Heinrich et al 2014-Eagle-JNP-77

A Perspective on Natural Products Research and Ethnopharmacologyin Mexico: The Eagle and the Serpent on the Prickly Pear CactusMichael Heinrich,*,† Barbara Frei Haller,‡ and Marco Leonti§

†Centre for Pharmacognosy and Phytotherapy, UCL School of Pharmacy, University of London, 29−39 Brunswick Square, LondonWC1N 1AX, United Kingdom‡Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland§Department of Biomedical Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy

ABSTRACT: Mexico’s extraordinarily rich cultural andfloristic diversity has fascinated explorers and researchersever since the “New World” was discovered for and byEuropeans. For many decades, natural product research hasbeen a very active field of research in Mexico, and there alsoare some ongoing ethnopharmacological research efforts. Thisreview provides an overview and critical appraisal on some keydevelopments in these fields and examples of medicinal plantsused by indigenous communities that have become of greatlocal importance in Mexican popular medicine. In this review,the focus is on plants with effects on the CNS, diabetes,metabolic syndrome, inflammatory processes, and gastro-intestinal disorders. While some of the major food plants consumed worldwide originate from southern North America, onlyvery few medicinal plants have become of major global importance. Opuntia species are now used increasingly to managediabetes and metabolic syndrome and represent an example of a novel medicinal product/supplement. Undoubtedly, narcoticand mind-altering drugs both have received the widest scientific interest and have attracted considerable popular attention. Thehistory of use of the indigenous Mexican Materia Medica in the context of research on local and popular resources specificallywith regard to the diverse challenges in the context of studying the world’s biodiversity and the development of comparative andsemiquantitative ethnobotanical research methods is discussed herein. Natural product and ethnopharmacological research inMexico seems to have been influenced by the political and societal developments originating from the Convention on BiologicalDiversity (CBD) and subsequent conventions, which have not yet had the desired effect of giving value to these local resources,as they might deserve. Their equitable and sustainable implementation remains a challenge. Natural product research andethnopharmacology will play a key role in developing an adequate evidence base for such products derived from local andtraditional knowledge in Mexico.

■ INTRODUCTION

Natural product research is commonly linked to knowledge-driven drug discovery and development1 and, consequently,also to ethnobotanical information. Many of the medicines usedtoday were developed from medicinal plants employed byindigenous peoples. There is a long and heated debate aboutthe role of such local knowledge-based research, and it is seenas an opportunity to develop pharmaceuticals2−4 and otherhigh-value products but also criticized as a means of exploitingindigenous and local communities.5 Often it is overlooked inacademic debates that ethnopharmacological research has thepotential to result in better health care in marginalized areas, atopic of research that might best be approached adopting asustainable dual local as well as global perspective.6,7 Researchon Mexican indigenous plants has played a crucial role in thisdevelopment and in the resulting scientific and politicaldebates, as will be described below.The extraordinary, rich cultural and floristic diversity in

Mexico gave rise to multifaceted coevolutionary interactions

and a rich pattern of ethnopharmacological practices.8 InMexico, the neotropical and the holarctic (circumboreal)floristic kingdoms intersect around the latitude of the Mexicanisthmus, adding up to around 30 000 vascular plant species forthe territory of Mexico.8,9 Of the originally ca. 120 indigenouslanguages and cultural groups flourishing at the time of theSpanish Conquest, depending on the classification, 68 persist tothe present day, although some are inevitably destined forextinction.10

The medicinal flora of Mexico, especially the pharmacopoeiaof the postconquest Aztecs, has soon come into the focus ofchroniclers, who condensed their observations into herbals andcodices.8,11,12 The oldest medical text from the Americas is theLibellus de Medicinalibus Indorum Herbis (Little Book of the

Special Issue: Special Issue in Honor of Otto Sticher

Received: November 29, 2013Published: February 21, 2014

Review

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Medicinal Herbs of the Indians), also called the Cruz-BadianusManuscript and named after Juan Badiano, who translated thetext originally written in Nahuatl by Martin de la Cruz in 1552,into Latin.11,13,14 This offers examples of indigenous medicinalplant use and tries to convey this cultural richness to the Kingof Spain: “A little book of Indian medicinal herbs composed bya certain Indian, physician of the College of Santa Cruz, whohas no theoretical learning, but is well taught by experiencealone. In the year of our Lord Saviour 1552”.15,16

The Florentine Codex compiled by Fray Bernardino deSahagun (ca. 1545−1590) is regarded as the first ethnographicstudy in the new world because of systematic inquiring and theimplementation of questionnaires.8,11 While the BadianusManuscript discusses around 250 medicinal taxa, Books 10and 11 of the Florentine Codex contain information on thetherapeutic uses of around 260 taxa, but apparently, there isonly a marginal overlap of taxa between the two works.8,13 Thelater work by Francisco Hernandez (1514−1587) History of thePlants of New Spain includes information for more than 3000culturally important species gathered between 1571 and 1576.12

The identification of most of the taxa described therein,especially to the species level, is difficult and remains oftendoubtful.17

Despite this diversity, surprisingly few medicinal plants nativeto the neotropics have become globally important plant-basedmedicines.18 While many food plants of Central American/Mexican origin are now of global importance (Zea mays L.,Capsicum spp., Lycopersicum esculentum Mill., Phaseolus vulgarisL., Cucurbita pepo L., Theobroma cacao L., Persea americanaMill.), the most famous examples of medicinal plants in thenarrower sense remain Guaiacum sanctum L. (Lignum Vitae orGuyacan) and different Smilax species. Since the connectionbetween syphilis outbreaks in Europe and the discovery of theNew World was recognized, and as it was thought that whereparticular diseases arise, there must also exist natural remedies,the heartwood of G. sanctum (Zygophyllaceae) and the roots ofvarious sarsaparilla species (Smilax spp., Smilacaceae) wereimported to Europe to treat syphilis.19

Other important plants include Chenopodium ambrosioides L.(today often classified as Dysphania ambrosioides (L.) Mosyakin& Clemants), which is used both as a spice, especially for disheswith Mexican black beans (frijoles), and as a medicine forgastrointestinal parasites. It was included in many pharmaco-poeias including, for example, those of Mexico, the UnitedStates, and many European countries. However, because of thetoxic side effects (mostly of the essential oil) and lack ofevidence for its purported vermicidal effects,20 this has nowbeen substituted by synthetic vermifuges. After a worldwide useas a medicine, this usage is today once more largely restricted toits region of origin, especially Mexico, where it provides apowerful symbol for the Mexican identity and is an essentialelement of the local cuisine and medical tradition. Anotherfamous example important in trade over many centuries hasbeen the medicinal plant complex named “Jalapa” or Jalaproots. Besides Ipomoea purga (Wender.) Hayne, several othercathartic Ipomoea species are part of the “jalapa complex”, ofwhich all contain purgative resin glycosides.21 The develop-ments in the context of discovering novel useful drugs havebeen a part of a much wider fascination in Europe with theexotic and their potential. For example, this is well representedby Prof. Dr. Carl Hartwich (1851−1917), who, from 1892 until1917, worked at ETH Zurich and its predecessor, theEidgenossisches Polytechnikum.22 Prof. Dr. Otto Sticher (*

1936), who was professor of pharmacognosy and phytochem-istry at the ETH (1972−2002), followed in this tradition, andthis review, dedicated to him, is embedded in his researchinterests and collaborative projects (especially with theUniversity of Freiburg, Germany) focusing on perspectivesthat are relevant to his research interests at the interface ofnatural product research and ethnopharmacology in Mexico.

■ CHALLENGES WITH ETHNOBOTANICAL ANDETHNOPHARMACOLOGICAL RESEARCHPROJECTS IN MEXICO

The early colonial history of medicinal plant research in Mexicohas been outlined above, and it is not surprising that Mexicoremained at the center of many research and developmentefforts focusing on new medicines from its own biodiversity.Mexico remained an important supplier of some medicalcommodities, perhaps most importantly of Dioscorea speciesused as a semisynthetic precursor of steroids.23 Natural productresearch in Mexico has flourished since at least the 1960s andhas resulted in a wide body of literature on secondarymetabolites found in Mexican plants.21 While no currentcomprehensive review on the phytochemistry of Mexican plantsexists, there is, for example, a large body of data on anticanceragents,24 one somewhat older review on antidiabetic plants, anda recent publication specifically on inhibitors of α-glucosi-dases.25,26

Without doubt, two of the most important examples ofnatural products related projects in recent years have been twoInternational Collaborative Biodiversity Groups (ICBGs)funded by a combined effort of the United States Agency forInternational Development (USAID), the National ScienceFoundation (NSF), and the National Institutes of Health(NIH). As a response to the Convention on BiologicalDiversity (the “CBD” or “Rio Convention”) signed by a largenumber of participant nations in 1992, the United States, acountry that did not sign the Convention, developed programsintegrating strategies for an “improvement of human healththrough drug discovery, incentives for conservation ofbiodiversity, and new models of sustainable economic activitythat focus on the equilibrated integration of environmentalaspects, human health, population, socio-economic growth andbasic democracy”.27 The focus of this collaborative endeavorwas on developing new drug leads for use in both the sourcecountries and more developed economies, the classical usercountries of such knowledge and materials. It was the expressedgoal of these projects to contribute to biodiversity conservationand economic development at both a local and internationallevel.From 1993 until 2003, Dr. Barbara Timmermann (then at

the University of Arizona) and colleagues (including theUniversidad Nacional Autonoma de Mexico, as well as PurdueUniversity, G. W. L. Hansen’s Disease Center, and the Medicaland Agricultural Divisions of Wyeth-Ayerst/American Cyana-mid Co.) focused on plant species growing in arid areas inChile, Argentina, and Mexico, in a study guided by the ICBGmechanism. Their project investigated a broad range ofbiological targets relevant to the treatment of infectiousdiseases, cardiovascular and central nervous system disorders,cancer and inflammation, and women’s health as well asillnesses prevalent in developing countries and included a focuson antimycobacterial compounds from certain Mexicanmedicinal plants (e.g., refs 28 and 29). Drs. Brent and EloisAnn Berlin developed an ambitious ICBG project with a strong

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emphasis on ascertaining local participation and a wide dialoguewith the relevant Mexican stakeholders. The project focused onthe local and traditional medicinal plant use in Chiapas,southern Mexico, but was not carried to completion. Keypartners included the University of Georgia (Athens, GA, USA)with several departments involved. It planned to investigatepotential treatments for diarrhea, respiratory conditions,infectious diseases, contraception, and other locally importanthealth needs. The initial plan was to “discover, isolate, andpreclinically evaluate pharmacologically important species fromMexico, the third richest mega-diversity region of the world andone of the most threatened in terms of biodiversity loss due toincreased environmental destruction”.30 This was to be basedon previous and new ethnobotanical fieldwork among Maya-speaking peoples of Chiapas in the south of Mexico, an areathat only five years earlier had been the center of a popularuprising led by the “EZLN” [Ejercito Zapatista de LiberacionNacional (Zapatista Army of National Liberation)], a leftistgroup of insurgents.The focus of this research group was to be on the complex

ethnobotanical and ethnomedical knowledge available, and itcentered on documenting medicinal taxa used by theindigenous groups in the state.31 In addition, it was plannedto collect microorganisms from the region, which together withhigher plant samples were to be evaluated with a focus oncancer, opportunistic diseases associated with HIV/AIDS, CNSdisorders, contraception, cardiovascular disease, and locallyserious gastrointestinal, respiratory/pulmonary, and skindisorders. Another focus was agro-ecological development fora sustainable production of selected species with high potentialas phytomedicines, crop protection agents, and commerciallyviable ornamentals. Training of Mayan participants andacademic exchanges were an integral part of this short-livedproject. This involved both the training of U.S. students inChiapas and that of younger researchers from Chiapas in U.S.institutions. The information was to be transmitted locallyusing a series of innovative and culturally adapted techniquessuch as theater performances in the local languages describingthe goals of the ICBG. However, this was then criticized asdistracting attention from the involvement of commercialinterest.32,33

In 2002 J. Rosenthal concluded: “The ending of the ICBGMaya has a chilling effect on the ability of scientists to developtransparent and ethical collaborations in natural-products drugdiscovery, biotechnology and other sustainable uses ofbiodiversity for local and global benefit”.34 The example isone of the clearest as to how changing political frameworkshave impacted research and development in the area of naturalproducts (as they have in some areas of biotechnology). Itneeds to be highlighted that Drs. Brent and Elois Ann Berlinhad followed the strictest rules as had been laid down at thetime, including pioneering ones from the Declaration of Belemand principles of the CBD (as they were outlined at the time).Of course, current research in Mexico is very much

conducted in the context of the legal and ethical requirementsbased on the Convention on Biological Diversity (the RioConvention, 1992) and subsequent agreements, most recently,the “Nagoya Protocol on Access to Genetic Resources and theFair and Equitable Sharing of Benefits Arising from theirUtilization (ABS) to the Convention on Biological Diversity(2010)” and the interoperations of these agreements.The interdepartmental Mexican commission for the Knowl-

edge and Use of Biodiversity (CONABIO) summarizes the

present legal issues around the intellectual property rightsrelated to biocultural diversity in Mexico as follows:35

“The current legal framework with respect to the use andintellectual property of indigenous and traditional communities’practices, knowledge and innovations remains insufficient:some elements are in place but even these may becontradictory.” Also, “Article 176 of the Sustainable RuralDevelopment Law, establishes that an Inter-MinisterialCommission will oversee the defense of the intellectual rightsof indigenous and local communities.” However, CONABIOconcludes that “The Federal Law on Authors Rights, in itsArticles 20, 154, 157−161, establishes the protection of theuses, customs and traditions of the pluricultural compositionwhich makes up the Mexican State, having no identifiableauthor, their validity will be indefinite and their publicationmust give the corresponding credits. However, it alsoestablishes the free use of these protected works, the ownershipof which abides with the State, thereby contravening theprinciples enshrined in the CBD, the General Law on Wildlife(Ley General de Vida Silvestre, LGVS) and The SustainableRural Development Law (LDRS).”More than 20 years after the signing of the CBD, there still

are limited examples of a successful translation of its principlesinto benefits based on the development of new products, butthe recent example of an antidiarrheal medication for use inHIV patients derived from Croton lechleriMuell. Arg. (Sangre dedrago), a Peruvian plant, offers hope that such developmentsare possible.3 However, it seems that small nationalbioprospecting endeavors have not suffered political pressuresand that the problem is confined to the state of Chiapas.

■ QUANTITATIVE ETHNOPHARMACOLOGY,CONSENSUS, AND VARIATION

The rich cultural diversity of Mexico allows for comprehensiveanalyses of patterns of medicinal plant use within and amongcultures, highlighting consensus and variation to varyingdegrees. On the basis of the principle of empiricism andvertical and horizontal knowledge transmission, it has beenhypothesized that ethnopharmacological resources with a highintracultural or intercultural acceptance are more effective thanspecies receiving limited consensus.36,37 While initially theinterest was generally on documenting the use of a specificplant resulting in a simple positive list of taxa used (e.g., thetremendous body of work by R. E. Schultes), since the late1980s the quantification of individual use-reports (per categoryof use and species) has been developed as a key tool to assessthe cultural relevance of a set of species known and used in agiven culture. It is a straightforward and transparent form ofassessing the cultural importance of species and recommendedfor the selection of candidate species for phytochemical analysisand pharmacological testing.36,38,39

For the assessment of intracultural consensus with respect tothe remedies used for a certain ailment category, Trotter andLogan36 proposed the measurement of an “informant agree-ment ratio” (or consensus factor; ranging between 0 and 1).This consensus factor may also be applied for interculturalcomparisons. In collaboration with Prof. Dr. Otto Sticher(Figure 1), Heinrich et al.37 used it for the first time in acomparative cross-cultural ethnopharmacological and quantita-tive study identifying key species of particular ethnopharmaco-logical salience. Remedies for gastrointestinal diseases, forinstance, show a relatively high consensus with indigenouspeoples in southern Mexico and Guatemala.37,40,41 An updated

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consensus analysis (Table 1) incorporating data from theCh’orti’ in eastern Guatemala,41 the Mazatecs of Oaxaca,42 thePopoloca/Mestizo in Puebla,43 and the Popoluca in Veracruz40

(all Mexico, Figure 2), based on simple use-report counts of themost important herbal remedies used to treat gastrointestinalconditions, results in an essentially very similar outcome byidentifying a group of core species used commonly in thesegeographically distant and culturally distinct communities.Many introduced species evidently owe their interculturalimportance to a more or less uniform post-Conquestknowledge transmission, while the native species have gainedthe high agreement due to independently perceived effective-ness and/or intercultural exchange.Also, an intercultural consensus analysis of remedies used to

treat central nervous system disorders shows the importance inMexico of many introduced Eurasian species.38 Several of thehigh-consensus taxa observed such as Citrus aurantium,Cymbopogon citratus (DC.) Stapf, Agastache mexicana (Kunth)Lint & Epling, Ruta chalepensis, Tagetes spp., Ocimum spp.,Artemisia spp., Matricaria chamomilla L., and Galphimia glaucaCav. are also of importance in the treatment of gastrointestinaldisorders (Table 1; refs 7, 46). Over 30% of the 81 speciesrecorded for the treatment of central nervous system disorders

belong to the Asteraceae (20%) and Lamiaceae (12%).38

Asteraceae are highly prominent and widely used as herbalremedies in Mexico, but some are not unproblematic due totoxicological risks.47 In terms of numbers of species used, theAsteraceae are also the most important taxa in diabetes type 2treatment.26,48 Among these are several species of thehepatotoxic Senecionae49 such as Packera candidissima(Greene) W.A. Weber & A. Love and Psacalium spp. (exCacalia and Senecio), forming a “plant complex” called“Matarique”.47,50 The prominent position of the Asteraceae inphytotherapy also reflects their species richness. The Asteraceaereach their diversity center in Mexico with 2700−3000 spp.,while the Lamiaceae are present in Mexico with over 500species.51,52 With respect to the overall flora, both theAsteraceae and the Lamiaceae are overproportionally reliedupon in traditional Mexican medicine, as analyses with theTzeltal/Tzotziles in Chiapas, the Sierra Popoluca in southernVeracruz, and the inhabitants of the Tehuacan−CuicatlanValley suggest.53−55 Thus, there seems to be also anintercultural consensus with respect to the taxonomic sourceof plant-derived medicines. As far as it seems, this consensus isnot merely influenced by universal cultural selection criteria orcommon human perception but also conditioned by ecologi-cally factors, such as weed ecology and plant coevolutionbetween allelopathy and the adaptation to broader biogeo-graphic environments.56,57

■ EXAMPLES OF RESEARCH ON BIOACTIVENATURAL PRODUCTS ANDETHNOPHARMACOLOGY IN MEXICO

In the following sections key research developments andachievements specifically on Mexican plants with a history inmedicine and food are highlighted. Excluded are plants used inthe treatment of cancer, since a direct relation to ethno-pharmacological observations is often missing and because acomprehensive review was published only recently,58 or speciesthat have been developed for other purposes such as colorantsor flavors.59,60

■ CNS-ACTIVE PLANTS FROM TRADITIONALKNOWLEDGE OF MEXICO

The ritualistic use of different narcotic and mind-altering drugsdispleased the post-Conquest authorities but attracted theinterest of a range of botanists, mycologists, ethnologists, andchemists.61−63 Undoubtedly it is the aspect of natural productresearch and ethnopharmacology in Mexico that has both hadthe widest scientific impact and also attracted considerablepopular attention. Interestingly, species such as Nicotianatabacum L. and N. rustica L. (tobacco), Theobroma spp. (cacaospecies), Lophophora williamsii (Lem. ex Salm-Dyck) J.M.Coult. (peyote), Turbina corymbosa (L.) Raf. and Ipomoeaviolacea L. (morning glory), Datura spp. (e.g., jimson weed),and the fruiting bodies of certain Agaricales (Psilocybe spp.,Paneolus spp., Stropharia spp.) were not consumed exclusivelyfor shamanistic and hedonistic purposes but also as medicinesin subnarcotic doses.13,64

Salvia divinorum Epling & Ja tiva (Lamiaceae). S.divinorum (Mazatec: “ska maria pastora”) has developed froma sacred plant restricted to a small region inhabited by theMazatec Indians of southern Mexico to a widely usedpsychoactive commodity.65 Aside from inducing visions, theMazatec use S. divinorum to treat a poorly described

Figure 1. Prof. Dr. Otto Sticher on a field work visit in Oaxaca in 1992collecting plant samples from a species used in local and traditionalZapotec medicine for phytochemical research at the ETH Zurich(photo Barbara Frei).

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ethnomedical syndrome, called “panzon de borrego” (“sheep’sbelly”) characterized by a swollen stomach.66 Subhallucinogenicinfusions made from about a dozen of the leaves of this plantare also used as a general tonic and to treat defecationproblems, headache, and rheumatism.66 Ethnomedical literatureon the traditional use of S. divinorum is limited and conditionedby the natural distribution of this species, which is restricted tothe Sierra Mazateca of Oaxaca. Remarkably, salvinorin A (1),the main active principle, which appears to be the most potentnaturally occurring hallucinogen known to date, is a non-nitrogenous neoclerodane diterpene.67−69 The screeningagainst a panel of cloned human G protein-coupled receptors(GCPRs), ion channels, and transporter proteins revealed theselectivity of 1 against the κ-opioid receptor (KOR) with a Ki of16 nM.70 More recently, data sustaining a potential role of

dopamine 2 (D2) receptors in the overall pharmacologic actionof compound 1 have been presented,71 although being inconflict with earlier data by Siebert et al.,70,72 who reported nosignificant activity at the D2 receptor. Intriguingly, whilesalvinorin A acts as a KOR agonist, salvinicin B (2), anotherneoclerodane-type diterpene found in S. divinorum, shows anantagonistic interaction.73 Salvinorin A has challenged the ideathat nonpeptidic opioid receptor ligands must feature a basicamino group and provides a template for the design of novelsemisynthetic μ (MOR) and δ (DOR) opioid receptorligands.74,75 Evidence that ligands of the KOR are oftherapeutic relevance in terms of nociception, anxiety disorders,depression, and drug abuse point to a promising pharmaceuticalfuture for neoclerodane-type opioid receptor agonists.76,77

Table 1. Interregional Consensus of Species Used to Treat Gastrointestinal Illnesses among the Maya,37 Nahua,37 Zapotec,37

Popoluca,44 Mazatecs,42 Mestizos/Popoloca,43 Tzeltal/Tzotzil,7 and Mixe45 in Southern Mexico and Ch’orti’ Maya41 of EasternGuatemala

plant species

Maya(Yucatan)b

Fic 0.71

Nahua(Zongolica)a

Fic 0.68

Zapotec(Oaxaca,isthmus)b

Fic 0.66

Popoluca(Veracruz,isthmus)Fic 0.70

Ch’orti’ Maya(eastern

Guatemala)Fic 0.69

Mazatecs(Oaxaca)

Mesitizo/Popoloca(Puebla)

Tzeltal/Tzotzil(Maya; Chiapas,

CentralHighland)c

Mixe(isthmus,Oaxaca)c

Parallel Use-Reports of the Species with All Nine Indigenous Groups

Chenopodium ambrosioides L. (=Dysphania ambrosioides (L.)Mosyakin & Clemants)

10 6 10 17 16 7 5 + +

Psidium guajava L. 10 7 10 11 14 18 22 + +

Parallel Use-Reports of the Species with Seven Indigenous Groups

Artemisia ludoviciana ssp.mexicana (Willd. ex Spreng.)D.D. Keck

9 7 7 7 3 14 +

Parallel Use-Reports of the Species with Six Indigenous GroupsdCitrus limon (L.) Osbeck (+) 7 5 13 2 +

Mentha spp. 18 6 2 5 43 +dRuta chalepensis L. 9 10 10 13 5 +

Parallel Use-Reports of the Species with Five Indigenous Groups

Byrsonima crassifolia (L.) Kunth (+) 6 22 + +

Cissampelos pareira L. 9 21 5 + +

Lippia alba (Mill.) N.E. Br. exBritton & P. Wilson

9 9 (+) 3 +

Matricaria chamomilla L.d 8 (+) 6 39 +

Parallel Use-Reports of the Species with Four Indigenous Groups

Guazuma ulmifolia Lam. 6 3 10 +

Punica granatum L.d 7 (+) 2 7

Tagetes erecta L. 11 (+) 2 11

Parallel Use-Reports of the Species with Three Indigenous Groups

Anethum graveolens L.d 6 7 +

Artemisia absinthium L.d 6 (+) +

Cocos nucifera L.d 6 6 6

Pluchea symphytifolia (Mill.)Gillise

7 4 +

Rosa sp.d 6 (+) 1

Zingiber of f icinale Roscoed 8 12 13

Parallel Use-Reports of the Species with Two Indigenous Groups

Annona reticulata L. 6 21

Aristolochia maxima Jacq. 11 12

Citrus aurantium L.d 9 1

Citrus sinensis (L.) Osbeckd 6 4

Malvaviscus arboreus Cav. 9 7

Marrubium vulgare L.d 10 4

Psidium salutare (Kunth) O.Berg

8 13

aOnly the species mentioned six or more times are listed. b(+) = less than six use-reports. c+ = No information on citation frequency. dExotic, i.e.,introduced species. eThere is some taxonomic and systematic debate about this species; P. symphytitfolia auct. is now also included in Plucheacarolinensis (Jacq.) G. Don.

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Theobroma cacao L. (Malvaceae). Apart from its culinaryand ritual use, T. cacao (cacao and chocolate, “cacahuatl” in16th century Nahuatl) has also a rich history in indigenous andmodern medicine. Out of the huge diversity of recordedmedical uses and applications, Dillinger et al.78 have distilledthe overall consensus for the medicinal value of cocoa productsas (i) a weight gain integrator, (ii) a stimulator or tranquilizerof the nervous system, and (iii) as a digestion-improving agent.In the 11th book of the Florentine Codex, Sahagun reports,“This cacao, when much is drunk, when much is consumed,especially that which is green, which is tender, makes onedrunk, takes effect on one, makes one dizzy, confuses one,makes one sick, deranges one. When an ordinary amount isdrunk, it gladdens one, refreshes one, consoles one, invigoratesone. Thus it is said: I take cacao. I wet my lips. I refreshmyself.”79 The use of cocoa products for putting on weight

might be associated with the appealing organoleptic property ofchocolate and correlated with the ingested amount of fat andsugar. Explaining the use of cacao and chocolate as a stimulatorand tranquilizer of the central nervous system, especially withrespect to the much-debated addictive potential of chocolate ismore complex.80 Cacao and its products contain severalbiogenic amines involved in human neurotransmission (e.g.,dopamine, tyramine, histamine, serotonin, and 2-phenylethyl-amine) and CNS-stimulatory methylated xanthines (caffeine,theobromine, and theophylline), of which theobromine is themost abundant but its CNS effects are far less potent whencompared to theophylline and caffeine.81−83 Identical improve-ments of cognitive performance and mood states between theingestion of 11.6 g of encapsulated cocoa powder and theadministration of caffeine and theobromine contained onaverage in a 50 g chocolate bar (19 and 250 mg, respectively)were observed in a placebo-controlled study with humanvolunteers.84 Therefore, Smit et al.82 concluded that otherpharmacologically active components contained in cacao addonly marginally, if at all, to the overall stimulatory effect ofchocolate. Newer results obtained with a larger sample size andhigher theobromine doses are, however, inconclusive regardingtheobromine’s role in the psychological effects of chocolate.85

The biogenic amines present in chocolate and cocoa aregenerally rapidly degraded upon consumption, and theirconcentration in cocoa products is relatively low whencompared to other food sources.86 Also, a series of biogenicamine-related tetrahydro-β-carbolines known for their MAO-inhibiting activity have been detected in cocoa and chocolate,but their total amount does not exceed 1 mg/100 g chocolate.87

Moreover, the dopamine-related tetrahydroisoquinoline salso-linol (3, 4) was found in chocolate and cocoa up to aconcentration of 2 and 2.5 mg/100 g, respectively.88 Thisracemic alkaloid, which is also formed under normalphysiological conditions in humans, has been implicated inalcohol craving and the etiopathology of Parkinson’s dis-ease.89,90 An in vivo microdialysis study showed that at high

Figure 2. Ethnobotanical field study-sites in southern Mexico and eastern Guatemala used for the consensus analysis in Table 1.

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concentrations both salsolinol enantiomers (dialysate concen-tration: (R)-SAL (3) = 287 μM; (S)-SAL (4) = 422 μM) wereable to raise 5-HT levels in the rat striatum from undetectablesources to 2.53 and 3.69 μM, respectively, while dopaminelevels increased from 4.2 nM to 300 nM ((R)-SAL) and 21.5nM ((S)-SAL).91 Physiologically more relevant is SAL’s indirectdopaminergic excitation effect in rat brain slices at lowconcentrations between 0.01 and 1 μM via the activation ofMORs situated on GABAergic neurons.92 In the posteriorventral tegmental area, SAL is around 1−2 million times moreeffective in stimulating dopaminergic neurons than ethanol.93

(S)-SAL was also found to be a D2 (Ki = 5 μM) and D3 (Ki =0.5 μM) receptor agonist, inhibiting the formation of cAMPand after long-term treatment also the release of theneuropeptides β-endorphine and corticotropin in vitro.88

While (R)-SAL showed far less affinity toward dopaminereceptors than (S)-SAL,88 (R)-SAL is a competitive MAO-Ainhibitor (Ki = 31 μM).94 Since there is no obvious reason whySAL should not be absorbed and be able to pass the blood−brain barrier, it might well, as suggested by Melzig et al.,88

interact with brain physiology and add to the stimulatory effectsreported by chocolate consumers. A placebo-controlled trialadditionally considering a representative amount of SAL andeventually tetrahydro-β-carbolines and biogenic amines couldreveal synergies between the different constituents or lendadditional support to the plausible methyxanthine hypothesis.84

Galphimia glauca Cav. (Malpighiaceae). A nation-widedatabase on the popular and traditional use of medicinal plantsacross Mexico was evaluated with respect to applications relatedto the central nervous system.38 The ethnomedical informationwas standardized, and the alleged properties were classified intoanticonvulsants, sedatives, and hypnotics.38

In Mexico, Galphimia glauca Cav. is used against a variety ofdiseases and health conditions including gastrointestinaldisorders, allergies, asthma, malaria, and nervous excitement.95

Although crude extracts of G. glauca showed moderateantiprotozoal activity in vitro, with the exception of thecommon flavonoid quercetin, none of the other isolatedcompounds, galphins A−C and galphimidin (all with IC50values of >100 μM), have shown any activity.96 Similarly,common compounds present in G. glauca such as gallic acidand its derivatives, as well as quercetin, seem to mediate theinhibitory activity of experimentally induced asthmaticsymptoms in guinea pigs.97 Responsible for the sedative andanxiolytic effects are a series of nor-secofriedelanes of whichgalphimine B (5) is the main active constituent.98−100 Thespasmolytic effects of galphimines A and B evaluated via theirinhibition of electrically induced contractions of guinea pigileum ex vivo99 correlated with the anxiolytic effects determinedthrough the plus-maze test with mice.101

A metabolomic profiling of six different G. glaucaprovenances showed drastic differences in content of bioactiveconstituents and pharmacologic activities with several acces-sions devoid of anxiolytic properties and detectable amounts ofgalphimines.102 A follow-up study proved the discrimination ofG. glauca populations by means of 1H NMR spectroscopy,pharmacological screening, and multivariate data analysis to be

a robust approach for the selection of chemotypes with specificphytotherapeutic potential.103 While environmental factorssurely contribute to the diverse metabolic profiles of thedifferent samples, the profound chemical differences betweenthe different populations were due to the inclusion of different,hitherto botanically not yet characterized, species.103

A double-blind, randomized, lorazepam-controlled clinicaltrial with patients diagnosed with generalized anxiety disorderrevealed a greater anxiolytic effectiveness of G. glauca extractstandardized in 0.175 mg of galphimine B than administrationof 0.5 mg of lorazepam.104 In rats, the sedative effect ofgalphimine B is apparently caused by a non-GABA receptormediated depression of dopaminergic neurons of the ventraltegmental area105 and by a poorly characterized interaction withthe serotonergic system in the dorsal hippocampus.106

Agastache mexicana (Kunth) Lint & Epling (Lamia-ceae). Two subspecies of A. mexicana (H.B.K.) Lint & Epling,A. mexicana ssp. xolocotziana Bye, Linares & Ramamoorthy andA. mexicana ssp. mexicana Bye, Linares & Ramamoorthy,together with Dracocephalum moldavica L., form a medicinalplant complex called “los tres toronjiles”.107 Their infusion,reported to have sedative properties, is applied for differentgastrointestinal, nervous, and cardiovascular ailments.12,107 Thepolar extracts of A. mexicana ssp. xolocotziana showed highconcentration levels of the common triterpenoid ursolic acidand the 4′-O-methylated flavone acacetin.46 Experimentallyinduced nociception in mice was reduced to 50% by acacetin at2 mg/kg ip and ursolic acid at 3 mg/kg ip, and additionally foracacetin a spasmolytic response with an IC50 of 1.1 μM wasfound using the isolated guinea pig ileum.46 Anxiolytic effectswere, however, not observed at relevant doses with either ofthese compounds. Also D. moldavica, a species of Eurasianorigin, contains acacetin glycosides and ursolic acid togetherwith other flavonoids and triterpenoids.108 In parallel with A.mexicana, the aqueous extract of D. moldavica showed sedativeeffects in mice but no anxiolytic properties.108 Since Estrada-Reyes et al.107 have demonstrated for the two recognizedsubspecies of A. mexicana that, apart from showingmorphological differences, these may be distinguished by adifferent composition of the essential oil; nonpolar fractions ofboth subspecies should be evaluated together with that of D.moldavica for their anxiolytic responses.

■ DIABETESOne key area of research interest in recent years has been plantswith potential antidiabetic effects and their chemistry andpharmacology.26 For 2012, the total number of people inMexico with diabetes was estimated to be 6.4 million,109

equivalent to about 5.6% of the entire population. Diabetesmortality in Mexico is substantially greater than in higher-income countries.110 “Medicinal foods” are widely used as partof home treatments generally after a medical diagnosis ofdiabetes mellitus type 2 has been made. A detailed review of

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alpha-glycosidase inhibitors from Mexican plants was publishedrecently, highlighting the potential of developing novelantidiabetic agents from plants commonly used as food ormedicine in Mexico and covering most of the relevantpreclinical literature on antidiabetic compounds obtained thusfar.25

Opuntia spp. (Cactaceae). Since the 1980s, considerableinterest has focused on the hypoglycemic effect of Opunitaspecies, most importantly, Opuntia f icus-indica (L.). Mill.(Spanish: “nopal”, Nahua: “nopalli”) and O. streptacanthaLem. after an oral intake of fleshy stems (cladodes).Preparations derived from these plants have been studiedboth in experimental animals and in humans (e.g., refs 111 and112). Initially, crude and boiled plant materials were used inexperimental settings, and more recently a series of partiallycharacterized extracts were applied, for example, in a smalldouble-blind placebo-controlled intervention study (15 verum2 × 200 mg extract preparation; 14 placebo), using a waterextract with a drug-to-extract ratio of 2−4:1 for each material.The acute response was tested in an oral glucose tolerance test(OGTT) with a 400 mg bolus of the preparation given 30 minprior to ingesting a 75 g glucose drink,113 and longer-termsafety was evaluated. Statistically significant decreases (p <0.05) in the blood glucose concentrations were achieved at alltime points (60, 90, and 120 min) measured, but the O. f icus-indica extract was shown to not influence blood parameters ifconsumed over a period of 16 weeks. During the chronic phaseno differences after OGTT challenge were found as comparedto the pretreatment tests, indicating that the extract has nodirect glucose-lowering effects if administered over a prolongedperiod of time. The cladodes of O. f icus-indica are known tocontain carbohydrates (3−7%), fiber (1−2%), and protein(0.5−1%) as well as kaempferol and isorhamnetin glycosides(glucoside and rhamnoside).114 While antidiabetic metabolitesin Opuntia spp. have so far not been detected, the bulky andwater-absorbing polysaccharides present in Opuntia cladodesmay act as barriers/mechanistic sponges in the intestine,influencing sugar uptake and the feeling of satiety.Cecropia obtusifolia Bertol. (Urticaceae). In Mexican

local and traditional medicine, Cecropia spp. and mostimportantly C. obtusifolia have a high reputation as antidiabeticagents, and an experimental work and several clinical trialssupport the purported hypoglycemic properties of Cecropiaspecies. This has been linked to the presence of chlorogenicacid and isoorientin, two widely distributed secondarymetabolites,115 and associated with the stimulation of 2-NBDglucose uptake both in insulin-sensitive and insulin-resistant3T3 adipocytes in a murine cell line.116 Already by 1997 it hadbeen shown that chlorogenic acid inhibits glucose-6-phospha-tase (EC 3.1.3.9), resulting in an inhibition of hepatic glucoseproduction.117 After iv administration, chlorogenic acid (5 mg/kg body weight/day rat for three weeks) was found to improveglucose tolerance, decrease plasma cholesterol and triacylgly-cerols and liver triacylglycerols, and improve mineral pooldistribution.118 However, sound clinical evidence for itseffectiveness is still missing.

■ GASTROINTESTINAL DISORDERSDiarrhea remains a key health problem in many countriesincluding Mexico, and there continues to be comparatively littleresearch into these syndromes and their treatment. In terms ofdeveloping new medical agents in this therapeutic area,undoubtedly, the marketing authorization of a semipurified

proanthocyanidin oligomer mixture from Croton lechlerii Muell.Arg. (Euphorbiaceae) for HIV-associated diarrhea has been themost important breakthrough.119,120 This species is well knownfor being used traditionally in the Amazon region to treatgastrointestinal problems.121

Research on proanthocyanidins from commonly usedMexican medicinal plants (led by Prof. Dr. H. Rimpler,Freiburg, Germany) resulted in the identification of a range ofproanthocyanidins from Mexican medicinal plants commonlyused in the treatment of diarrhea including from Byrsonimacrasssifolia (L.) Kunth (Malpighiaceae)122 and Guazumaulmifolia Lam. (Malvaceae),123 both widely used in thelowlands of Mexico, most importantly by the Mixe, Zapotecs,and Popoluca (Table 1).In the case of G. ulmifolia, ex vivo experiments showed that a

bark-extract (40 μg/mL) completely inhibited cholera toxin-induced chloride secretion in the rabbit distal colon in a Ussingchamber, while PGE2-induced chloride secretion was notinhibited. Also, the extract had to be added directly to themucosal bath prior to the toxin, indicating that the compoundsexert a direct effect on the toxin, a concept substantiated bySDS-PAGE analysis. One of the authors (M.H. andcollaborators) was able to show that the extract specificallyinteracted with the A subunit of the toxin.124 Bioassay-guidedfractionation led to the isolation of polymeric proanthocyani-dins, with the most active ones having a degree ofpolymerization higher than 8.123 Only a limited number ofother studies on this species are available, which are of directrelevance to the treatment of gastrointestinal conditions. In anacute gastric ulcer model (diclofenac-induced ulcers in rats),pretreatment with an extract from leaves and flowers of G.ulmifolia decreased the ulcerated area in a dose-dependentmanner.125

The best studied plant widely used in Mexican local andtraditional medicine for treating gastrointestinal problems isPsidium guajava L. (Myrtaceae), which was reviewed in detailby Perez Gutierrez et al.126 For example, one of the earlierstudies used the guinea pig ileum model for bioassay-guidedisolation of spasmolytic constituents and identified theflavanoid aglycone quercetin as a key bioactive constituentfrom P. guajava leaves.127 A similar approach was used in thecase of Baccharis conferta Kunth. (Asteraceae), another speciesused to treat gastrointestinal problems and diarrhea in Mexico,which resulted in the identification of a series of flavonoidsacting as antispasmodic agents.128 Also, the fractionation ofCasimiroa tetrameria Millsp. (Rutaceae) led to the identificationof polymethoxylated flavonoids acting as antisecretory andantispasmodic agents.129

In general terms, while some studies focusing on the effectsof Mexican medicinal plants on acute gastrointestinalconditions are available, there is a lack of research that wouldhelp in further developing an evidence-base for this usage.

■ ACUTE INFLAMMATORY CONDITIONSThere has been a continuous and strong interest in anti-inflammatory natural products with a range of key targetsexplored. Much of this research is based on in vitro studies oron research in classical animal models. Classical targets includeCOX-1, COX-2, TNF-α, and, since the mid 1990s, NF-κB.More recently, TOLL-like receptors have become a target thatcould be of therapeutic benefit.A considerable body of research on natural products and

ethnopharmacology of Mexican plants in the last decades

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centered on the so-called “arnica” complex. According to Obonet al., in 1533 the term arnica was first introduced by the editorof St. Hildegard’s Physica to name an unidentified magical plantspecies.130 Around 1785, the term arnica was introduced inSpain associated with the reports of successful use in hospitalsof Arnica montana L. (Asteraceae) to treat an ophthalmologicalproblem, a loss of vision occurring without an apparent lesionaffecting the eye (amaurosis). This species is found in Centraland North Eastern Europe and in some regions of NorthernSpain, where it has other common names and anothersubspecies that has a more southerly distribution. Obon et al.conclude, “The [a]rnica medicinal plant complex wasdeveloped in the Iberian Peninsula between 1785 and 1895influenced by the medical advances of the time and the work oflocal apothecaries and plant collectors.”130 The spread of theconcept arnica to the Spanish colonies has not been researchedin detail so far, but it is apparent that with the colonizers bothpreparations containing A. montana and the concept of arnicawere introduced to the “New World”. Today in Mexico, a largenumber of Asteraceae species131 including Neurolaena lobata(L.) R. Br. ex. Cass. and Tithonia diversifolia (Hemsl.) A. Grayare referred to commonly as arnica or derivatives (like arnicadel monte). In fact, it seems that in Mexico the use of A.montana as such was practically unknown. However, due to thepopular name, research into the phytochemistry andphytopharmacology of arnicas was started with an interest instudying the potential therapeutic benefits of the Mexicanarnica,132 which in this case referred to Heterotheca inuloidesCass (Asteraceae). Considerable research has gone into thechemistry of this species as well as its in vitro and in vivobiological properties,133−136 yielding sesquiterpene derivatives(cadalenes), coumarins, triterpenes, and flavonoids andproviding evidence for the local and traditional use in Mexicoas an anti-inflammatory and analgesic herbal medicine. Of note,H. inuloides does not contain sesquiterpene lactones.132

An example of how the systematic screening for a series ofplant extracts used traditionally can result in the identificationof a new class of potent inhibitors is based on a systematicstudy of medicinal plants used in Zongolica, Veracruz, and SanJuan Guichicovi, Oaxaca, which resulted in the identification ofsesquiterpene lactones as NF-κB inhibitors137 and thesubsequent identification of parthenolide (6) as a potentiallead compound.138,139 In the last decades, many reports oninhibitors within this class varying widely in their IC50 values forinhibiting NF-κB have been reported, including the effects ofhelenalin (7) isolated from A. montana140 and sesquiterpenelactones, for example from N. lobata,141 and T. diversifolia (aspecies that has become a pantropical problem weed).142

Overall, aside from parthenolide, the risks seem to outweigh thebenefits. Due to its ability to target multiple cascades crucial forcancer stem cell survival, parthenolide (6) shows particularpotential as a prototype for novel anticancer agents138,143 and isan important constituent in a widely available traditional herbalmedical product used in cases of migraine: Tanacetumparthenium (L.) Sch. Bip. (Asteraceae).Despite the enormous biodiversity, only a relatively small

number of plants widely distributed in Mexico have beeninvestigated phytochemically for anti-inflammatory effects. Forexample, terpenoids (labdanolic acid) from the fruits ofHymenaea courbaril L. (Fabaceae) showed an inhibition ofcyclooxygenase and lipid peroxidation,144 but no data onpotential specific clinical benefits are available. Similarly,nitrogen-containing phorbol esters from Croton ciliatoglandu-

lifer Ortega (Euphorbiaceae) from Northern Mexico showedinhibitory effects on cyclooxygenases-1 and -2145 and anti-inflammatory effects in the ear edema model in mice.

■ CONCLUSIONSThis review highlights the great advances made over the lastseveral decades in the field of natural product research andethnopharmacology in Mexico and more specifically onMexican (higher) plants. Famously, the coat of arms of Mexicoshows a golden eagle sitting on a prickly pear cactus (Opuntiasp.) devouring a snake. For Mexican indigenous groups andmany Mexicans this symbolizes the founding of Tenochtitlan(now Mexico, D.F.), but for foreigners it depicts the victory ofgood over evil. Natural product research on Mexican plants hasdeveloped in a complex political context and has been seenboth as a threat and as a golden opportunity. In this review, aneffort has been made to highlight scientific achievements overseveral centuries and most importantly in the last decades.The content of this review has to be selective and is based

both on the main developments in the field and on a personaland thus somewhat subjective assessment. Considerableadvances have been made in phytochemical research as wellas in the pharmacological evaluation of the plants covered. TheCBD and subsequent conventions have not yet had the desiredeffect of providing scientific value to these local resources, andthe CBD’s equitable and sustainable implementation remains achallenge. On the other hand, basic and applied research hasreally highlighted the benefits and risk of Mexican local andtraditional medicines. This may well be the most importantoutcome of the efforts of the many researchers involved in thisthriving field. Whileas Corson and Crews highlighted“many natural products have become “poster children” for thepower and promise of turning traditional medicines intomodern drugs”,1 one can argue equally that the species studiedby natural product scientists and ethnopharmacologists are infact simply poster children for the power and promise of localand traditional medicines.

■ AUTHOR INFORMATIONCorresponding Author*E-mail: [email protected]. Tel: +44(0)207 753 5844. Fax:+44 (0)207 753 5560.NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSWe are grateful to all our collaborators: native informants,colleagues in Mexico and Guatemala, and colleagues andstudents who have contributed to this research on Mexicanlocal medicines and their phytochemical and pharmacologicalinvestigation.

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■ DEDICATION

Dedicated to Prof. Dr. Otto Sticher of ETH-Zurich, Zurich,Switzerland, for his pioneering work in pharmacognosy andphytochemistry.

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