Alvarez; Juan Jose Maldonado-Miranda
Journal: Evidence-Based Complementary and Alternative Medicine
 (2017)

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## Abstract

The consumption of medicinal plants has notably increased over the past two decades. People consider herbal products as safe 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 ofChenopodium ambrosioides,Argemone mexicana, andThevetia peruviana. In most of the cases, the principle of the plant 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.


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## Body

## 1. Introduction

The use of herbal medicine has increased around the world due to its presumptive efficiency, availability, and general acceptance. Approximately 80% of the general population, especially in developing countries, uses medicinal herbs for primary health care [1, 2]. Worldwide, the interest in medicinal plants by patients has increased over the past two decades. The global market for medicinal plants and plant-derived drugs in 2015 was estimated at 25.6 billion dollars and is expected to rise to 35.4 billion dollars in 2020 [3]. This clearly indicates that the consumption of medicinal plants is a current topic of interest. Despite the high consumption of medicinal plants and related products, their toxicity remains to be evaluated. In addition, many medicinal plants require scientific evidence for their medicinal use, particularly those that are sold as food supplements.Some medicinal plants might trigger undesirable side effects for human health because of (a) pharmacodynamic interaction with prescribed drugs, (b) intrinsic effects, (c) pharmacokinetic interaction with prescribed drugs, and (d) the presence of contaminants and/or pathogenic microorganisms. Other factors that impact the toxicity of medicinal plants in humans include the age of the patient, nutritional status, and the presence of chronic diseases. The concentration of toxic metabolites in plants is determined by the season of collection, nutrients in the soil, and growth stage, among others [4].The main reasons for focusing this review on medicinal flora with supposed toxicological effects from Mexico, Central America, and the Caribbean are as follows: (a) the ancient importance of traditional medicine in this region, (b) their great biodiversity, and (c) the current use of herbal products. This review will be useful for physicians, toxicologists, pharmacologists, and general audiences. We have tried to describe in detail some toxic symptoms reported with the consumption of the medicinal plants covered in this review.


## 2. Methodology

A bibliographic search was conducted from July 2016 to May 2017 of published scientific material on native plants from Mexico, Central America, and the Caribbean that describes the ethnomedical and toxicological information for medicinal plants reputed to be toxic for humans. The following keywords were searched in different scientific databases: plant extract, toxicity, Mexico, and Central America. Additional data were acquired from undergraduate and postgraduate theses, as well as published and electronic books. The admittance criteria for the selection of scientific information in this review were as follows: (i) plants native to North and Central America and the Caribbean, (ii) plants used for medicinal purposes with or without toxicological studies, (iii) plants with experimental reports on theirin vitro and/orin vivo toxicity, (iv) plants thought to be toxic for humans, (v) studies where the concentrations were presented as weight/volume relationship in international units (mg/ml, μg/ml), (vi) studies where the doses were presented as weight/weight relationship in international units (mg/kg, g/kg), and (vii) plants with information obtained from a clear source. Scientific studies reporting the combination of plant extracts were excluded. Medicinal plants considered toxic were classified into two categories: (1) plants with toxicological evidence reported in a scientific source and (2) plants without toxicological evidence. All plant names and their distributions were confirmed at the Missouri botanical garden [73]. Many of the medicinal plants cited in this review have no common name in English. Therefore, the common names were given in Spanish (Table 1).Table 1
Ethnobotanical information of medicinal plants from Mexico and Central America considered as toxic.
Family
Scientific name
Common name in Spanish
Medicinal use
Signs of toxicity[plant part]
Reference
Amaranthaceae
Amaranthus spinosus L.∗∗
Quelite de Puerco
Rheumatism, diuretic, wound healing
Nephrotoxicity[whole plant]
[5]
Chenopodium ambrosioides L.∗∗
Epazote
Vermifuge, vomit
Nephrotoxicity abortifacient, hepatotoxicity[whole plant]
[6]
Amaryllidaceae
Allium glandulosum Link & Otto
Cebolla de monte
Cough, flu, tuberculosis
Numbness, nausea, and vomiting[bulb]
[7]
Anacardiaceae
Metopium brownei (Jacq.) Urb.
Chechém negro
Antiviral, Rheumatism
Skin burns[latex from leaves]
[8]
Toxicodendron radicans (L.) Kuntze
Hiedra venenosa
Headache, rheumatism
Dermatitis[latex]
[9]
Annonaceae
Annona cherimola Mill.∗∗
Chirimoya
Diarrhea, dysentery
Abortifacient[aerial parts, fruits]
[10]
Apiaceae
Conium maculatum L.∗∗
Cicuta
Body pain
Hypertension and sweating[whole plant]
[11]
Apocynaceae
Asclepias curassavicaL.
Rompemuelas
Vermifuge, cancer, wound healing, diuretic
Nausea and vomiting, muscle paralysis[whole plant]
[12]
Asclepias linariaCav.
Algodoncillo
Cough, fever, purgative, diuretic
Muscle paralysis[leaves]
[13]
Asclepias mexicana Cav.
Venenillo cimarrón
Warts
Numbness[leaves]
[12]
Asclepias oenotheroides Schltdl. & Cham
Hierba lechosa
Tooth ache
Numbness, nausea, and vomiting[leaves]
[5]
Asclepias subverticillata (A. Gray) Vail
Hierba lechosa
Snake bite
Severe diarrhea[leaves]
[5]
Plumeria rubraL.∗∗
Zacalazúchil
Stomachache, toothache
Dermatitis[latex]
[14]
Rauvolfia tetraphylla L.∗∗
Cinco negritos
Wound healing, rheumatism
Diarrhea, nausea, and vomiting, hypertension, depression[aerial parts]
[15]
Thevetia ahouai(L.) A. DC.
Bola de venado
Toothache, headache
Cardiotoxicity[fruits and seeds]
[8]
Thevetia gaumeri Hemsl.
Campanilla
Toothache, cancer
Tooth loss[leaves, latex]
[16]
Thevetia peruviana (Pers.) K. Schum.∗∗
Troncomin
Stomachache
Cardiotoxicity[leaves]
[17]
Thevetia thevetioides (Kunth) K. Schum
Yoyote
Warts, analgesic
Cardiotoxicity[whole plant]
[18]
Aquifoliaceae
Ilex opacaAiton
American holly
Digestive
Cardiotoxicity and vomiting[fruits]
[19]
Araceae
Anthurium crassinervium(Jacq.) Schott
Kiilbal chaak
Warts
Dermatitis[sap]
[8]
Anthurium pentaphyllum(Aubl.) G. Don
Hoja de reumatismo de bejuco
Rheumatism
Dermatitis[aerial parts]
[8]
Anthurium schlechtendaliiKunth
Hoja de piedra
Hemorrhage postpartum
Dermatitis[aerial parts]
[8]
Caladium bicolor(Aiton) Vent.∗∗
Heart of Jesus
Antiseptic
Dermatitis, diarrhea[aerial parts]
[4]
Monstera deliciosaLiebm.∗∗
Cerimán
Flu, rheumatism
Dysphagia[aerial parts]
[20]
Aristolochiaceae
Aristolochia foetidaKunth
Guaco
Snake bite, headache
Hepatotoxicity[whole plant]
[21]
Aristolochia grandifloraSw.
Flor de pato
Stomachache, snake bite
Abdominal pain, gastritis[roots]
[15]
Aristolochia odoratissima L.
Guaco
Diarrhea, stomachache, belly cramps
Nephrotoxicity and hepatotoxicity[roots]
[22]
Aristolochia pentandra Jacq
Camotillo guaco
Fever, diarrhea
Nephrotoxicity[roots]
[22]
Aristolochia reticulataNutt.
Texas dutchman’s pipe
Digestive
Nephrotoxicity[roots]
[19]
Aristolochia serpentariaL.
Virginia snakeroot
Digestive, diuretic
Nephrotoxicity[roots]
[19]
Asparagaceae
Yucca filifera Chabaud
Palma
Cough
Nausea and vomiting[aerial parts]
[14]
Asteraceae
Acmella repens(Walter) Rich.
Yerba de San Pedro
Malaria
Hallucinations[aerial parts]
[23]
Ambrosia confertiflora DC.
Amargosa
Diarrhea, vomiting
Gastritis[whole plant]
[13]
Ambrosia peruviana Willd.∗∗
Altamisa
Rheumatism, pain, fever
Neurotoxicity[whole plant]
[24]
Ambrosia psilostachya DC.
Estafiate
Stomachache
Nausea and vomiting[whole plant]
[25]
Artemisia ludovicianasubsp. mexicana (Willd. ex Spreng.) D.D. Keck
Estafiate
Vermifuge, fever
Numbness, carcinogenic[aerial parts]
[14]
Barkleyanthus salicifolius(Kunth) H. Rob. & Brettell
Jaral Amarillo
Fever, diuretic, rheumatism
Hepatotoxicity[whole plant]
[14]
Conyza filaginoides (DC.) Hieron.
Simonillo
Stomachache, diabetes, anxiolytic
Nausea and vomiting[whole plant]
[7]
Eupatorium odoratum L.
Rama de la cruz
Wound healing, anti-inflammatory
Nausea and vomiting[whole plant]
[5]
Flourensia cernua DC.∗∗
Hojasén
Stomachache, diarrhea
Hepatotoxicity[leaves]
[13]
Gymnosperma glutinosum (Spreng.) Less.∗∗
Tatalencho
Diuretic, rheumatism, analgesic
Sleepiness, muscle paralysis[seeds, leaves]
[5]
Haplopappus gymnocephalusDC.
Arnica morada
Body pain, hemorrhoids
Gastritis[aerial parts]
[14]
Helenium mexicanumKunth
Cabezona
Flu
Gastritis and vomiting[flowers]
[15]
Heliopsis longipes(A. Gray) S.F. Blake∗∗
Chilcuague
Analgesic
Narcotic[roots]
[26]
Montanoa tomentosaCerv.
Zoapatle
Rheumatism, cough, menstrual colic
Abortifacient, respiratory failure[aerial parts]
[27]
Packera aurea (L.) Á. Löve & D. Löve
Life root
Amenorrhea, menopause and leucorrhea.
Hepatotoxicity[aerial parts]
[19]
Packera candidissima(Greene) W.A. Weber & Á. Löve
Chuca
Cough
Hepatotoxicity[aerial parts]
[28]
Parthenium hysterophorusL.∗∗
Escoba amarga
Stomachache, headache
Hypotensive, bradycardia[whole plant]
[29]
Parthenium incanum Kunth
Mariola
Stomachache, diarrhea
Nausea and vomiting[whole plant]
[13]
Psacalium decompositum (A. Gray) H. Rob. & Brettell
Matarique
Diabetes, rheumatism
Neurotoxicity[roots]
[30]
Tagetes erectaL.∗∗
Flor de muerto (cempaxochitl)
Diarrhea, vermifuge, diabetes, rheumatism
Gastritis[flowers]
[31]
Tagetes lucida Cav∗∗
Pericón
Stomachache, diarrhea, vomit
Abortifacient[whole plant]
[32]
Zinnia peruviana(L.) L.∗∗
Mal de ojo
Stomachache, diarrhea
Eye irritant
[14]
Berberidaceae
Berberis moranensisSchult. & Schult. f.
Palo amarillo
Rheumatism
Numbness, nausea, and vomiting[aerial parts]
[33]
Caulophyllum thalictroides(L.) Michx.∗∗
Blue cohosh
Dysmenorrhea, rheumatism
Nausea and vomiting, gastritis[seeds and roots]
[11]
Podophyllum peltatumL.∗∗
Mayapple
Genital warts
Altered mental states, tachypnea, peripheral neuropathy, nausea and vomiting, hypotension, and fever[whole plant]
[19]
Bignoniaceae
Crescentia alataKunth
Cuatecomate
Cough, asthma
Vomiting, abdominal pain[fruit]
[21]
Crescentia cujete L.∗∗
Güiro
Cough, tuberculosis
Abortifacient, severe diarrhea[fruits]
[18]
Boraginaceae
Cordia dentataPoir.∗∗
Uvita
Cough
Severe diarrhea[fruits]
[8]
Heliotropium curassavicumL.
Alacrancillo
Asthma, anemia, snake bite
Hepatitis[whole plant]
[11]
Bromeliaceae
Bromelia pinguinL.
Piñuela
Cough
Dermatitis[fruits]
[34]
Bromelia plumieri(E. Morren) L.B. Sm.
Timbiriche
Inflammation
Dermatitis[fruits]
[8]
Cactaceae
Cereus marginatus DC.
Oregano de zopilote
Rabies
Cardiotoxicity[aerial parts]
[13]
Coryphantha pycnacantha(Mart.) Lem.
Falso peyote
Rheumatism, analgesic
Sedation in tongue[fruit]
[14]
Lophophora williamsii (Lem. ex Salm-Dyck) J.M. Coult.
Peyote
Rheumatism, analgesic
Hallucinations[whole plant]
[30]
Campanulaceae
Lobelia cardinalis L.
Lobelia
Cough, flu
Hypothermia, vomiting, abdominal pain[aerial parts]
[4]
Lobelia inflataL.∗∗
Lobelia
Asthma, muscle relaxant
Hypotension[whole plant]
[35]
Canellaceae
Canella winterana (L.) Gaertn.
Cúrbana
Rheumatism, stomachache
Edema, hemorrhage[whole plant]
[36]
Caprifoliaceae
Lonicera periclymenumL.
Woodbine
Diuretic, cough
Cardiotoxicity and neurotoxicity[fruits]
[11]
Symphoricarpos albus(L.) S.F. Blake
Snowberry
Tuberculosis
Nausea and vomiting, abdominal pain[whole plant]
[11]
Celastraceae
Celastrus scandensL.
Falsa dulcamara
Diuretic, tuberculosis
Gastritis, nausea and vomiting, diarrhea[fruit]
[11]
Euonymus atropurpureusJacq.
Wahoo
Purgative
Vomiting[bark]
[11]
Commelinaceae
Commelina elegans Kunth
Hierba del pollo
Conjunctivitis
Edema, dermatitis[whole plant]
[8]
Tradescantia spathaceaSw.
Maguey morado
Cancer, wound healing, asthma, cough
Skin burns[sap]
[8]
Convulvulaceae
Ipomoea murucoides Roem. & Schult.
Cazahuate
Hair loss, wound healing, cough, diuretic
Gastritis[bark]
[37]
Ipomoea purga (Wender.) Hayne
Raíz de Jalapa
Purgative
Vomiting and abdominal pain[roots]
[15]
Ipomoea stans Cav.
Tumbavaqueros
Epileptic seizures
Neurotoxicity[roots]
[38]
Ipomoea tricolorCav.
Hiedra de flores grandes
Analgesic
Hallucinations[aerial parts]
[14]
Turbina corymbosa(L.) Raf.
Flor de pascua
Fever, wound healing
Hallucinations[seeds]
[4]
Coriariaceae
Coriaria ruscifolia L.
Huique
Pneumonia
Hallucinations[aerial parts]
[33]
Cucurbitaceae
Apodanthera undulataA. Gray
Gualaista
Gastritis
Vomiting and abdominal pain[roots and seeds]
[14]
Dioscoreaceae
Dioscorea floribundaM. Martens & Galeotti
Barbasco amarillo
Rheumatism, body pain
Abortifacient[roots]
[8]
Equisetaceae
Equisetum hyemaleL.∗∗
Carricillo
Abdominal pain, urinary tract infections
Hepatotoxicity[whole plant]
[39]
Ericaceae
Arbutus arizonica(A. Gray) Sarg.
Madroño
Diuretic
Nausea and vomiting[fruit]
[14]
Comarostaphylis discolor(Hook.) Diggs
Madroño
Diuretic
Nausea and vomiting[fruit]
[33]
Kalmia latifoliaL.
Ivy brush
Syphilis
Neurotoxicity, cardiotoxicity[aerial parts]
[11]
Euphorbiaceae
Acalypha monostachyaCav. Cav
Hierba del cancer
Cancer
Skin burns[latex]
[14]
Adelia barbinervis Schltdl. & Cham.
Espino blanco
Body pain, wounds
Dermatitis[aerial parts]
[8]
Cnidoscolus  chayamansa McVaugh∗∗
Chaya
Diabetes
Dermatitis[aerial parts]
[8]
Cnidoscolus  souzae McVaugh
Ch’iinchay
Rheumatism
Dermatitis[aerial parts]
[8]
Cnidoscolus  urens (L.) Arthur∗∗
Ortiga
Diuretic
Hypotension, skin burns, nausea and vomiting[whole plant]
[24]
Croton  ciliatoglandulosus Ortega
Hierba de la cruz
Constipation
Gastritis, excessive salivation[whole plant]
[4]
Croton humilisL.
ik’ja’aban
Wounds
Skin burns[aerial parts]
[8]
Dalechampia scandensL.
Mo’ol koj
Headache
Edema, dermatitis[aerial parts]
[11]
Euphorbia cotinifoliaL.
Lechero rojo
Purgative
Skin burns[seeds]
[24]
Euphorbia hirta L.
∗
∗
Hierba de la golondrina
Stomachache
Skin burns[aerial parts]
[14]
Euphorbia maculataL.
Hierba de la golondrina
Tooth ache
Severe diarrhea, vomiting[seeds]
[4]
Euphorbia prostrataAiton∗∗
Hierba de la golondrina
Pain in the kidney, wounds, diarrhea
Gastritis, abdominal pain[whole plant]
[31]
Euphorbia pulcherrima Willd. ex Klotzsch∗∗
Noche buena
Wound healing
Vomiting, diarrhea, abdominal pain[whole plant]
[40]
Euphorbia tithymaloidesL.
Redbird flower
Asthma, skin cancer, warts
Irritation of the mouth and throat, vomiting[whole plant]
[20]
Hura crepitans L.∗∗
Catahua
Laxative
Skin burns[seeds]
[41]
Hura polyandraBaill.
Haba
Stomachache, body pain,
Skin burns[latex], nausea and vomiting, gastritis [seeds and fruits]
[15]
Jatropha curcas L.∗∗
Piñon
Fever, warts
Dermatitis, vomiting, diarrhea[seeds, leaves]
[36]
Jatropha dioica Sessé∗∗
Sangre de grado
Cancer, rheumatism, hair loss, wound healing
Dermatitis, vomiting, muscle paralysis[stem, fruits]
[13]
Jatropha gossypiifolia L.∗∗
Tua tua
Cough, flu, fever
Skin burns, abortifacient[seeds, leaves]
[42]
Jatropha multifidaL.∗∗
Palmeado
Wound healing, to purify blood
Severe diarrhea[seeds]
[43]
Manihot esculenta Crantz∗∗
Yuca
Wound healing, vermifuge
Poisoning and neurotoxicity[leaves]
[41]
Tragia nepetifoliaCav.
Ortiguilla
Diuretic
Skin burns[Aerial parts]
[44]
Tragia yucatanensis Millsp.
P’oop’ox
Rheumatism
Dermatitis[aerial parts]
[8]
Fabaceae
Abrus precatoriusL∗∗
Semilla de culebra
Diabetes, asthma
Stomachache, diarrhea[aerial parts]
[4]
Andira inermis(W. Wright) Kunth ex DC.
Yaba
Vermifuge
Vomiting, fever, hypotension, mental confusion, respiratory insufficiency[bark]
[36]
Astragalus plattensisNutt.
Garbancillo
Diuretic
Vomiting[leaves]
[26]
Caesalpinia pulcherrima (L.) Sw.∗∗
Clavellina colorada
Fever, pain, cough
Dermatitis and neurotoxicity[Aerial parts]
[18]
Calliandra grandiflora (L’Hér.) Benth.
Cabello de ángel
Fever
Dermatitis[leaves]
[45]
Calliandra molinaeStandl.
Palo de corcho
Hypertension
Hepatotoxicity, hypotension[leaves]
[46]
Crotalaria pumilaOrtega
Tronador
Cough, diabetes
Abdominal pain, nausea and vomiting[whole plant]
[14]
Crotalaria sagittalisL.
Cocuite
Fever, snake bite
Anoxia, gastritis, abdominal pain, blood in feces[Aerial parts]
[4]
Dalea bicolorHumb. & Bonpl. ex Willd.
Engordacabra
Diarrhea
Vomiting[aerial parts]
[14]
Diphysa robinioidesBenth.
Flor de gallito
Fever, headache
Nausea and vomiting[leaves]
[47]
Entada polystachya(L.) DC.
Bejuco de agua
To promote hair growth
Abdominal pain and severe diarrhea[Fruits]
[4]
Enterolobium cyclocarpum(Jacq.) Griseb.∗∗
Cascabel sonaja
Bronchitis, sore throat
Severe diarrhea and abdominal pain[Aerial parts]
[4]
Erythrina americana Mill∗∗
Colorin
Diuretic
Immobilization, hypotension, and respiratory paralysis[seeds]
[15]
Erythrina standleyanaKrukoff
Cancer
Cancer
Somnolence, vomit[aerial parts]
[8]
Gliricidia sepium (Jacq.) Kunth ex Walp
Matarratón
Vermifuge
Nausea and vomiting[roots, leaves, seeds]
[24]
Indigofera microcarpaDesv.
Yaga-cohui-pichacha
Purgative
Severe diarrhea[leaves]
[4]
Indigofera suffruticosaMill.∗∗
Añil
Vermifuge
Severe diarrhea[leaves]
[4]
Leucaena esculenta (Moc. & Sessé ex DC.) Benth.
Guaje
Wound healing
Nausea and vomiting[seeds]
[48]
Myroxylon pereirae(Royle) Klotzsch∗∗
Indian balsam
Burns, wounds and ulcers
Allergies, contact urticaria and dermatitis[resin]
[49]
Phaseolus lunatusL.
Frijol ancho
Fever, headache
Seizures, immobilization[whole plant]
[4]
Prosopis juliflora(Sw.) DC.
Mezquite
Fever, diabetes
Nausea and vomiting[seeds]
[4]
Robinia pseudoacaciaL.
Black locust
Diuretic, laxative
Anorexia, hypothermia, dyspnoea[bark, leaves and seeds]
[4]
Senna multiglandulosa (Jacq.) H.S. Irwin & Barneby
Parral
Diabetes
Abortifacient[fruit]
[33]
Senna occidentalis(L.) Link∗∗
Frijolillo
Fever
Gastritis, dermatitis, and conjunctivitis[fruit]
[4]
Garryaceae
Garrya ovataBenth.
Cuauhchichic
Diarrhea
Muscle paralysis[bark]
[26]
Gelsemiaceae
Gelsemium sempervirens (L.) J. St.-Hil.∗∗
Retama
Stomachache, asthma, headache, rheumatism
Sedative, vertigo, hypotension, blurred vision[whole plant]
[10]
Gesneriaceae
Moussonia deppeana(Schltdl. & Cham.) Hanst.∗∗
Cacahuapaxtle
Diuretic, gastritis
Abortifacient[aerial parts]
[50]
Lamiaceae
Hedeoma drummondiiBenth.
Drummond’s false pennyroyal
Muscle relaxing
Abortifacient[whole plant]
[26]
Hedeoma pulegioides(L.) Pers.
American pennyroyal
Antispasmodic, pneumonia
Abortifacient, kidney toxicity[aerial parts]
[19]
Salvia leucantha Cav
Lana
Cough, stomachache
Abortifacient[aerial parts]
[27]
Satureja brownei (Sw.) Briq.
Poleo
Colic, cough
Nausea and vomiting, dermatitis, bleeding[whole plant]
[24]
Scutellaria laterifloraL.
Scullcap
Nervousness, headache, fever, anxiety
Giddiness, stupor, confusion, twitching of the limbs, intermission of the pulse[whole plant]
[19]
Loasaceae
Mentzelia hispidaWilld.
Pegajilla
Rheumatism, anemia
Vomiting[resin]
[14]
Loranthaceae
Psittacanthus calyculatus(DC.) G. Don∗∗
Muerdago o injerto
Hypertension, seizures, rheumatism, wound healing
Nausea and vomiting[whole plant]
[26]
Lythraceae
Cuphea aequipetala Cav.∗∗
Hierba del cáncer
Cancer, wound healing
Numbness, nausea and vomiting[aerial parts]
[10]
Magnoliaceae
Magnolia grandifloraL.∗∗
Magnolia
Nervousness, menstrual colics
Dermatitis[leaves]
[51]
Malpighiaceae
Malpighia glabra L.
Acerola
Dysentery, fever
Dermatitis[fruits]
[19]
Malvaceae
Ceiba pentandra (L.) Gaertn.∗∗
Ceiba
Diuretic, cough, fever
Dermatitis[seeds]
[24]
Tilia mexicanaSchltdl.∗∗
Tilia
Nervousness, menstrual pain
Hepatotoxicity[flower]
[39]
Marantaceae
Thalia geniculataL.
Kento
Anaemia, hemorrhoids
Edema, gastritis[aerial parts]
[8]
Martyniaceae
Martynia annua L.∗∗
Uña de gato
Snake bite
Nausea and vomiting[seeds]
[18]
Melanthiaceae
Veratrum californicumDurand∗∗
California corn lily
Cancer
Neurotoxicity[whole plant]
[11]
Trillium erectumL.
Bethroot
To prevent obstetric hemorrhage
Skin burns[leaves]
[19]
Menispermaceae
Menispermum canadenseL.
Canada moonseed
Warts
Cardiotoxicity[fruits]
[11]
Myrtaceae
Pimenta dioica(L.) Merr.∗∗
Pimiento
Rheumatism, stomachache
Neurotoxicity[whole plant]
[19]
Nartheciaceae
Aletris farinosaL.
Unicorn root
Laxative, diarrhea, rheumatism
Narcotic[whole plant]
[19]
Nyctaginacea
Mirabilis jalapaL∗∗
Maravilla
Rheumatism, stomachache, fever
Severe diarrhea[roots and seeds]
[4]
Oxalidaceae
Oxalis alpina (Rose) Rose ex R. Knuth
Acedera
Gastritis
Poisoning[whole plant]
[7]
Papaveraceae
Argemone mexicana L.∗∗
Cardo santo
Wound healing, fever, diuretic, analgesic
Dermatitis, abortifacient immobilizing, neurotoxicity[whole plant]
[35]
Sanguinaria canadensis L.∗∗
Bloodroot
Skin cancer, polyps and warts
Narcotic[root]
[19]
Passifloraceae
Passiflora caerulea L.
Pasionaria azul
Epilepsy, anxiolytic
Nausea and vomiting, dizziness[flower]
[24]
Passiflora edulis Sims∗∗
Maracuya
Relaxing
Hallucinations, dizziness, confusion, ataxia, nausea and vomiting, drowsiness, and tachycardia;[flower]
[39, 41]
Passiflora quadrangularis L.
Badea
Vermifuge, obesity
Nausea and vomiting, dizziness[leaves and seeds]
[24]
Petiveriaceae
Rivina humilisL.∗∗
Coralillo
Varicose veins, snake bite, wound healing, stomachache
Nausea and vomiting, abdominal pain[whole plant]
[11]
Phytolaccaceae
Phytolacca americana L.
Hierba carmine
Warts
Blurred vision, vomit, vertigo[whole plant]
[52]
Phytolacca icosandraL.∗∗
Mazorquilla
Cancer, vermifuge, rheumatism
Blurred vision, vomiting,[roots]
[14]
Phytolacca rivinoidesKunth & C.D. Bouché
Mazorquilla
Headache, wound healing, vermifuge
Blurred vision, vomit, vertigo[whole plant]
[30]
Plantaginaceae
Scoparia dulcisL.∗∗
Culantrillo
Diarrhea, stomachache, asthma, nervousness
Hepatotoxicity[whole plant]
[39]
Plumbaginaceae
Plumbago pulchellaBoiss.
Jiricua
Diabetes, wound healing
Skin burns, vomiting[whole plant]
[14]
Polygalaceae
Monnina schlechtendaliana D. Dietr.
Aguacatillo
Dehydration
Nausea and vomiting[fruit]
[33]
Polygala senegaL.
rattlesnake root
Cough, diuretic
Gastritis[roots]
[19]
Rumex hymenosepalusTorr.∗∗
Canaigre
Wound healing
Vomiting, abdominal pain[Aerial parts]
[19]
Ranunculaceae
Actaea alba(L.) Mill.
White cohosh
Arthritis, rheumatism, dysmenorrhea
Headache, vomiting, delirium, circulatory failure[whole plant]
[19]
Actaea rubra(Aiton) Willd.
Baneberry
Dysmenorrhea
Vomiting, abdominal pain, salivation[fruits and roots]
[11]
Anemone canadensisL.
Meadow anemone
Body pain and wound healing
Salivation, abdominal pain, and salivation[whole plant]
[11]
Cimicifuga racemosa (L.) Nutt.∗∗
Baneberry
To manage some symptoms of menopause
Vomiting, abdominal pain[fruit]
[19]
Clematis dioica L.
Barba de chivo
Rheumatism, cough, diuretic
Skin burns[leaves]
[10]
Clematis virginianaL.
Old man’s beard
For skin disorders (sores, cuts), itching and venereal eruptions
Dizziness, confusion, profuse salivation[leaves]
[19]
Hydrastis canadensisL.∗∗
Sello dorado
Laxative
Gastritis, abortifacient[rhizome]
[35]
Ranunculus geoides Humb. Bonpl. & Kunth ex DC
Pata de león
Cough
Skin burns[seeds and fruits]
[30]
Thalictrum strigillosum Hemsl.
Hierba del zorro
Cough
Nausea and vomiting[whole plant]
[7]
Rhamnaceae
Karwinskia humboldtiana(Schult.) Zucc.∗∗
Tullidora
Wound healing
Immobilization, abortifacient[fruit]
[53]
Karwinskia mollisSchltdl.
Capulín
Wound healing
Immobilization[fruit]
[54]
Rhamnus kcalifornicaEschsch
California buckthorn
Laxative
Gastritis[fruit and bark]
[11]
Rosaceae
Prunus serotina Ehrh.
Capulín blanco
Cough, diarrhea, abdominal pain
Spasm, nausea and vomiting[leaves and seeds]
[7]
Rubarwiaceae
Carapichea ipecacuanha(Brot.) L. Andersson
Ipecac
Dysentery
Rhinitis or asthma[whole plant]
[19]
Cephalanthus occidentalisL.
Guayabillo
Fever
Vomiting, seizures, anemia[bark]
[4]
Cinchona pubescensVahl∗∗
Quino
Malaria, varicose veins, internal hemorrhoids
Hypoglycemia, hematologic disorders, urticaria, contact dermatitis, and other hypersensitivity reactions.
[19]
Rutaceae
Casimiroa edulisLa Llave & Lex.∗∗
Matasanos
Hypertension, diabetes, rheumatism
Hepatotoxicity, peptic ulcer, hypotensive[leaves]
[46]
Ruta chalepensis L.∗∗
Ruda
Analgesic
Dermatitis, abortifacient[aerial parts]
[18]
Zanthoxylum fagara(L.) Sarg.
Colima
Nervousness
Narcotic[leaves]
[26]
Santalaceae
Phoradendron bolleanum (Seem.) Eichler
Muerdago
Diuretic
Nausea and vomiting[leaves and seeds]
[55]
Phoradendron quadrangulare(Kunth) Griseb.
Muerdago
Cancer
Nausea and vomiting, dehydration[aerial parts]
[11]
Phoradendron serotinum(Raf.) M.C. Johnst.∗∗
Muerdago
Cancer, diabetes
Nausea and vomiting, abdominal pain, dehydration[aerial parts]
[11]
Sapindaceae
Sapindus saponariaL.∗∗
Jaboncillo
Diuretic
Skin burns[seeds]
[24]
Sapotaceae
Pouteria sapota(Jacq.) H.E. Moore & Stearn∗∗
Zapote
To eliminate louse
Nausea and vomiting, dizziness[seeds]
[35]
Scrophulariaceae
Buddleja marrubiifoliaBenth.
Azafran de campo
Diuretic
Neurotoxicity[seeds]
[26]
Simaroubaceae
Picrasma excelsa(Sw.) Planch.
Palo Amarillo
Stomachache, diabetes
Hypotension[bark]
[35]
Castela tortuosa Liebm.
Chaparro amargo
Fever, amebas
Hepatotoxicity[stem]
[37]
Smilacaceae
Smilax aristolochiifoliaMill.
Zarzaparilla
Syphilis, psoriasis
Gastritis[whole plant]
[19]
Solanaceae
Capsicum annuumL.∗∗
Chile
Analgesic
Dermatitis by rubbing or gastritis, hemorrhoids, and colitis by oral administration[seeds, fruits]
[35]
Cestrum fasciculatum (Schltdl.) Miers
Hierba del perro
Vomiting
Nausea and vomiting, dizziness[aerial parts]
[10]
Cestrum nocturnumL.
Dama de noche
Headache, stomachache
tachycardia, dyspnea, fever, hallucinations[leaves]
[4]
Datura inoxiaMiller.∗∗
Toloache
Diabetes, asthma, wound healing
Narcotic, anorexic, cardiotoxicity, blurred vision[seeds]
[15]
Solanum americanum Mill∗∗
Quelite mora
Headache, wound healing
Dermatitis, vomiting, severe diarrhea, paralysis[fruits]
[29]
Solanum elaeagnifolium Cav.
Trompillo
Rattlesnake bite
Dermatitis[whole plant]
[13]
Solanum mammosumL.
Chichigua
Diuretic, cough
Narcotic, cardiotoxicity[fruits]
[35]
Solanum nigrescens M. Martens & Galeotti∗∗
Hierba mora
Fever, rheumatism
Immobilization[leaves and seeds]
[7]
Solanum rostratum Dunal
Duraznillo
Diuretic, stomachache, diarrhea
Dermatitis[aerial parts]
[13]
Witheringia solanacea L’Hér.
Merengena
To purify blood
Nausea and vomiting[leaves and seeds]
[47]
Urticaceae
Urera baccifera (L.) Gaudich. ex Wedd.∗∗
Ortiga brava
Diuretic, rheumatism, body pain
Dermatitis, edema[aerial parts]
[11]
Urtica mexicana Liebm.
Ortiga
Diabetes, rheumatism
Skin burns[aerial parts]
[10]
Verbenaceae
Duranta repensL.
Mohuite de huerto
To purify blood, fever
Nausea and vomiting, seizures[flowers]
[4]
Lantana camara L.∗∗
Hierba de San Pedro
Stomachache, diarrhea, rheumatism
Hepatotoxicity, nausea, and vomiting[aerial parts]
[52]
Lippia dulcis Trevir.
Hierbabuena dulce
Cough, diarrhea, stomachache
Vertigo, hypotension[aerial parts]
[18]
Zygophyllaceae
Larrea divaricata Cav.∗∗
Chaparral
Rheumatism, tuberculosis, snake bite
Hepatotoxicity[aerial parts]
[56]
Larrea tridentata (DC.) Coville∗∗
Gobernadora
Diabetes, diuretic
Hepatotoxicity, nausea and vomiting, abortifacient, gastritis[aerial parts]
[37]
∗
∗ indicates plant with toxicological information obtained from preclinical or clinical studies.


## 3. Medicinal Plants Considered to Be Toxic for Humans

A total of 216 medicinal plants belonging to 77 families reported as toxic were recorded. Of these plants, 76 had been studied, and 140 plants lacked studies regarding their toxicological effects (Table1).Aristolochia (6 plant species),Euphorbia (6 plant species),Solanum (5 plant species), andAsclepias (5 plant species) are the plant genera most often reported to induce toxicity (Table 1). Chemotaxonomic studies should be performed to identify the toxic principle in these genera. The parts of the plants considered toxic are listed in the following order: aerial parts including branches, leaves and flowers (22%), whole plant (22%), leaves exclusively (15%), seeds (14%), roots (8%), fruits (8%), bark (4%), latex (3%), and other plant parts.The signs and symptoms of toxicity induced by medicinal plants are reported in Table1. The main toxic effects occur in the following order: nausea and vomiting (20%), dermatitis (14%), gastritis (9%), abdominal pain (9%), abortifacient (8%), skin burns (8%), hepatotoxicity (7%), severe diarrhea (6%), cardiotoxicity (5%), nephrotoxicity (2%), numbness (2%), dizziness (2%), and hallucinations (2%), among others.


### 3.1. Dosages

In most of the cases, the dose for the induction of toxic effects by medicinal plants is not indicated. Usually, consumers of medicinal plants believe that increasing the consumption of these products will increase the efficacy of the treatment. In these cases, the daily dosage is exceeded, which triggers toxicity. For instance, the roots ofIpomoea purga, a purgative agent, are used at a dose of 2 g/L/day. Administration of higher doses induces vomiting and abdominal pain [15]. Fresh leaves ofPrunus serotina, used for the treatment of cough, orZanthoxylum fagara, an anxiolytic agent, each must be consumed in a maximum quantity of five leaves in 250 ml of water per day. Higher doses produce spasms and nausea [26]. Approximately 5 mL of an infusion ofPicrasma excelsa (10 g/L) should be administered three times per day. Higher doses induce hypotension. This infusion should not be prepared with ethanol and orally administered. If a person consumes the hydroalcoholic infusion, the consequences could be lethal [35]. The maximum consumption ofManilkara zapota seeds should be 10 seeds per day. A higher consumption of these seeds might induce vomiting and gastroenteritis [26]. On the other hand, Sosa-Gómez [35] recommends the preparation of an infusion using approximately 1–3 gArgemone mexicana leaves in 1 L of water. This infusion should be taken 3 times per day. A higher dose might induce immobilization.Studies analyzing the range of doses considered safe for human consumption remain to be performed. The use of natural products needs scientific evidence to corroborate the medicinal uses attributed to different plant species. Many medicinal plants sold as “food supplements” lack warnings if the suggested dosage is exceeded.


### 3.2. Toxic Principles

In some cases, the toxic principle is known. For instance, it is reported that cefalatin, the main toxic compound inCephalanthus occidentalis bark, induces vomiting, anemia, and seizures, among other toxic effects. Similarly, hederagenin is the main toxic compound inClematis dioica, which is a caustic substance [4]. Monocrotaline is the compound responsible for the toxic effects inCrotalaria sagittalis. Cianhidric acid, one of the most toxic compounds in plants, is found inCrescentia cujete fruit,Phaseolus lunatus whole plant, andPrunus serotina leaves and seeds [4]. InPhaseolus lunatus, the concentration of cianhidric acid ranges 6.8–533 mg/kg dw [74, 75]. There is limited information on the major toxic compounds cited in this review. Therefore, the identification of toxic principles in medicinal plants is necessary.


## 3.1. Dosages

In most of the cases, the dose for the induction of toxic effects by medicinal plants is not indicated. Usually, consumers of medicinal plants believe that increasing the consumption of these products will increase the efficacy of the treatment. In these cases, the daily dosage is exceeded, which triggers toxicity. For instance, the roots ofIpomoea purga, a purgative agent, are used at a dose of 2 g/L/day. Administration of higher doses induces vomiting and abdominal pain [15]. Fresh leaves ofPrunus serotina, used for the treatment of cough, orZanthoxylum fagara, an anxiolytic agent, each must be consumed in a maximum quantity of five leaves in 250 ml of water per day. Higher doses produce spasms and nausea [26]. Approximately 5 mL of an infusion ofPicrasma excelsa (10 g/L) should be administered three times per day. Higher doses induce hypotension. This infusion should not be prepared with ethanol and orally administered. If a person consumes the hydroalcoholic infusion, the consequences could be lethal [35]. The maximum consumption ofManilkara zapota seeds should be 10 seeds per day. A higher consumption of these seeds might induce vomiting and gastroenteritis [26]. On the other hand, Sosa-Gómez [35] recommends the preparation of an infusion using approximately 1–3 gArgemone mexicana leaves in 1 L of water. This infusion should be taken 3 times per day. A higher dose might induce immobilization.Studies analyzing the range of doses considered safe for human consumption remain to be performed. The use of natural products needs scientific evidence to corroborate the medicinal uses attributed to different plant species. Many medicinal plants sold as “food supplements” lack warnings if the suggested dosage is exceeded.


## 3.2. Toxic Principles

In some cases, the toxic principle is known. For instance, it is reported that cefalatin, the main toxic compound inCephalanthus occidentalis bark, induces vomiting, anemia, and seizures, among other toxic effects. Similarly, hederagenin is the main toxic compound inClematis dioica, which is a caustic substance [4]. Monocrotaline is the compound responsible for the toxic effects inCrotalaria sagittalis. Cianhidric acid, one of the most toxic compounds in plants, is found inCrescentia cujete fruit,Phaseolus lunatus whole plant, andPrunus serotina leaves and seeds [4]. InPhaseolus lunatus, the concentration of cianhidric acid ranges 6.8–533 mg/kg dw [74, 75]. There is limited information on the major toxic compounds cited in this review. Therefore, the identification of toxic principles in medicinal plants is necessary.


## 4. Toxicology

### 4.1.In Vitro Studies

TheArtemia salina (brine shrimp) bioassay has been widely used for the analysis of acute toxicityin vitro. Although there are no range values to consider an extract or compound as toxic in the brine shrimp test, vincristine, the positive control for toxicity, has a lethal concentration 50 (LC50) = 0.91 μg/ml [76]. Considering this value, plant extracts or compounds with LC50 values 1000-fold higher than vincristine could be considered nontoxic.The following plant extracts have been tested for theirin vitrotoxicology using the brine shrimp test and had LC50 values higher than 1000 μg/ml. The ethyl acetate fraction ofSolanum nigrescens aerial parts [77], the ethanol extract ofAmbrosia peruvianawhole plant [78], the aqueous extract ofJatropha gossypifolia aerial parts [79], the methanol extract ofJatropha dioica leaves [80], the aqueous extract ofCnidoscolus urens whole plant [79], the ethanol extract ofCrescentia cujete fruits [81], the aqueous extract ofEnterolobium cyclocarpum bark [82], and the ethanol extract ofCordia dentata leaves and their fractions [83].The plant extract and compounds that could be considered dangerous (LC50 = 100–1000 μg/ml) include the following: methanol and hexane proportions derived from a hexane extract ofGymnosperma glutinosum aerial parts [84], the ethyl acetate extracts ofMonstera deliciosa branches [85], and icosandrin, a cyclic homoflavonoid isolated fromPhytolacca icosandra [86].The plant extract and compounds that could be considered toxic (LC50 = 10–100 μg/ml) include the following: the ethyl acetate extracts ofMonstera deliciosa leaves [85], the ethanol extract ofSolanum americanum fruits [87], the ethanol extract ofScoparia dulcis aerial parts [76], the methanol extract ofEnterolobium cyclocarpumleaves [88], the ethanol extract ofPimenta dioica leaves [89], and the hydroalcoholic extract ofSanguinaria canadensis whole plant [90]. None of the plant extracts or compounds included in this review were considered highly toxic (LC50 < 10 μg/ml).


#### 4.1.1. Cytotoxicity

Other plant extracts and their compounds have been tested in otherin vitro models, including cytotoxicity test in nontumorigenic cells, genotoxicity using the comet assay on lymphocytes, and the mutagenic test using lymphocytes orSalmonella spp. The positive controls for cytotoxicity in nontumorigenic cells include cisplatin and Taxol. These compounds have inhibitory concentration 50 (IC50) values ranging from 0.1 to 4 μg/ml [91]. Some plants extracts have been reported to lack cytotoxic effects (IC50 > 250 μg/ml) in nontumorigenic cells. These include the ethanol extract ofPhoradendron serotinum leaves tested on peripheral blood mononuclear cells [91], the aqueous extract ofCnidoscolus chayamansaleaves on baby hamster kidney (BHK) cells [92], and the aqueous extract ofEnterolobium cyclocarpum bark assayed on 3T3 murine preadipocytes [82]. Additionally, the ethanol extract ofEquisetum hyemale aerial parts evaluated on rabbit corneal fibroblasts (SIRC) [93], the methanol extract ofEnterolobium cyclocarpum leaves evaluated on Vero cells (obtained from kidney epithelial cells extracted from the African green monkey(Cercopithecus aethiops) [88], and the diterpene ent‐kaur‐16‐en‐19‐oic acid, obtained fromAnnona cherimola, tested on rat embryo primary striatal cultures [94]. On the other hand, the hydroalcoholic extract ofHura crepitans leaves had an IC50 = 107.7 μg/ml in lung fibroblasts [95].


#### 4.1.2. Mutagenicity and Genotoxicity

Regarding mutagenicity, parthenin, isolated fromParthenium hysterophorus, lacked mutagenicity (0.19 to 19 μM) but showed chromosomal aberrations at concentrations of 10–60 μM in blood lymphocytes [96]. These results suggested genotoxic effects of parthenin. A methanol extract ofIndigofera suffruticosa aerial parts (1.25–7.5 mg/plate) showed mutagenic activity in aSalmonella microsome assay [97]. The acetone extract ofHeliopsis longipes roots (10–80 μg/Petri dish) and its active compound affinin (6.25–50 μg/Petri dish) were not mutagenic, as evaluated by the Ames test [98]. Lobeline (5–10 mg/kg i.p.), an alkaloid isolated fromLobelia inflata, had no genotoxic or mutagenic effects in the comet assay, the micronucleus test in bone marrow, or the Salmonella/microsome mutagenic assay [99].For genotoxicity, the ethyl acetate/n-hexane extract ofZinnia peruviana aerial parts tested using 5 and 20 mg/ml extracts showed genotoxic effects in PBMC compared to the positive control of copper sulfate (1%) [100]. A butanol fraction ofUrera baccifera roots at a 1.8 mg/g concentration of oxalic acid decreased leukocyte number significantly and increased cell death and DNA damage in primary cultures of leukocytes in comparison to the control treatment [101]. The methanolic extract ofPsittacanthus calyculatus aerial parts (200 and 400 mg/kg i.p.) did not induce chromosomal damage in peripheral blood erythrocytes obtained from mice after 72 h of exposure [102]. An ethanol extract ofHeliopsis longipes roots (3–100 mg/kg p.o.) did not produce genotoxic or cytotoxic effects on peripheral blood mononuclear cells obtained from mice 24–96 h after administration [103]. Parthenin, isolated fromParthenium hysterophorus, showed genotoxic effects at 4–31 mg/kg i.p. in micronuclei in mouse peripheral blood after 48 and 72 h of treatment [96].


### 4.2.In Vivo Acute Studies

#### 4.2.1. Lethal Dose 50 (LD50)

The guideline 423 of the Organization for Economic Cooperation and Development (OECD) establishes that substances with an LD50 < 5 mg/kg are highly toxic, whereas LD50 values from 5 to 50 mg/kg are very toxic, LD50 values from 50 to 300 mg/kg are toxic, LD50 values from 300 to 2000 mg/kg are dangerous, and LD50 values higher than 2000 mg/kg are not dangerous [104].Some plant extracts showed LD50 > 2000 mg/kg p.o. in mice: ethanol extracts of leaves ofCasimiroa edulis [105] andCnidoscolus chayamansa [106], ethanol extracts of aerial parts ofMoussonia deppeana [107],Equisetum hyemale [93], andRuta chalepensis [108], as well as methanol extracts of leaves ofChenopodium ambrosioides [109] andRauvolfia tetraphylla [110]. The same pattern was also shown in aqueous extract ofCuphea aequipetala aerial parts [111], ethanol extract ofPlumeria rubraflowers [112], aqueous extract ofLarrea divaricata leaves [113], ethanol extract ofCaesalpinia pulcherrimaleaves and bark [114, 115]. aqueous extract ofEuphorbia prostrata whole plant [116], aqueous-methanol extract ofCeiba pentandra leaves [117], petroleum ether, chloroform, and methanol extracts ofGelsemium sempervirens roots [118], acetone extract ofCapsicum annum fruits [119], and aqueous and ethanol extract ofScoparia dulcis leaves and whole plant [120, 121].The following extracts have shown LD50 > 2000 mg/kg p.o. in rats: aqueous extract ofPouteria sapota seeds [122], methanol extract ofMartynia annua leaves [123], ethanol extract ofFlourensia cernua leaves [124], aqueous extract ofEnterolobium cyclocarpum bark [82], ethanol and aqueous extractC. pulcherrima aerial parts [125], aqueous extract ofPassiflora edulis leaves [126], hydroalcoholic extract ofMagnolia grandiflora seeds [127], and ethanol extract ofCrescentia cujete fruits [128]. The same pattern was also shown in methanol extracts of leaves ofAmaranthus spinosus [129], andRauvolfia tetraphylla [130], chloroform-methanol extract ofCnidoscolus chayamansa leaves [131], aqueous extract ofR. humilis fruits [132], a chloroform fraction from an ethanol extract ofTagetes erecta flowers [133], aqueous extract ofKarwinskia humboldtiana seeds [134], and hydroalcoholic extract ofSenna occidentalis aerial parts [135], as well as lutein and lutein ester, obtained fromTagetes erecta [136], and ethanol extract ofJatropha gossypiifolia aerial parts [137], and aqueous extract ofCaladium bicolor [138].Other plant extracts showed LD50 > 2000 mg/kg i.p. in mice: hexane extract ofTilia mexicana inflorescences [139], aqueous extract ofTagetes lucida aerial parts [140], ethanol extract ofMirabilis jalapaaerial parts [141], and aqueous extract ofUrera baccifera leaves [142].Some plant extracts and plant compounds had LD50 values from 300 to 2000 mg/kg, which is considered dangerous [104]. These plant extracts were intraperitoneally administered to mice: the ethanol extract ofTagetes lucida aerial parts (LD50 = 970 mg/kg) [140], the aqueous extract ofCaladium bicolor leaves (LD50 = 1778.28 mg/kg) [138], and the ethanol extract ofTagetes lucida aerial parts (LD50 = 970 mg/kg i.p.) [140]. On the other hand, the ethanol extract ofPhoradendron serotinum leaves had an LD50 = 375 mg/kg p.o. in mice [143], and sanguinarine, an alkaloid isolated fromSanguinaria canadensis, had an LD50 = 1658 mg/kg p.o. in rats [144]. Methanol extracts ofTilia mexicana inflorescences had LD50 values of 375 mg/kg i.p. in mice [139].Other plant extracts and plant compounds had LD50 values varying from 50 to 300 mg/kg, which is considered toxic [104]. Ethanol extract ofPhoradendron serotinum leaves had an LD50 = 125 mg/kg i.p. in mice, [143], whereas capsaicin, the main active principle ofCapsicum annum, had an LD50 = 190 mg/kg p.o. [145]. The acetone extract ofHeliopsis longipes roots had an LD50 = 62.14 mg/kg p.o. in mice, whereas its active compound affinin had an LD50 = 113.13 mg/kg p.o. in mice [98]. The ethanol extract ofHeliopsis longipes roots had an LD50 = 288 mg/kg p.o. in mice [103].The following plant extracts and compounds can be considered very toxic (5–50 mg/kg) [104]: the free alkaloid fraction in hexane and methanol extracts fromErythrina americana seeds (LD50 = 38.54 to 40.37 mg/kg i.p.) in mice [146],Jatropha curcas oil (LD50 = 23.34 mg/kg p.o.) in mice [147], and α-solamargine, isolated fromSolanum americanum, with an LD50 = 42±2 mg/kg i.p. in rats [148]. The alkaloid N-methylisocorydinium, obtained fromMagnolia grandiflora trunk wood, had an LD50 = 10 mg/kg i.p. in mice [149] and γ-coniceine, isolated fromConium maculatum, had an LD50 = 12 mg/kg p.o in mice [150]. Parthenin, the toxic compound ofParthenium hysterophorus, had an LD50 = 42 mg/kg i.p. in rats [151]. Capsaicin had an LD50 = 8 mg/kg i.p. and 7.80 mg/kg i.m in mice [152]. Sanguinarine, an alkaloid isolated fromSanguinaria canadensis, was toxic at 29 mg/kg i.v. in rats [144].The following plant compounds had LD50 values < 5 mg/kg, which is considered highly toxic [104]. Capsaicin had an LD50 = 0.56 mg/kg i.v. [152].


#### 4.2.2. Biochemical and Hematological Parameters

Treatment with plant extracts in short-term studies have effects on biochemical and hematological parameters, as well as the levels of the hepatic enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). An aqueous extract ofLarrea divaricata aerial parts (0.5–200 mg/kg i.p.) did not affect the levels of ALT in mice after 2 days [153]. Aqueous extract ofKarwinskia humboldtiana fruits (1250 mg/kg p.o.) administered to rats for 3 days increased the levels of hepatic enzymes compared to the untreated group [154]. An aqueous extract ofPassiflora edulis (30 mg/kg p.o.) did not affect motor coordination in mice or change the biochemical measurements in serum after 4 days [155]. α-Solamargine (15–35 mg/kg i.p.) did not affect hematological parameters or the levels of hepatic enzymes in rats after 5 days [148], whereas an aqueous extract ofKarwinskia humboldtiana fruit (5000 mg/kg p.o.) in rats for 5 days induced weight loss (15%) in rats, as well as toxicity in the pancreas [156]. An aqueous extract ofPassiflora edulis leaves (100–400 mg/kg p.o.) did not affect organ body weight or hematological parameters but decreased the levels of ALT in rats after 7 days of treatment at all doses [126]. A methanol extract ofR. tetraphylla leaves (1000 mg/kg p.o.) decreased body weight change and food consumption and increased total bilirubin in rats after 7 days [157]. An aqueous extract ofK. humboldtiana (1000–2000 mg/kg p.o.) administered for 7 days in rats induced alterations in membrane fluidity and ATPase activity in liver submitochondrial particles [158]. An ethanol extract ofEuphorbia hirta leaves (60.4–483 mg/kg i.p.) [159] and a chloroform fraction from an ethanol extract ofTagetes erecta flowers (200–400 mg/kg p.o.) [133] did not affect hematological or biochemical parameters in rats after 14 days. An aqueous extract ofEuphorbia hirta whole plant administered at a single dose of 2000 mg/kg p.o. significantly decreased the levels of ALP and ALT after 14 days in broiler chickens [160]. Lobeline (5–10 mg/kg i.p.) did not affect the levels of AST, ALT, ALP, and LDH after 4 days of exposure [99].


#### 4.2.3. Toxicity to Reproduction and Pregnancy

α-Solamargine (15–35 mg/kg i.p.) did not affect the number of spermatozoa or the weight of the testicles and epididymis of male rats after 24 h of treatment [148]. Jervine (70–300 mg/kg p.o.), a steroidal alkaloid found inVeratrum californicum, administered on days 8–10 of gestation induced malformations in the offspring, including isolated cleft palate, mandibular micrognathia, and limb malformations in C57BL/6J and A/J mice [161]. The administration of an aqueous extract ofRuta chalepensis leaves (10 mg/kg p.o.) to pregnant rats from day 9 to day 17 of gestation decreased the uterine weight, the number of live fetuses, and the fetal weight. The number of fetal resorptions was also increased, and the fetuses showed skeletal malformations [162]. Additionally, an aqueous extract ofR. chalepensisleaves (0.8 and 1.6 g/kg p.o.) administered to mice from day 1 to day 14 post coitum caused perinatal changes in mice such as righting reflex, cliff avoidance, and swimming ability, among others [163].


#### 4.2.4. Dermal Tests

An aqueous extract ofPouteria sapota seeds lacked dermal irritation in rabbits and showed mild reversible eye irritation in rabbits [122].Jatropha multifida sap did not induce skin lesions in rats after 14 days of treatment [164]. A diethyl ether extract ofJatropha multifida showed the presence of 16-hydroxyphorbol. This compound showed an irritant dose 50 (ID50) of 0.05 μg/ear [165].


### 4.3.In Vivo Subacute and Chronic Studies

#### 4.3.1. Biochemical and Hematological Parameters

Some plant extracts and their active compounds have been tested for their effects on biochemical and hematological parameters in rodents for at least 18 days of exposure. A histological study has also been included in some reports. A hydroalcoholic extractof Senna occidentalisaerial parts (100–2500 mg/kg p.o.) [135] and a hydroalcoholic extract ofSapindus saponaria leaves (44.76 mg/kg p.o.) and fruits (45.0 mg/kg p.o.) [166] did not change the biochemical profile or hematological parameters or alter body weight and organ weight for 30 days in rats. An ethanol extract of the pod ofPlumeria rubra (50–200 mg/kg p.o) [167] and an aqueous-methanol extract ofCeiba pentandra leaves (250 and 500 mg/kg p.o.) [117] did not alter hematological or biochemical parameters in rats and mice, respectively, after 21 days [167]. A chloroform-methanol extract ofCnidoscolus chayamansa leaves (1000 mg/kg p.o.) [131] and an ethanol extract ofMoussonia deppeana aerial parts (1000 mg/kg p.o.) [107] did not affect biochemical or hematological parameters in mice after 28 days of daily administration. In addition, histological examinations of the spleen, kidney, and liver showed no abnormalities. Capsaicin (5–100 mg/kg p.o.) [168], obtained fromCapsicum annum, and lutein and lutein ester (4–400 mg/kg p.o.) [136], obtained fromTagetes erecta, did not affect hematological or biochemical parameters, growth, food consumption, or body weight in mice and rats, respectively, after 28 days. An aqueous extract ofRivina humilis fruits (2500 and 5000 mg/kg p.o.) administered daily for 35 days showed no changes in the hematological profile or in the relative organ weight, whereas the same extract administered daily for 90 days at 0.5–2 g/100 g in a powdered diet did not affect hematological parameters, biochemical determinations, or the levels of hepatic enzymes [132].In contrast, some plant extracts have altered biochemical and/or hematological parameters. An aqueous extract ofAbrus precatorius leaves (400–1600 mg/kg p.o.) was administered to rats for 18 days. Only the highest dose (1600 mg/kg p.o.) decreased levels of hematological parameters and increased the levels of hepatic enzymes [169]. An aqueous extract ofScoparia dulcis leaves (250–500 mg/kg p.o.) showed mild vascular and portal congestion in the heart and the liver, respectively, of rats treated daily with this extract for 30 days. Nevertheless, there were effects in the lungs and testis [120]. A methanol extract ofRauvolfia tetraphylla leaves did not affect hematological parameters. However, a significant decrease in the total bilirubin and glucose levels was observed in the mice treated at 100 and 300 mg/kg, with a significant increase in triglycerides at doses of 10–300 mg/kg after 28 days in mice [130]. An ethanol extract of the aerial parts fromJatropha gossypifolia (135 mg/kg p.o. or higher doses) reduced the activity in the central nervous system and showed hepatotoxicity, pulmonary damage, and digestive disturbances in rats over 13 weeks of treatment [170]. The lethality was 46.6% and 13.3% among male and female rats under the highest tested dose (405 mg/kg), respectively [170].


#### 4.3.2. Toxicity during Reproduction and Pregnancy

Yao et al. [171] reported that an aqueous extract ofHydrastis canadensis (1.86 g/kg p.o.) containing 9.6 mg/ml of berberine and 8.4 mg/ml of hydrastine did not affect fetal development in pregnant rats over 20 days of treatment. AProsopis juliflora seedcase added at 70% to the diet of pregnant rats resulted to be teratogenic (13-fold) compared to the untreated group [172]. Aqueous and ethanol extracts ofPlumeria rubra pods (200 mg/kg p.o.) had 51% and 100% abortifacient activity, respectively, in female albino rats from day 11 to day 15 of pregnancy [173]. The hydroalcoholic extract ofLantana camara leaves (1000–7000 mg/kg p.o.) administered during premating, mating, pregnancy, and lactation (56 days in total) in rats did not affect mating, pregnancy, delivery, and live birth. Nevertheless, the two highest doses tested (3000 and 7000 mg/kg p.o.) produced an increase in the resorption rate and parallel increases in the postimplantation loss index, as well as embryotoxicity characterized by skeletal abnormalities [174].


#### 4.3.3. Carcinogenicity

Only one plant extract has been tested for its carcinogenic effects. Rats (treated with doses ranging 136–1175 mg/kg p.o.) and mice (treated with doses ranging 375–3275 mg/kg) received an aqueous extract ofHydrastis canadensis root for 2 years (106 weeks). At the end of the treatment, the doses of 1175 mg/kg in rats and the doses varying from 1120 to 3275 mg/kg in mice showed hepatocarcinoma [175].


### 4.4. Clinical Cases

The toxicity of sixteen species plants has been reported in clinical cases. Fourteen of the sixteen plants are enlisted in Table2. The other two plants are described in Section 4.4.1. The Naranjo algorithm [176], which consists of 10 questions that address the factors considered to determine the causal relationship in case reports, was used to assess causality. A score is obtained (maximum 13) and the results are classified as doubtful or unlikely (0), possible (from 1 to 4), probable (from 5 to 8), and clear or definite (socre > 9). The event must be definitive from a pharmacological or phenomenological point of view, using, if necessary, a conclusive procedure of reexposure [177].Table 2
Evaluation of causality and exclusion of alternate causes in clinical cases of medicinal plants from Mexico and Central America considered as toxic.
Information of the patient (age, gender, country of residence)
Plant, way of administration, dose and part of the plant consumed, time of consumption if indicated
First symptoms (onset, in days, of the first symptoms)
Toxic effects(onset, in days, of the toxic effects)
Clinical complications
Evaluation of causality (score)
Amount of information
Outcome(days)
Alternate causes excluded
Reference
9, M, Israel
Jatropha multifida Oral: >10 fruits
Vomiting, watery diarrhea, and abdominal pain (1 h)
Gastroenteritis (1)
Hepatic enzymes elevation
Naranjo (5): probable
Enough
Recovered (5)
ND
[43]
8, M, Israel
Vomiting, watery diarrhea, and abdominal pain (1 h)
Gastroenteritis (1)
Hepatic enzymes elevation
Naranjo (5): probable
Enough
Recovered (5)
ND
20 children;8–13 years old, India
Jatropha curcas,Oral: 1–4 seeds
1-2 h
Vomiting (95%)Headache (40%) Fever (40%)Diarrhea (50%)
ND
Regular
Recovered(6 hours)
ND
[57]
4, M, United States of America
Conium maculatum (piperidina 850 Ug/g plant), ND
Drowsiness (0.5 h)
Central nervous system depression (3 hours)
ND
Naranjo (6): probable
Regular
Recovered (6)
ND
[58]
19, F, Turkey
Conium maculatum,ND
Headache, blurred vision, and difficulty speaking (0.5 h)
Central nervous system depression (ND)
Difficulty breathing
Naranjo (5): probable
Regular
Recovered (1)
ND
[59]
5, M, India
Argemone mexicana Oral: oil
Abdominal pain, loos of movements and swelling throughout the body (20)
Epidemic dropsy (ND)
ND
Naranjo (6):Probable
Regular
Fatal (4)
Thalassemia and sickle cell disease (postmortem)
[60]
10, M, India
Abdominal pain, fever, and shortness of breath (20)
ND
Naranjo (6):Probable
Regular
Fatal (11)
Thalassemia and sickle cell disease (postmortem)
2, F, Mexico
Chenopodium ambrosioides,Oral: oil 80 ml (1,560 mg ascaridol)
Vomiting and CNS depression (3 h)
Multiple organ dysfunction syndrome (ND)
Seizures, periods of apnea
Naranjo (6): probable
Enough
Fatal (3)
Encephalopathy due to lead poisoning and organophosphates
[61]
64, F, United States of America
Cimicifuga racemosa,Oral: capsules (80 mg/day/2 months)
Painful nodules on her left foot (ND)
Cutaneous vasculitis (42)
ND
Naranjo (5): Probable
Regular
Recovered (90)
ND
[62]
54, F, United States of America
Cimicifuga racemosa Oral: capsules (80 mg/day/4 months)
Ulcers (ND)
Cutaneous vasculitis (90)
ND
Naranjo (4): Possible
Regular
Recovered (90)
ND
57, F, United States of America
Cimicifuga racemosa,Oral: capsules (without more specifications)
Lethargy and fatigue (14)
Autoimmune hepatitis (21)
ND
RUCAM (6)probable (Hepatocellular)Naranjo (7):Probable
Enough
Recovered (14)
Hepatic disease, serology of negative hepatitis, normal Antinuclear antibodies
[63]
16, F, United States of America
Podophyllum peltatum Topical; 20% of the resin in tincture
Vomiting, watery diarrhea, and abdominal pain (7 h)
Multiple organ dysfunction syndrome (<1)
Neurological toxicity and respiratory complications
Naranjo (6): probable
Enough
Recovered(120)
ND
[64]
18, F, United Kingdom
Podophyllum peltatum,Topical; 25% of the resin in tincture (7.5 ml = 1.88 g)
ND
Hypokalemia and peripheral neuropathy (<1)
Hypokalemia and peripheral neuropathy
Naranjo (5): probable
Regular
Recovered(90)
Previous cesarean anesthesia not discarded
[65]
21, F, United States of America
Caulophyllum thalictroides,ND
ND
Nicotinic toxicity (<1)
Tachycardia, diaphoresis, abdominal pain, vomiting and muscle weakness
Naranjo (5): probable
Poor
Recovered(1)
ND
[66]
40, M
Thevetia peruviana Oral: seeds
ND
Atrioventricular block (1)
Hyperkalemia, bradycardia
Naranjo (3): Possible
Regular
Recovered (3)
No cardiac history or vascular risk factor
[67]
25, F
Cinchona pubescens Oral: leaves
ND
Atrioventricular block (1)
bradycardia
Naranjo (3): Possible
Regular
Recovered (2)
ND
75, F
Cinchona pubescens Oral: infusion
ND
Multiple organ dysfunction syndrome (ND)
ND
Naranjo (3): Possible
Poor
ND
ND
20 patients:9–50 years old, Mexico
Metopium brownie,ND
1–4
Erythema (95%)Vesicles (60%)Papules (4%)Blebs (2%)
ND
Regular
Recovered (ND)
Poison ivy
[68]
27, M, United States of America
Larrea tridentata,Oral: 500 capsules (3–7/day/10 months)
Vomiting, watery diarrhea, and abdominal pain (ND)
Hepatic damage (ND)
ND
Naranjo (4): PossibleRUCAM (4):Possible (Hepatocellular)
Regular
ND
Hepatic disease, serology of negative hepatitis, (cytomegalovirus positive, ingestion of other plants and history of alcohol abuse)
[69]
13, M, Siri Lanka
Abrus precatorius Oral: 1 seed
Vomiting, watery diarrhea, and abdominal pain (5)
Pulmonary edema associated with hypertension (1)
Early renal parenchymal disease
Naranjo (5): probable
Enough
Recovered (3)
Organophosphate poisoning, acute glomerular nephritis,viral myocarditis, and dengue
[70]
17, F, India
Abrus precatorius,Oral: 10 seeds
Gastrointestinal (4)
Idiopathic intracranial hypertension (6)
Hepatic failure, hyponatremia, and hypokalemia
Naranjo (5):Probable
Enough
Recovered (21)
ND,intentional intake
[71]
28, F, India
Abrus precatorius,Oral: 7 seeds
Gastrointestinal (20)
Idiopathicintracranial hypertension (4)
Seizures and respiratory failure
Naranjo (5):Probable
Enough
Fatal (4)
18, M, United States of America
Datura inoxia, Oral: seeds
Incoherences and hallucination (ND)
Anticholinergic intoxication(<1)
ND
Naranjo (4): Possible
Enough
Recovered(4)
Methamphetamine intake, and intake of other unknown substances
[72]
Age is given in years old; ND, not described; F, female; M, male.Those cases that report hepatic damage were also evaluated using the method proposed by the Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method (CIOMS/RUCAM) [178], which is an organospecific instrument designed for the assessment of hepatotoxicity. This method evaluates the temporal relationship between the consumption of a substance (drug or natural remedy) and the appearance of hepatic damage, the absence or presence of risk factors, the exclusion of alternative causes of liver injury, among others. The sum of the scores leads to a final score between −8 and 14 points, which results in the following categories: highly probable or definite, probable, possible, or excluded. The amount of information of each clinical case considered for this review was classified as enough (number of criteria: 5-6), regular (number of criteria: 3-4), and poor (number of criteria: 1-2). The following criteria were used to evaluate the amount of information: (1) clear information regarding the intake and time elapsed for the onset of symptoms, (2) information of the dose ingested, (3) explanation and clinical management of the intoxication, (4) information for the exclusion of other causes that might induce the toxic effect, (5) information of the withdrawal of the plant substance, and (6) time of recovery from the toxicity or death of the patient.The toxicity presented in clinical cases was mainly due to the accidental consumption of toxic medicinal plants, especially by children. In all the cases, the toxic effects occurred after the administration of the plant. The symptoms of toxicity were confirmed using objective evidence. None of the reports provided information about the presence of similar toxic effects compared to a previous experience. Improvement of symptoms occurred in some cases (i.e., [58, 62–64, 69, 71, 72]). The information about the number of ingestion with the plant is only reported in some cases (i.e., [43, 57, 59, 60, 65, 67, 70]).


#### 4.4.1. Case Series

Krenzelok et el. [179] gathered information aboutEuphorbia pulcherrima exposure during an 8-year period in the United States of America. The results showed that children accounted for 93.3% of cases of exposure, which were accidental (98.9% of cases) and by ingestion (94.5% of cases). No deaths were reported. However, this study did not report the symptomatology. The toxicity ofCimicifuga racemosa has been extensively studied. The reviews of Borrelli and Ernst [180] and Teschke et al. [181] can be consulted for more information regarding the adverse effects ofCimicifuga racemosa in other clinical cases. The prevalence of allergy toMyroxylon pereirae resin has been reported in many countries, ranging from 5.4 to 11.8% (i.e., [49, 182–185]). From a total of 27815 patients recorded over 5 years in Croatia, 8.4% were positive to contact dermatitis upon exposure toMyroxylon pereirae bark [186]. In another case, the prevalence of toxicity by medicinal plants was also reported.Jatropha curcas,Andira inermis, andCanella winterana were the third, the fourth, and the fifth most cited plant species, respectively, associated with cases of toxicity in Cuba from 1998–2007 [36]. Eddleston et al. [187] reported 351 patients with a history ofT. peruviana consumption for 2 years. No deaths were reported.


## 4.1.In Vitro Studies

TheArtemia salina (brine shrimp) bioassay has been widely used for the analysis of acute toxicityin vitro. Although there are no range values to consider an extract or compound as toxic in the brine shrimp test, vincristine, the positive control for toxicity, has a lethal concentration 50 (LC50) = 0.91 μg/ml [76]. Considering this value, plant extracts or compounds with LC50 values 1000-fold higher than vincristine could be considered nontoxic.The following plant extracts have been tested for theirin vitrotoxicology using the brine shrimp test and had LC50 values higher than 1000 μg/ml. The ethyl acetate fraction ofSolanum nigrescens aerial parts [77], the ethanol extract ofAmbrosia peruvianawhole plant [78], the aqueous extract ofJatropha gossypifolia aerial parts [79], the methanol extract ofJatropha dioica leaves [80], the aqueous extract ofCnidoscolus urens whole plant [79], the ethanol extract ofCrescentia cujete fruits [81], the aqueous extract ofEnterolobium cyclocarpum bark [82], and the ethanol extract ofCordia dentata leaves and their fractions [83].The plant extract and compounds that could be considered dangerous (LC50 = 100–1000 μg/ml) include the following: methanol and hexane proportions derived from a hexane extract ofGymnosperma glutinosum aerial parts [84], the ethyl acetate extracts ofMonstera deliciosa branches [85], and icosandrin, a cyclic homoflavonoid isolated fromPhytolacca icosandra [86].The plant extract and compounds that could be considered toxic (LC50 = 10–100 μg/ml) include the following: the ethyl acetate extracts ofMonstera deliciosa leaves [85], the ethanol extract ofSolanum americanum fruits [87], the ethanol extract ofScoparia dulcis aerial parts [76], the methanol extract ofEnterolobium cyclocarpumleaves [88], the ethanol extract ofPimenta dioica leaves [89], and the hydroalcoholic extract ofSanguinaria canadensis whole plant [90]. None of the plant extracts or compounds included in this review were considered highly toxic (LC50 < 10 μg/ml).


### 4.1.1. Cytotoxicity

Other plant extracts and their compounds have been tested in otherin vitro models, including cytotoxicity test in nontumorigenic cells, genotoxicity using the comet assay on lymphocytes, and the mutagenic test using lymphocytes orSalmonella spp. The positive controls for cytotoxicity in nontumorigenic cells include cisplatin and Taxol. These compounds have inhibitory concentration 50 (IC50) values ranging from 0.1 to 4 μg/ml [91]. Some plants extracts have been reported to lack cytotoxic effects (IC50 > 250 μg/ml) in nontumorigenic cells. These include the ethanol extract ofPhoradendron serotinum leaves tested on peripheral blood mononuclear cells [91], the aqueous extract ofCnidoscolus chayamansaleaves on baby hamster kidney (BHK) cells [92], and the aqueous extract ofEnterolobium cyclocarpum bark assayed on 3T3 murine preadipocytes [82]. Additionally, the ethanol extract ofEquisetum hyemale aerial parts evaluated on rabbit corneal fibroblasts (SIRC) [93], the methanol extract ofEnterolobium cyclocarpum leaves evaluated on Vero cells (obtained from kidney epithelial cells extracted from the African green monkey(Cercopithecus aethiops) [88], and the diterpene ent‐kaur‐16‐en‐19‐oic acid, obtained fromAnnona cherimola, tested on rat embryo primary striatal cultures [94]. On the other hand, the hydroalcoholic extract ofHura crepitans leaves had an IC50 = 107.7 μg/ml in lung fibroblasts [95].


### 4.1.2. Mutagenicity and Genotoxicity

Regarding mutagenicity, parthenin, isolated fromParthenium hysterophorus, lacked mutagenicity (0.19 to 19 μM) but showed chromosomal aberrations at concentrations of 10–60 μM in blood lymphocytes [96]. These results suggested genotoxic effects of parthenin. A methanol extract ofIndigofera suffruticosa aerial parts (1.25–7.5 mg/plate) showed mutagenic activity in aSalmonella microsome assay [97]. The acetone extract ofHeliopsis longipes roots (10–80 μg/Petri dish) and its active compound affinin (6.25–50 μg/Petri dish) were not mutagenic, as evaluated by the Ames test [98]. Lobeline (5–10 mg/kg i.p.), an alkaloid isolated fromLobelia inflata, had no genotoxic or mutagenic effects in the comet assay, the micronucleus test in bone marrow, or the Salmonella/microsome mutagenic assay [99].For genotoxicity, the ethyl acetate/n-hexane extract ofZinnia peruviana aerial parts tested using 5 and 20 mg/ml extracts showed genotoxic effects in PBMC compared to the positive control of copper sulfate (1%) [100]. A butanol fraction ofUrera baccifera roots at a 1.8 mg/g concentration of oxalic acid decreased leukocyte number significantly and increased cell death and DNA damage in primary cultures of leukocytes in comparison to the control treatment [101]. The methanolic extract ofPsittacanthus calyculatus aerial parts (200 and 400 mg/kg i.p.) did not induce chromosomal damage in peripheral blood erythrocytes obtained from mice after 72 h of exposure [102]. An ethanol extract ofHeliopsis longipes roots (3–100 mg/kg p.o.) did not produce genotoxic or cytotoxic effects on peripheral blood mononuclear cells obtained from mice 24–96 h after administration [103]. Parthenin, isolated fromParthenium hysterophorus, showed genotoxic effects at 4–31 mg/kg i.p. in micronuclei in mouse peripheral blood after 48 and 72 h of treatment [96].


## 4.1.1. Cytotoxicity

Other plant extracts and their compounds have been tested in otherin vitro models, including cytotoxicity test in nontumorigenic cells, genotoxicity using the comet assay on lymphocytes, and the mutagenic test using lymphocytes orSalmonella spp. The positive controls for cytotoxicity in nontumorigenic cells include cisplatin and Taxol. These compounds have inhibitory concentration 50 (IC50) values ranging from 0.1 to 4 μg/ml [91]. Some plants extracts have been reported to lack cytotoxic effects (IC50 > 250 μg/ml) in nontumorigenic cells. These include the ethanol extract ofPhoradendron serotinum leaves tested on peripheral blood mononuclear cells [91], the aqueous extract ofCnidoscolus chayamansaleaves on baby hamster kidney (BHK) cells [92], and the aqueous extract ofEnterolobium cyclocarpum bark assayed on 3T3 murine preadipocytes [82]. Additionally, the ethanol extract ofEquisetum hyemale aerial parts evaluated on rabbit corneal fibroblasts (SIRC) [93], the methanol extract ofEnterolobium cyclocarpum leaves evaluated on Vero cells (obtained from kidney epithelial cells extracted from the African green monkey(Cercopithecus aethiops) [88], and the diterpene ent‐kaur‐16‐en‐19‐oic acid, obtained fromAnnona cherimola, tested on rat embryo primary striatal cultures [94]. On the other hand, the hydroalcoholic extract ofHura crepitans leaves had an IC50 = 107.7 μg/ml in lung fibroblasts [95].


## 4.1.2. Mutagenicity and Genotoxicity

Regarding mutagenicity, parthenin, isolated fromParthenium hysterophorus, lacked mutagenicity (0.19 to 19 μM) but showed chromosomal aberrations at concentrations of 10–60 μM in blood lymphocytes [96]. These results suggested genotoxic effects of parthenin. A methanol extract ofIndigofera suffruticosa aerial parts (1.25–7.5 mg/plate) showed mutagenic activity in aSalmonella microsome assay [97]. The acetone extract ofHeliopsis longipes roots (10–80 μg/Petri dish) and its active compound affinin (6.25–50 μg/Petri dish) were not mutagenic, as evaluated by the Ames test [98]. Lobeline (5–10 mg/kg i.p.), an alkaloid isolated fromLobelia inflata, had no genotoxic or mutagenic effects in the comet assay, the micronucleus test in bone marrow, or the Salmonella/microsome mutagenic assay [99].For genotoxicity, the ethyl acetate/n-hexane extract ofZinnia peruviana aerial parts tested using 5 and 20 mg/ml extracts showed genotoxic effects in PBMC compared to the positive control of copper sulfate (1%) [100]. A butanol fraction ofUrera baccifera roots at a 1.8 mg/g concentration of oxalic acid decreased leukocyte number significantly and increased cell death and DNA damage in primary cultures of leukocytes in comparison to the control treatment [101]. The methanolic extract ofPsittacanthus calyculatus aerial parts (200 and 400 mg/kg i.p.) did not induce chromosomal damage in peripheral blood erythrocytes obtained from mice after 72 h of exposure [102]. An ethanol extract ofHeliopsis longipes roots (3–100 mg/kg p.o.) did not produce genotoxic or cytotoxic effects on peripheral blood mononuclear cells obtained from mice 24–96 h after administration [103]. Parthenin, isolated fromParthenium hysterophorus, showed genotoxic effects at 4–31 mg/kg i.p. in micronuclei in mouse peripheral blood after 48 and 72 h of treatment [96].


## 4.2.In Vivo Acute Studies

### 4.2.1. Lethal Dose 50 (LD50)

The guideline 423 of the Organization for Economic Cooperation and Development (OECD) establishes that substances with an LD50 < 5 mg/kg are highly toxic, whereas LD50 values from 5 to 50 mg/kg are very toxic, LD50 values from 50 to 300 mg/kg are toxic, LD50 values from 300 to 2000 mg/kg are dangerous, and LD50 values higher than 2000 mg/kg are not dangerous [104].Some plant extracts showed LD50 > 2000 mg/kg p.o. in mice: ethanol extracts of leaves ofCasimiroa edulis [105] andCnidoscolus chayamansa [106], ethanol extracts of aerial parts ofMoussonia deppeana [107],Equisetum hyemale [93], andRuta chalepensis [108], as well as methanol extracts of leaves ofChenopodium ambrosioides [109] andRauvolfia tetraphylla [110]. The same pattern was also shown in aqueous extract ofCuphea aequipetala aerial parts [111], ethanol extract ofPlumeria rubraflowers [112], aqueous extract ofLarrea divaricata leaves [113], ethanol extract ofCaesalpinia pulcherrimaleaves and bark [114, 115]. aqueous extract ofEuphorbia prostrata whole plant [116], aqueous-methanol extract ofCeiba pentandra leaves [117], petroleum ether, chloroform, and methanol extracts ofGelsemium sempervirens roots [118], acetone extract ofCapsicum annum fruits [119], and aqueous and ethanol extract ofScoparia dulcis leaves and whole plant [120, 121].The following extracts have shown LD50 > 2000 mg/kg p.o. in rats: aqueous extract ofPouteria sapota seeds [122], methanol extract ofMartynia annua leaves [123], ethanol extract ofFlourensia cernua leaves [124], aqueous extract ofEnterolobium cyclocarpum bark [82], ethanol and aqueous extractC. pulcherrima aerial parts [125], aqueous extract ofPassiflora edulis leaves [126], hydroalcoholic extract ofMagnolia grandiflora seeds [127], and ethanol extract ofCrescentia cujete fruits [128]. The same pattern was also shown in methanol extracts of leaves ofAmaranthus spinosus [129], andRauvolfia tetraphylla [130], chloroform-methanol extract ofCnidoscolus chayamansa leaves [131], aqueous extract ofR. humilis fruits [132], a chloroform fraction from an ethanol extract ofTagetes erecta flowers [133], aqueous extract ofKarwinskia humboldtiana seeds [134], and hydroalcoholic extract ofSenna occidentalis aerial parts [135], as well as lutein and lutein ester, obtained fromTagetes erecta [136], and ethanol extract ofJatropha gossypiifolia aerial parts [137], and aqueous extract ofCaladium bicolor [138].Other plant extracts showed LD50 > 2000 mg/kg i.p. in mice: hexane extract ofTilia mexicana inflorescences [139], aqueous extract ofTagetes lucida aerial parts [140], ethanol extract ofMirabilis jalapaaerial parts [141], and aqueous extract ofUrera baccifera leaves [142].Some plant extracts and plant compounds had LD50 values from 300 to 2000 mg/kg, which is considered dangerous [104]. These plant extracts were intraperitoneally administered to mice: the ethanol extract ofTagetes lucida aerial parts (LD50 = 970 mg/kg) [140], the aqueous extract ofCaladium bicolor leaves (LD50 = 1778.28 mg/kg) [138], and the ethanol extract ofTagetes lucida aerial parts (LD50 = 970 mg/kg i.p.) [140]. On the other hand, the ethanol extract ofPhoradendron serotinum leaves had an LD50 = 375 mg/kg p.o. in mice [143], and sanguinarine, an alkaloid isolated fromSanguinaria canadensis, had an LD50 = 1658 mg/kg p.o. in rats [144]. Methanol extracts ofTilia mexicana inflorescences had LD50 values of 375 mg/kg i.p. in mice [139].Other plant extracts and plant compounds had LD50 values varying from 50 to 300 mg/kg, which is considered toxic [104]. Ethanol extract ofPhoradendron serotinum leaves had an LD50 = 125 mg/kg i.p. in mice, [143], whereas capsaicin, the main active principle ofCapsicum annum, had an LD50 = 190 mg/kg p.o. [145]. The acetone extract ofHeliopsis longipes roots had an LD50 = 62.14 mg/kg p.o. in mice, whereas its active compound affinin had an LD50 = 113.13 mg/kg p.o. in mice [98]. The ethanol extract ofHeliopsis longipes roots had an LD50 = 288 mg/kg p.o. in mice [103].The following plant extracts and compounds can be considered very toxic (5–50 mg/kg) [104]: the free alkaloid fraction in hexane and methanol extracts fromErythrina americana seeds (LD50 = 38.54 to 40.37 mg/kg i.p.) in mice [146],Jatropha curcas oil (LD50 = 23.34 mg/kg p.o.) in mice [147], and α-solamargine, isolated fromSolanum americanum, with an LD50 = 42±2 mg/kg i.p. in rats [148]. The alkaloid N-methylisocorydinium, obtained fromMagnolia grandiflora trunk wood, had an LD50 = 10 mg/kg i.p. in mice [149] and γ-coniceine, isolated fromConium maculatum, had an LD50 = 12 mg/kg p.o in mice [150]. Parthenin, the toxic compound ofParthenium hysterophorus, had an LD50 = 42 mg/kg i.p. in rats [151]. Capsaicin had an LD50 = 8 mg/kg i.p. and 7.80 mg/kg i.m in mice [152]. Sanguinarine, an alkaloid isolated fromSanguinaria canadensis, was toxic at 29 mg/kg i.v. in rats [144].The following plant compounds had LD50 values < 5 mg/kg, which is considered highly toxic [104]. Capsaicin had an LD50 = 0.56 mg/kg i.v. [152].


### 4.2.2. Biochemical and Hematological Parameters

Treatment with plant extracts in short-term studies have effects on biochemical and hematological parameters, as well as the levels of the hepatic enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). An aqueous extract ofLarrea divaricata aerial parts (0.5–200 mg/kg i.p.) did not affect the levels of ALT in mice after 2 days [153]. Aqueous extract ofKarwinskia humboldtiana fruits (1250 mg/kg p.o.) administered to rats for 3 days increased the levels of hepatic enzymes compared to the untreated group [154]. An aqueous extract ofPassiflora edulis (30 mg/kg p.o.) did not affect motor coordination in mice or change the biochemical measurements in serum after 4 days [155]. α-Solamargine (15–35 mg/kg i.p.) did not affect hematological parameters or the levels of hepatic enzymes in rats after 5 days [148], whereas an aqueous extract ofKarwinskia humboldtiana fruit (5000 mg/kg p.o.) in rats for 5 days induced weight loss (15%) in rats, as well as toxicity in the pancreas [156]. An aqueous extract ofPassiflora edulis leaves (100–400 mg/kg p.o.) did not affect organ body weight or hematological parameters but decreased the levels of ALT in rats after 7 days of treatment at all doses [126]. A methanol extract ofR. tetraphylla leaves (1000 mg/kg p.o.) decreased body weight change and food consumption and increased total bilirubin in rats after 7 days [157]. An aqueous extract ofK. humboldtiana (1000–2000 mg/kg p.o.) administered for 7 days in rats induced alterations in membrane fluidity and ATPase activity in liver submitochondrial particles [158]. An ethanol extract ofEuphorbia hirta leaves (60.4–483 mg/kg i.p.) [159] and a chloroform fraction from an ethanol extract ofTagetes erecta flowers (200–400 mg/kg p.o.) [133] did not affect hematological or biochemical parameters in rats after 14 days. An aqueous extract ofEuphorbia hirta whole plant administered at a single dose of 2000 mg/kg p.o. significantly decreased the levels of ALP and ALT after 14 days in broiler chickens [160]. Lobeline (5–10 mg/kg i.p.) did not affect the levels of AST, ALT, ALP, and LDH after 4 days of exposure [99].


### 4.2.3. Toxicity to Reproduction and Pregnancy

α-Solamargine (15–35 mg/kg i.p.) did not affect the number of spermatozoa or the weight of the testicles and epididymis of male rats after 24 h of treatment [148]. Jervine (70–300 mg/kg p.o.), a steroidal alkaloid found inVeratrum californicum, administered on days 8–10 of gestation induced malformations in the offspring, including isolated cleft palate, mandibular micrognathia, and limb malformations in C57BL/6J and A/J mice [161]. The administration of an aqueous extract ofRuta chalepensis leaves (10 mg/kg p.o.) to pregnant rats from day 9 to day 17 of gestation decreased the uterine weight, the number of live fetuses, and the fetal weight. The number of fetal resorptions was also increased, and the fetuses showed skeletal malformations [162]. Additionally, an aqueous extract ofR. chalepensisleaves (0.8 and 1.6 g/kg p.o.) administered to mice from day 1 to day 14 post coitum caused perinatal changes in mice such as righting reflex, cliff avoidance, and swimming ability, among others [163].


### 4.2.4. Dermal Tests

An aqueous extract ofPouteria sapota seeds lacked dermal irritation in rabbits and showed mild reversible eye irritation in rabbits [122].Jatropha multifida sap did not induce skin lesions in rats after 14 days of treatment [164]. A diethyl ether extract ofJatropha multifida showed the presence of 16-hydroxyphorbol. This compound showed an irritant dose 50 (ID50) of 0.05 μg/ear [165].


## 4.2.1. Lethal Dose 50 (LD50)

The guideline 423 of the Organization for Economic Cooperation and Development (OECD) establishes that substances with an LD50 < 5 mg/kg are highly toxic, whereas LD50 values from 5 to 50 mg/kg are very toxic, LD50 values from 50 to 300 mg/kg are toxic, LD50 values from 300 to 2000 mg/kg are dangerous, and LD50 values higher than 2000 mg/kg are not dangerous [104].Some plant extracts showed LD50 > 2000 mg/kg p.o. in mice: ethanol extracts of leaves ofCasimiroa edulis [105] andCnidoscolus chayamansa [106], ethanol extracts of aerial parts ofMoussonia deppeana [107],Equisetum hyemale [93], andRuta chalepensis [108], as well as methanol extracts of leaves ofChenopodium ambrosioides [109] andRauvolfia tetraphylla [110]. The same pattern was also shown in aqueous extract ofCuphea aequipetala aerial parts [111], ethanol extract ofPlumeria rubraflowers [112], aqueous extract ofLarrea divaricata leaves [113], ethanol extract ofCaesalpinia pulcherrimaleaves and bark [114, 115]. aqueous extract ofEuphorbia prostrata whole plant [116], aqueous-methanol extract ofCeiba pentandra leaves [117], petroleum ether, chloroform, and methanol extracts ofGelsemium sempervirens roots [118], acetone extract ofCapsicum annum fruits [119], and aqueous and ethanol extract ofScoparia dulcis leaves and whole plant [120, 121].The following extracts have shown LD50 > 2000 mg/kg p.o. in rats: aqueous extract ofPouteria sapota seeds [122], methanol extract ofMartynia annua leaves [123], ethanol extract ofFlourensia cernua leaves [124], aqueous extract ofEnterolobium cyclocarpum bark [82], ethanol and aqueous extractC. pulcherrima aerial parts [125], aqueous extract ofPassiflora edulis leaves [126], hydroalcoholic extract ofMagnolia grandiflora seeds [127], and ethanol extract ofCrescentia cujete fruits [128]. The same pattern was also shown in methanol extracts of leaves ofAmaranthus spinosus [129], andRauvolfia tetraphylla [130], chloroform-methanol extract ofCnidoscolus chayamansa leaves [131], aqueous extract ofR. humilis fruits [132], a chloroform fraction from an ethanol extract ofTagetes erecta flowers [133], aqueous extract ofKarwinskia humboldtiana seeds [134], and hydroalcoholic extract ofSenna occidentalis aerial parts [135], as well as lutein and lutein ester, obtained fromTagetes erecta [136], and ethanol extract ofJatropha gossypiifolia aerial parts [137], and aqueous extract ofCaladium bicolor [138].Other plant extracts showed LD50 > 2000 mg/kg i.p. in mice: hexane extract ofTilia mexicana inflorescences [139], aqueous extract ofTagetes lucida aerial parts [140], ethanol extract ofMirabilis jalapaaerial parts [141], and aqueous extract ofUrera baccifera leaves [142].Some plant extracts and plant compounds had LD50 values from 300 to 2000 mg/kg, which is considered dangerous [104]. These plant extracts were intraperitoneally administered to mice: the ethanol extract ofTagetes lucida aerial parts (LD50 = 970 mg/kg) [140], the aqueous extract ofCaladium bicolor leaves (LD50 = 1778.28 mg/kg) [138], and the ethanol extract ofTagetes lucida aerial parts (LD50 = 970 mg/kg i.p.) [140]. On the other hand, the ethanol extract ofPhoradendron serotinum leaves had an LD50 = 375 mg/kg p.o. in mice [143], and sanguinarine, an alkaloid isolated fromSanguinaria canadensis, had an LD50 = 1658 mg/kg p.o. in rats [144]. Methanol extracts ofTilia mexicana inflorescences had LD50 values of 375 mg/kg i.p. in mice [139].Other plant extracts and plant compounds had LD50 values varying from 50 to 300 mg/kg, which is considered toxic [104]. Ethanol extract ofPhoradendron serotinum leaves had an LD50 = 125 mg/kg i.p. in mice, [143], whereas capsaicin, the main active principle ofCapsicum annum, had an LD50 = 190 mg/kg p.o. [145]. The acetone extract ofHeliopsis longipes roots had an LD50 = 62.14 mg/kg p.o. in mice, whereas its active compound affinin had an LD50 = 113.13 mg/kg p.o. in mice [98]. The ethanol extract ofHeliopsis longipes roots had an LD50 = 288 mg/kg p.o. in mice [103].The following plant extracts and compounds can be considered very toxic (5–50 mg/kg) [104]: the free alkaloid fraction in hexane and methanol extracts fromErythrina americana seeds (LD50 = 38.54 to 40.37 mg/kg i.p.) in mice [146],Jatropha curcas oil (LD50 = 23.34 mg/kg p.o.) in mice [147], and α-solamargine, isolated fromSolanum americanum, with an LD50 = 42±2 mg/kg i.p. in rats [148]. The alkaloid N-methylisocorydinium, obtained fromMagnolia grandiflora trunk wood, had an LD50 = 10 mg/kg i.p. in mice [149] and γ-coniceine, isolated fromConium maculatum, had an LD50 = 12 mg/kg p.o in mice [150]. Parthenin, the toxic compound ofParthenium hysterophorus, had an LD50 = 42 mg/kg i.p. in rats [151]. Capsaicin had an LD50 = 8 mg/kg i.p. and 7.80 mg/kg i.m in mice [152]. Sanguinarine, an alkaloid isolated fromSanguinaria canadensis, was toxic at 29 mg/kg i.v. in rats [144].The following plant compounds had LD50 values < 5 mg/kg, which is considered highly toxic [104]. Capsaicin had an LD50 = 0.56 mg/kg i.v. [152].


## 4.2.2. Biochemical and Hematological Parameters

Treatment with plant extracts in short-term studies have effects on biochemical and hematological parameters, as well as the levels of the hepatic enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). An aqueous extract ofLarrea divaricata aerial parts (0.5–200 mg/kg i.p.) did not affect the levels of ALT in mice after 2 days [153]. Aqueous extract ofKarwinskia humboldtiana fruits (1250 mg/kg p.o.) administered to rats for 3 days increased the levels of hepatic enzymes compared to the untreated group [154]. An aqueous extract ofPassiflora edulis (30 mg/kg p.o.) did not affect motor coordination in mice or change the biochemical measurements in serum after 4 days [155]. α-Solamargine (15–35 mg/kg i.p.) did not affect hematological parameters or the levels of hepatic enzymes in rats after 5 days [148], whereas an aqueous extract ofKarwinskia humboldtiana fruit (5000 mg/kg p.o.) in rats for 5 days induced weight loss (15%) in rats, as well as toxicity in the pancreas [156]. An aqueous extract ofPassiflora edulis leaves (100–400 mg/kg p.o.) did not affect organ body weight or hematological parameters but decreased the levels of ALT in rats after 7 days of treatment at all doses [126]. A methanol extract ofR. tetraphylla leaves (1000 mg/kg p.o.) decreased body weight change and food consumption and increased total bilirubin in rats after 7 days [157]. An aqueous extract ofK. humboldtiana (1000–2000 mg/kg p.o.) administered for 7 days in rats induced alterations in membrane fluidity and ATPase activity in liver submitochondrial particles [158]. An ethanol extract ofEuphorbia hirta leaves (60.4–483 mg/kg i.p.) [159] and a chloroform fraction from an ethanol extract ofTagetes erecta flowers (200–400 mg/kg p.o.) [133] did not affect hematological or biochemical parameters in rats after 14 days. An aqueous extract ofEuphorbia hirta whole plant administered at a single dose of 2000 mg/kg p.o. significantly decreased the levels of ALP and ALT after 14 days in broiler chickens [160]. Lobeline (5–10 mg/kg i.p.) did not affect the levels of AST, ALT, ALP, and LDH after 4 days of exposure [99].


## 4.2.3. Toxicity to Reproduction and Pregnancy

α-Solamargine (15–35 mg/kg i.p.) did not affect the number of spermatozoa or the weight of the testicles and epididymis of male rats after 24 h of treatment [148]. Jervine (70–300 mg/kg p.o.), a steroidal alkaloid found inVeratrum californicum, administered on days 8–10 of gestation induced malformations in the offspring, including isolated cleft palate, mandibular micrognathia, and limb malformations in C57BL/6J and A/J mice [161]. The administration of an aqueous extract ofRuta chalepensis leaves (10 mg/kg p.o.) to pregnant rats from day 9 to day 17 of gestation decreased the uterine weight, the number of live fetuses, and the fetal weight. The number of fetal resorptions was also increased, and the fetuses showed skeletal malformations [162]. Additionally, an aqueous extract ofR. chalepensisleaves (0.8 and 1.6 g/kg p.o.) administered to mice from day 1 to day 14 post coitum caused perinatal changes in mice such as righting reflex, cliff avoidance, and swimming ability, among others [163].


## 4.2.4. Dermal Tests

An aqueous extract ofPouteria sapota seeds lacked dermal irritation in rabbits and showed mild reversible eye irritation in rabbits [122].Jatropha multifida sap did not induce skin lesions in rats after 14 days of treatment [164]. A diethyl ether extract ofJatropha multifida showed the presence of 16-hydroxyphorbol. This compound showed an irritant dose 50 (ID50) of 0.05 μg/ear [165].


## 4.3.In Vivo Subacute and Chronic Studies

### 4.3.1. Biochemical and Hematological Parameters

Some plant extracts and their active compounds have been tested for their effects on biochemical and hematological parameters in rodents for at least 18 days of exposure. A histological study has also been included in some reports. A hydroalcoholic extractof Senna occidentalisaerial parts (100–2500 mg/kg p.o.) [135] and a hydroalcoholic extract ofSapindus saponaria leaves (44.76 mg/kg p.o.) and fruits (45.0 mg/kg p.o.) [166] did not change the biochemical profile or hematological parameters or alter body weight and organ weight for 30 days in rats. An ethanol extract of the pod ofPlumeria rubra (50–200 mg/kg p.o) [167] and an aqueous-methanol extract ofCeiba pentandra leaves (250 and 500 mg/kg p.o.) [117] did not alter hematological or biochemical parameters in rats and mice, respectively, after 21 days [167]. A chloroform-methanol extract ofCnidoscolus chayamansa leaves (1000 mg/kg p.o.) [131] and an ethanol extract ofMoussonia deppeana aerial parts (1000 mg/kg p.o.) [107] did not affect biochemical or hematological parameters in mice after 28 days of daily administration. In addition, histological examinations of the spleen, kidney, and liver showed no abnormalities. Capsaicin (5–100 mg/kg p.o.) [168], obtained fromCapsicum annum, and lutein and lutein ester (4–400 mg/kg p.o.) [136], obtained fromTagetes erecta, did not affect hematological or biochemical parameters, growth, food consumption, or body weight in mice and rats, respectively, after 28 days. An aqueous extract ofRivina humilis fruits (2500 and 5000 mg/kg p.o.) administered daily for 35 days showed no changes in the hematological profile or in the relative organ weight, whereas the same extract administered daily for 90 days at 0.5–2 g/100 g in a powdered diet did not affect hematological parameters, biochemical determinations, or the levels of hepatic enzymes [132].In contrast, some plant extracts have altered biochemical and/or hematological parameters. An aqueous extract ofAbrus precatorius leaves (400–1600 mg/kg p.o.) was administered to rats for 18 days. Only the highest dose (1600 mg/kg p.o.) decreased levels of hematological parameters and increased the levels of hepatic enzymes [169]. An aqueous extract ofScoparia dulcis leaves (250–500 mg/kg p.o.) showed mild vascular and portal congestion in the heart and the liver, respectively, of rats treated daily with this extract for 30 days. Nevertheless, there were effects in the lungs and testis [120]. A methanol extract ofRauvolfia tetraphylla leaves did not affect hematological parameters. However, a significant decrease in the total bilirubin and glucose levels was observed in the mice treated at 100 and 300 mg/kg, with a significant increase in triglycerides at doses of 10–300 mg/kg after 28 days in mice [130]. An ethanol extract of the aerial parts fromJatropha gossypifolia (135 mg/kg p.o. or higher doses) reduced the activity in the central nervous system and showed hepatotoxicity, pulmonary damage, and digestive disturbances in rats over 13 weeks of treatment [170]. The lethality was 46.6% and 13.3% among male and female rats under the highest tested dose (405 mg/kg), respectively [170].


### 4.3.2. Toxicity during Reproduction and Pregnancy

Yao et al. [171] reported that an aqueous extract ofHydrastis canadensis (1.86 g/kg p.o.) containing 9.6 mg/ml of berberine and 8.4 mg/ml of hydrastine did not affect fetal development in pregnant rats over 20 days of treatment. AProsopis juliflora seedcase added at 70% to the diet of pregnant rats resulted to be teratogenic (13-fold) compared to the untreated group [172]. Aqueous and ethanol extracts ofPlumeria rubra pods (200 mg/kg p.o.) had 51% and 100% abortifacient activity, respectively, in female albino rats from day 11 to day 15 of pregnancy [173]. The hydroalcoholic extract ofLantana camara leaves (1000–7000 mg/kg p.o.) administered during premating, mating, pregnancy, and lactation (56 days in total) in rats did not affect mating, pregnancy, delivery, and live birth. Nevertheless, the two highest doses tested (3000 and 7000 mg/kg p.o.) produced an increase in the resorption rate and parallel increases in the postimplantation loss index, as well as embryotoxicity characterized by skeletal abnormalities [174].


### 4.3.3. Carcinogenicity

Only one plant extract has been tested for its carcinogenic effects. Rats (treated with doses ranging 136–1175 mg/kg p.o.) and mice (treated with doses ranging 375–3275 mg/kg) received an aqueous extract ofHydrastis canadensis root for 2 years (106 weeks). At the end of the treatment, the doses of 1175 mg/kg in rats and the doses varying from 1120 to 3275 mg/kg in mice showed hepatocarcinoma [175].


## 4.3.1. Biochemical and Hematological Parameters

Some plant extracts and their active compounds have been tested for their effects on biochemical and hematological parameters in rodents for at least 18 days of exposure. A histological study has also been included in some reports. A hydroalcoholic extractof Senna occidentalisaerial parts (100–2500 mg/kg p.o.) [135] and a hydroalcoholic extract ofSapindus saponaria leaves (44.76 mg/kg p.o.) and fruits (45.0 mg/kg p.o.) [166] did not change the biochemical profile or hematological parameters or alter body weight and organ weight for 30 days in rats. An ethanol extract of the pod ofPlumeria rubra (50–200 mg/kg p.o) [167] and an aqueous-methanol extract ofCeiba pentandra leaves (250 and 500 mg/kg p.o.) [117] did not alter hematological or biochemical parameters in rats and mice, respectively, after 21 days [167]. A chloroform-methanol extract ofCnidoscolus chayamansa leaves (1000 mg/kg p.o.) [131] and an ethanol extract ofMoussonia deppeana aerial parts (1000 mg/kg p.o.) [107] did not affect biochemical or hematological parameters in mice after 28 days of daily administration. In addition, histological examinations of the spleen, kidney, and liver showed no abnormalities. Capsaicin (5–100 mg/kg p.o.) [168], obtained fromCapsicum annum, and lutein and lutein ester (4–400 mg/kg p.o.) [136], obtained fromTagetes erecta, did not affect hematological or biochemical parameters, growth, food consumption, or body weight in mice and rats, respectively, after 28 days. An aqueous extract ofRivina humilis fruits (2500 and 5000 mg/kg p.o.) administered daily for 35 days showed no changes in the hematological profile or in the relative organ weight, whereas the same extract administered daily for 90 days at 0.5–2 g/100 g in a powdered diet did not affect hematological parameters, biochemical determinations, or the levels of hepatic enzymes [132].In contrast, some plant extracts have altered biochemical and/or hematological parameters. An aqueous extract ofAbrus precatorius leaves (400–1600 mg/kg p.o.) was administered to rats for 18 days. Only the highest dose (1600 mg/kg p.o.) decreased levels of hematological parameters and increased the levels of hepatic enzymes [169]. An aqueous extract ofScoparia dulcis leaves (250–500 mg/kg p.o.) showed mild vascular and portal congestion in the heart and the liver, respectively, of rats treated daily with this extract for 30 days. Nevertheless, there were effects in the lungs and testis [120]. A methanol extract ofRauvolfia tetraphylla leaves did not affect hematological parameters. However, a significant decrease in the total bilirubin and glucose levels was observed in the mice treated at 100 and 300 mg/kg, with a significant increase in triglycerides at doses of 10–300 mg/kg after 28 days in mice [130]. An ethanol extract of the aerial parts fromJatropha gossypifolia (135 mg/kg p.o. or higher doses) reduced the activity in the central nervous system and showed hepatotoxicity, pulmonary damage, and digestive disturbances in rats over 13 weeks of treatment [170]. The lethality was 46.6% and 13.3% among male and female rats under the highest tested dose (405 mg/kg), respectively [170].


## 4.3.2. Toxicity during Reproduction and Pregnancy

Yao et al. [171] reported that an aqueous extract ofHydrastis canadensis (1.86 g/kg p.o.) containing 9.6 mg/ml of berberine and 8.4 mg/ml of hydrastine did not affect fetal development in pregnant rats over 20 days of treatment. AProsopis juliflora seedcase added at 70% to the diet of pregnant rats resulted to be teratogenic (13-fold) compared to the untreated group [172]. Aqueous and ethanol extracts ofPlumeria rubra pods (200 mg/kg p.o.) had 51% and 100% abortifacient activity, respectively, in female albino rats from day 11 to day 15 of pregnancy [173]. The hydroalcoholic extract ofLantana camara leaves (1000–7000 mg/kg p.o.) administered during premating, mating, pregnancy, and lactation (56 days in total) in rats did not affect mating, pregnancy, delivery, and live birth. Nevertheless, the two highest doses tested (3000 and 7000 mg/kg p.o.) produced an increase in the resorption rate and parallel increases in the postimplantation loss index, as well as embryotoxicity characterized by skeletal abnormalities [174].


## 4.3.3. Carcinogenicity

Only one plant extract has been tested for its carcinogenic effects. Rats (treated with doses ranging 136–1175 mg/kg p.o.) and mice (treated with doses ranging 375–3275 mg/kg) received an aqueous extract ofHydrastis canadensis root for 2 years (106 weeks). At the end of the treatment, the doses of 1175 mg/kg in rats and the doses varying from 1120 to 3275 mg/kg in mice showed hepatocarcinoma [175].


## 4.4. Clinical Cases

The toxicity of sixteen species plants has been reported in clinical cases. Fourteen of the sixteen plants are enlisted in Table2. The other two plants are described in Section 4.4.1. The Naranjo algorithm [176], which consists of 10 questions that address the factors considered to determine the causal relationship in case reports, was used to assess causality. A score is obtained (maximum 13) and the results are classified as doubtful or unlikely (0), possible (from 1 to 4), probable (from 5 to 8), and clear or definite (socre > 9). The event must be definitive from a pharmacological or phenomenological point of view, using, if necessary, a conclusive procedure of reexposure [177].Table 2
Evaluation of causality and exclusion of alternate causes in clinical cases of medicinal plants from Mexico and Central America considered as toxic.
Information of the patient (age, gender, country of residence)
Plant, way of administration, dose and part of the plant consumed, time of consumption if indicated
First symptoms (onset, in days, of the first symptoms)
Toxic effects(onset, in days, of the toxic effects)
Clinical complications
Evaluation of causality (score)
Amount of information
Outcome(days)
Alternate causes excluded
Reference
9, M, Israel
Jatropha multifida Oral: >10 fruits
Vomiting, watery diarrhea, and abdominal pain (1 h)
Gastroenteritis (1)
Hepatic enzymes elevation
Naranjo (5): probable
Enough
Recovered (5)
ND
[43]
8, M, Israel
Vomiting, watery diarrhea, and abdominal pain (1 h)
Gastroenteritis (1)
Hepatic enzymes elevation
Naranjo (5): probable
Enough
Recovered (5)
ND
20 children;8–13 years old, India
Jatropha curcas,Oral: 1–4 seeds
1-2 h
Vomiting (95%)Headache (40%) Fever (40%)Diarrhea (50%)
ND
Regular
Recovered(6 hours)
ND
[57]
4, M, United States of America
Conium maculatum (piperidina 850 Ug/g plant), ND
Drowsiness (0.5 h)
Central nervous system depression (3 hours)
ND
Naranjo (6): probable
Regular
Recovered (6)
ND
[58]
19, F, Turkey
Conium maculatum,ND
Headache, blurred vision, and difficulty speaking (0.5 h)
Central nervous system depression (ND)
Difficulty breathing
Naranjo (5): probable
Regular
Recovered (1)
ND
[59]
5, M, India
Argemone mexicana Oral: oil
Abdominal pain, loos of movements and swelling throughout the body (20)
Epidemic dropsy (ND)
ND
Naranjo (6):Probable
Regular
Fatal (4)
Thalassemia and sickle cell disease (postmortem)
[60]
10, M, India
Abdominal pain, fever, and shortness of breath (20)
ND
Naranjo (6):Probable
Regular
Fatal (11)
Thalassemia and sickle cell disease (postmortem)
2, F, Mexico
Chenopodium ambrosioides,Oral: oil 80 ml (1,560 mg ascaridol)
Vomiting and CNS depression (3 h)
Multiple organ dysfunction syndrome (ND)
Seizures, periods of apnea
Naranjo (6): probable
Enough
Fatal (3)
Encephalopathy due to lead poisoning and organophosphates
[61]
64, F, United States of America
Cimicifuga racemosa,Oral: capsules (80 mg/day/2 months)
Painful nodules on her left foot (ND)
Cutaneous vasculitis (42)
ND
Naranjo (5): Probable
Regular
Recovered (90)
ND
[62]
54, F, United States of America
Cimicifuga racemosa Oral: capsules (80 mg/day/4 months)
Ulcers (ND)
Cutaneous vasculitis (90)
ND
Naranjo (4): Possible
Regular
Recovered (90)
ND
57, F, United States of America
Cimicifuga racemosa,Oral: capsules (without more specifications)
Lethargy and fatigue (14)
Autoimmune hepatitis (21)
ND
RUCAM (6)probable (Hepatocellular)Naranjo (7):Probable
Enough
Recovered (14)
Hepatic disease, serology of negative hepatitis, normal Antinuclear antibodies
[63]
16, F, United States of America
Podophyllum peltatum Topical; 20% of the resin in tincture
Vomiting, watery diarrhea, and abdominal pain (7 h)
Multiple organ dysfunction syndrome (<1)
Neurological toxicity and respiratory complications
Naranjo (6): probable
Enough
Recovered(120)
ND
[64]
18, F, United Kingdom
Podophyllum peltatum,Topical; 25% of the resin in tincture (7.5 ml = 1.88 g)
ND
Hypokalemia and peripheral neuropathy (<1)
Hypokalemia and peripheral neuropathy
Naranjo (5): probable
Regular
Recovered(90)
Previous cesarean anesthesia not discarded
[65]
21, F, United States of America
Caulophyllum thalictroides,ND
ND
Nicotinic toxicity (<1)
Tachycardia, diaphoresis, abdominal pain, vomiting and muscle weakness
Naranjo (5): probable
Poor
Recovered(1)
ND
[66]
40, M
Thevetia peruviana Oral: seeds
ND
Atrioventricular block (1)
Hyperkalemia, bradycardia
Naranjo (3): Possible
Regular
Recovered (3)
No cardiac history or vascular risk factor
[67]
25, F
Cinchona pubescens Oral: leaves
ND
Atrioventricular block (1)
bradycardia
Naranjo (3): Possible
Regular
Recovered (2)
ND
75, F
Cinchona pubescens Oral: infusion
ND
Multiple organ dysfunction syndrome (ND)
ND
Naranjo (3): Possible
Poor
ND
ND
20 patients:9–50 years old, Mexico
Metopium brownie,ND
1–4
Erythema (95%)Vesicles (60%)Papules (4%)Blebs (2%)
ND
Regular
Recovered (ND)
Poison ivy
[68]
27, M, United States of America
Larrea tridentata,Oral: 500 capsules (3–7/day/10 months)
Vomiting, watery diarrhea, and abdominal pain (ND)
Hepatic damage (ND)
ND
Naranjo (4): PossibleRUCAM (4):Possible (Hepatocellular)
Regular
ND
Hepatic disease, serology of negative hepatitis, (cytomegalovirus positive, ingestion of other plants and history of alcohol abuse)
[69]
13, M, Siri Lanka
Abrus precatorius Oral: 1 seed
Vomiting, watery diarrhea, and abdominal pain (5)
Pulmonary edema associated with hypertension (1)
Early renal parenchymal disease
Naranjo (5): probable
Enough
Recovered (3)
Organophosphate poisoning, acute glomerular nephritis,viral myocarditis, and dengue
[70]
17, F, India
Abrus precatorius,Oral: 10 seeds
Gastrointestinal (4)
Idiopathic intracranial hypertension (6)
Hepatic failure, hyponatremia, and hypokalemia
Naranjo (5):Probable
Enough
Recovered (21)
ND,intentional intake
[71]
28, F, India
Abrus precatorius,Oral: 7 seeds
Gastrointestinal (20)
Idiopathicintracranial hypertension (4)
Seizures and respiratory failure
Naranjo (5):Probable
Enough
Fatal (4)
18, M, United States of America
Datura inoxia, Oral: seeds
Incoherences and hallucination (ND)
Anticholinergic intoxication(<1)
ND
Naranjo (4): Possible
Enough
Recovered(4)
Methamphetamine intake, and intake of other unknown substances
[72]
Age is given in years old; ND, not described; F, female; M, male.Those cases that report hepatic damage were also evaluated using the method proposed by the Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method (CIOMS/RUCAM) [178], which is an organospecific instrument designed for the assessment of hepatotoxicity. This method evaluates the temporal relationship between the consumption of a substance (drug or natural remedy) and the appearance of hepatic damage, the absence or presence of risk factors, the exclusion of alternative causes of liver injury, among others. The sum of the scores leads to a final score between −8 and 14 points, which results in the following categories: highly probable or definite, probable, possible, or excluded. The amount of information of each clinical case considered for this review was classified as enough (number of criteria: 5-6), regular (number of criteria: 3-4), and poor (number of criteria: 1-2). The following criteria were used to evaluate the amount of information: (1) clear information regarding the intake and time elapsed for the onset of symptoms, (2) information of the dose ingested, (3) explanation and clinical management of the intoxication, (4) information for the exclusion of other causes that might induce the toxic effect, (5) information of the withdrawal of the plant substance, and (6) time of recovery from the toxicity or death of the patient.The toxicity presented in clinical cases was mainly due to the accidental consumption of toxic medicinal plants, especially by children. In all the cases, the toxic effects occurred after the administration of the plant. The symptoms of toxicity were confirmed using objective evidence. None of the reports provided information about the presence of similar toxic effects compared to a previous experience. Improvement of symptoms occurred in some cases (i.e., [58, 62–64, 69, 71, 72]). The information about the number of ingestion with the plant is only reported in some cases (i.e., [43, 57, 59, 60, 65, 67, 70]).


### 4.4.1. Case Series

Krenzelok et el. [179] gathered information aboutEuphorbia pulcherrima exposure during an 8-year period in the United States of America. The results showed that children accounted for 93.3% of cases of exposure, which were accidental (98.9% of cases) and by ingestion (94.5% of cases). No deaths were reported. However, this study did not report the symptomatology. The toxicity ofCimicifuga racemosa has been extensively studied. The reviews of Borrelli and Ernst [180] and Teschke et al. [181] can be consulted for more information regarding the adverse effects ofCimicifuga racemosa in other clinical cases. The prevalence of allergy toMyroxylon pereirae resin has been reported in many countries, ranging from 5.4 to 11.8% (i.e., [49, 182–185]). From a total of 27815 patients recorded over 5 years in Croatia, 8.4% were positive to contact dermatitis upon exposure toMyroxylon pereirae bark [186]. In another case, the prevalence of toxicity by medicinal plants was also reported.Jatropha curcas,Andira inermis, andCanella winterana were the third, the fourth, and the fifth most cited plant species, respectively, associated with cases of toxicity in Cuba from 1998–2007 [36]. Eddleston et al. [187] reported 351 patients with a history ofT. peruviana consumption for 2 years. No deaths were reported.


## 4.4.1. Case Series

Krenzelok et el. [179] gathered information aboutEuphorbia pulcherrima exposure during an 8-year period in the United States of America. The results showed that children accounted for 93.3% of cases of exposure, which were accidental (98.9% of cases) and by ingestion (94.5% of cases). No deaths were reported. However, this study did not report the symptomatology. The toxicity ofCimicifuga racemosa has been extensively studied. The reviews of Borrelli and Ernst [180] and Teschke et al. [181] can be consulted for more information regarding the adverse effects ofCimicifuga racemosa in other clinical cases. The prevalence of allergy toMyroxylon pereirae resin has been reported in many countries, ranging from 5.4 to 11.8% (i.e., [49, 182–185]). From a total of 27815 patients recorded over 5 years in Croatia, 8.4% were positive to contact dermatitis upon exposure toMyroxylon pereirae bark [186]. In another case, the prevalence of toxicity by medicinal plants was also reported.Jatropha curcas,Andira inermis, andCanella winterana were the third, the fourth, and the fifth most cited plant species, respectively, associated with cases of toxicity in Cuba from 1998–2007 [36]. Eddleston et al. [187] reported 351 patients with a history ofT. peruviana consumption for 2 years. No deaths were reported.


## 5. General Considerations

The identification of the compounds responsible for the toxicity has been reported only in some cases. Urushiol might be the compound responsible for the dermatitis reactions toMetopium brownei [188], whereas sanguinarine is the compound associated with the toxicity ofArgemone mexicana. Eddleston et al. [189] reported six fatalities in patients who ingested between 1 and 10 seeds ofT. peruviana. These fatalities occurred due to high concentrations of cardiac glycosides (neriifolin, thevetin A, thevetin B, and oleandrin) in seeds. Three toxins (T-544, T-514, and T-496) have been reported inKarwinskia humboldtiana [190].Manihot esculenta, an important dietary staple, is toxic because of the presence of cyanogenic compounds. Linamarin, the predominant cyanogenic glycoside inManihot esculenta, can be accumulated in a range of concentrations between 100 and 500 mg/kg in roots and leaves. The content of HCN inManihot esculenta has been reported 0.1–1 mg/g fresh weight in the leaves [191]. Several intoxications have been described in humans. The clinical pattern consists of neuropathy and hyperthyroidism [192].The mechanism of toxicity is also unknown in many cases. The mechanism of toxicity ofArgemone mexicana oil might be explained by the inhibitory effects of sanguinarine on Na+/K+ATPase, induction of cell membrane damage by reactive oxygen species and lipid peroxidation, and inhibition of DNA polymerase activity, among other effects [193].Larrea tridentataand nordihydroguaiaretic acid, its active compound, generate acute hepatotoxicity by the inhibition of cyclooxygenase and cytochrome P-450 [194].Special attention should be given in medicinal plants such asArgemone mexicana,Chenopodium ambrosioides, andThevetia peruviana. Effects in humans have been reported due the consumption of these medicinal plants. Other plant species, includingAbrus precatorius, Capsicum annum, Conium maculatum, Erythrina Americana, Heliopsis longipes, Hydrastis canadensis, Jatropha curcas, Jatropha gossypifolia, Karwinskia humboldtiana, Larrea tridentata, Magnolia grandiflora, Parthenium hysterophorus, Phoradendron serotinum, Plumeria rubra, Prosopis juliflora, Ruta chalepensis, Sanguinaria canadensis, Solanum americanum, andVeratrum californicum, have shown effects considered highly toxic, including hepatotoxicity, teratogenic, and cardiotoxicity, or with high toxicity in acute studies. Therefore, a total of 22 plants of 216 cited in this review should be extensively studied in terms of their toxicity. Regarding the hepatotoxicity induced by medicinal plants, Valdivia-Correa [39] reported 15 medicinal plants commonly used in Mexican traditional medicine that induce hepatotoxicity. Five (Equisetum hyemale,Tilia mexicana,Passiflora edulis, andScoparia dulcis) of these fifteen medicinal are considered as toxic, according to our bibliographic research. The induction of hepatotoxicity induced by herbal products represents a serious problem in Mexico since the symptoms and signs might be confused with other diseases, and the diagnosis can be incorrect [39].Some aspects that influence the toxicity of medicinal plants reported in this study are: (a) time of exposure, (b) misidentification of medicinal plants, and (c) adulteration of medicinal plants. Most of the acute symptoms reported in this review appear in the first 24 h after exposure. Nevertheless, more studies, including subacute and chronic assays, as well as the quantitation of hepatic enzymes, should be performed. In other cases, such as the intoxication ofCrotalaria sagittalis, the toxic symptoms appear 2 to 6 months after the exposure [4]. However, chronic poisoning induced by medicinal plants is not easily detected since the symptoms are multiple and variable and a diagnosis cannot be made. Many poisonings caused by medicinal plants are classified as of unknown origin because most of the patients deny the consumption of herbal products. For instance, the clinical picture of intoxication withKarwinskia humboldtiana might be confused with poliomyelitis [190]. In addition, in most of the cases, the plants are not taxonomically identified [36]. The misidentification of medicinal plants represents a serious problem for human health. The adulteration of medicinal plants sold as food products should be considered as a risk of intoxication by medicinal plants.Another aspect to consider for further studies is the evaluation of mixtures of medicinal plants and the combination of medicinal plants with allopathic medications. It is thought that the combination of medicinal plants might result in higher beneficial effects compared to those found with single preparations. Nevertheless, it might be the case that two toxic plants are combined and their toxic effects might result in a synergistic action. The self-medication of drugs along with the consumption of medicinal plants is a common practice among patients with chronic diseases [195], which can be considered as an alternative cause of intoxication. In the clinical record, it is not indicated whether the patient consumes medicinal plants. The interaction of herbal extracts and drugs remains to be studied. There are few documented cases that report the toxicity of the combination of plant extracts and drugs. For instance, the combination ofPicrasma excelsa coumarins are reported to potentiate the activity of warfarin [196]. The toxicity of mixtures of medicinal plants and the combination of medicinal plants with allopathic medication requires further investigation.


## 6. Conclusions

There is limited information about the toxicity of medicinal plants used in Mexico, Central America, and the Caribbean. The molecular mechanisms by which medicinal plants induce toxic effects should also be addressed. In many cases, intoxication by medicinal plants might be confused with other diseases. The detection of intoxication with medicinal plants could be difficult because the symptoms might be confused with other diseases.The prevention of poisoning in humans can be avoided if the chemical composition of medicinal plants is known.



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*Source: 9439868-2017-11-02.xml*