Indicazioni tradizionali: come valutarle, e perché?

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Ha senso interrogarsi sui dati tradizionali relativi all’uso delle piante medicinali, ai dati storici ed etnobotanici? Al di là di un mero interesse antiquario o accademico, che significato ha il sapere antico e tradizionale? Quale peso dobbiamo dare alle fonti tradizionali per le nostre decisioni rispetto all’oggetto piante medicinali?

Credo che proprio chi lavora con le piante medicinali, studiandole o usandole, dovrebbe porsi queste domande e tentare di dare loro risposte serie, credibili, aumentando la qualità della riflessione teorica senza usare scorciatoie.  Il fatto che le fonti storiche ed etnobotaniche siano abbondati è contemporaneamente un punto di forza ed un punto critico, perché può sembrare che la loro mera esistenza possa bastare a giustificare l’uso delle piante medicinali, la loro sicurezza, la loro efficacia, ecc.  Non è lo scopo di questo post approfondire le molteplici ragioni per cui questo assunto metodologico sia insostenibile.  Prenderò invece come assunto proprio il fatto che, appurata l’esistenza e la consistenza delle fonti, rimane da approfondire il problema della loro valutazione, della loro significatività, della loro interpretazione.

E allora, approfittando del traino di Erba Volant, tenterei di approfondire il ruolo dei metodi quantitativi in etnobotanica ed etnofarmacologia, e di mostrare come essi possano permettere una valutazione razionale dei dati, e di usare questi dati per intervenire nel mondo, per incidere sul reale, un argomento sul quale avevo discusso tempo fa con Andrea Pieroni.

Facciamo però un passo indietro per meglio definire i termini della questione. L’etnofarmacologia è stata definita come un campo di  studio interdisciplinare che si divide tra scienze mediche, naturali e sociali, e che ha a che vedere con l’osservazione, l’identificazione, la descrizione e la sperimentazione degli ingredienti e degli effetti delle droghe indigene.  Lo scopo di queste osservazioni è ampio, ed è cambiato nel tempo, come nel tempo sono cambiati gli scopi dell’etnobotanica, ma possiamo certamente dire che due possibili obiettivi sono la generazione di predizioni su piante non studiate, e la corroborazione dei dati sull’attività di piante poco studiate.  Il filtro etnobotanico è stato certamente il primo strumento che abbiamo utilizzato per individuare rimedi interessanti: l’osservazione del comportamento dell’uomo, e in qualche caso degli animali, ha portato alla scoperta delle piante che hanno fatto la storia della farmacologia classica, le piante cosiddette eroiche (Strophantus, Datura, Atropa, Ephedra, Physostigma venenosum, Papaver somniferum, ecc.).

Ma le piante eroiche, facilmente identificabili a causa dei loro effetti drastici, costituiscono una percentuale molto ridotta delle piante medicinali, ed identificare piante ad azione meno evidente si è fatto sempre più difficile. Il migliorare della tecnologia sembrava per un certo tempo avere scalzato il metodo della bioprospezione etnobotanica: i metodi di screening high throughput permettevano di testare migliaia di estratti in poco tempo, e la chimica combinatoria permetteva di creare decine di strutture da un unico modello naturale, e la tecnica di raccolta delle piante a random diveniva in questo modo competitiva prché permetteva la raccolta di moltissimi campioni in poco tempo e senza dover coinvolge le popolazioni locali.  Questo non ha impedito che, sotto la spinta di molti etnofarmacologi, negli anni ’80 e ’90 del secolo scorso l’uso del dato etnobotanico sia ritornato in auge.  Questo nonostante che lo screening etnobotanico soffra di alcuni problemi legati ad una sua non economicità (necessita infatti di operatori professionali, di molto tempo e sostegno economico), e a volte alla poca applicabilità dei dati ottenuti localmente a problematiche di salute tipiche dei paesi sviluppati.

Il problema metodologico che si presentava ai ricercatori era però importante: l’etnofarmacologia moderna doveva contemporaneamente evitare di ridursi ad una serie di rassegne meramente elencatorie senza consistenza teorica, slegate le une dalle altre, ed evitare approcci ingenui. C’era cioè la sentita necessità di produrre lavori veramente transdiciplinari, di dotarsi di strumenti analitici migliori, di metodi quantitativi in grado di generare ipotesi falsificabili, riproducibili e trattabili con strumenti statistici; solo in questo modo la disciplina poteva essere in grado di intervenire nel mondo, magari proprio in quelle comunità locali che erano state fino a quel momento solo una fonte informativa.

Un articolo determinante da questo punto di vista è certamente stato quello di Browner, De Montellano e Rubel del 1988, nel quale gli autori proponevano una piattaforma metodologica che comparasse la prospettiva “emica” (cioè determinata dagli elementi interni di una cultura e dal loro funzionamento piuttosto che da schemi esterni) dell’etnomedicina e quella “etica” (di tipo generale, non strutturale, oggettiva) delle bioscienze, per generare nuove interpretazioni dei dati provenienti dalla ricerca transculturale in antropologia medica.

Gli autori identificano come un obiettivo dell’antropologia medica quello di contribuire alla “riduzione del carico mondiale di malattie, disabilità e sofferenze” , oltre ad una nuova comprensione del significato di salute e malattia. Puntualmente essi riconoscono anche che questa proposta potrebbe sembrare a molti ricercatori qualitativi di matrice eccessivamente riduzionistica, incapace di catturare i fenomeni nel loro contesto, ma ribadiscono la loro convinzione che invece sia possibile effettuare analisi etnograficamente valide, capaci di produrre dati che siano allo stesso tempo rilevanti e significativi per gli informatori, e suscettibili di comparazione e valutazione oggettiva.

Gli autori propongono uno schema di lavoro che consiste:

A) nell’identificare i fenomeni da analizzate in termini “emici” (mal di testa, indigestione, ecc.) e le piante usate per trattarli

B) nel determinare in quale misura i fenomeni descritti possano essere compresi nei termini dei metodi e dei concetti biomedici

C) nell’identificare aree di convergenza e divergenza tra i fenomeni descritti e le spiegazioni biomediche.

Una volta effettuati i vari passaggi, sarebbe teoricamente possibile assegnare ad ogni pianta un livello di evidenza, che gli autori così definiscono:

L1: rapporti di utilizzo parallelo in popolazioni tra le quali la diffusione è improbabile.
L2: evidenza L1 supportata da analisi fitochimica che verifichi la presenza di composti chimici che possono produrre un effetto terapeutico, o che risultano positivi in saggi biologici legati all’attività terapeutica.
L3: evidenza L2 supportata da una modalità di azione plausibile che produrrebbe un effetto terapeutico in un paziente.
L4: evidenza L3 supportata da studi clinici

L’approccio di Browning e collaboratori è stato fondamentale ed ha influenzato moltissimi ricercatori nel cosiddetto paradigma biocomportamentale. Uno dei problemi riscontrati è però che, a parte il primo livello di evidenza (L1), tutti gli altri si basano su dati di tipo fitochimico, farmacologico o clinico. Ma come analizzare le moltissime piante per le quali questi dati non fossero disponibili, o lo fossero in minima parte?

Negli anni vari autori si sono cimentati nel tentativo di espandere il programma di Browner e colleghi, partendo da alcuni assunti, che riassumo in questo modo: 1. le piante importanti come medicinali secondo il sapere tradizionale di un popolo non sono campionature random delle Flore totali, 2. le piante producono una ampia gamma di sostanze interessanti per la salute umana, 3. la sperimentazione e la scelta di certe piante da parte dei gruppi umani viene aiutata da caratteristiche organolettiche delle piante legate al contenuto fitochimico, 4. esiste una correlazione tra filogenesi e fitochimica, 5. popolazioni culturalmente e geograficamente distanti hanno meno probabilità di aver condiviso sapere etnobotanico.

Come vedremo, ognuno di questi punti, se esaminato nel dettaglio, presenta delle criticità.

Iniziamo ad esempio dall’assunto della distribuzione non random delle piante medicinali e del significato di questa distribuzione.  Come si quantifica la segregazione delle piante medicinali nei taxa di una Flora specifica, e come si compara tra Flore differenti?  Inoltre, secondo quali criteri vengono selezionate le piante medicinali da parte delle popolazioni umane? E infine, parlando di sapere tradizionale, come si identifica, e come lo si compara tra culture diverse?

Uno degli studi che hanno iniziato ad analizzare il problema della segregazione tassonomica delle piante è certamente quello di Moerman e collaboratori (1999), che hanno effettuato una analisi di 5 Flore distanti fra loro, domandandosi se vi fossero famiglie botaniche dove il numero di piante medicinali fosse superiore a quello che ci si poteva aspettare da una scelta casuale.  Nello studio gli autori hanno usato il metodo della regressione lineare per identificare i valori più probabili data una distribuzione casuale, ed hanno analizzato i valori che differivano dal valore aspettato (i residui). Ad un residuo positivo elevato corrispondeva una famiglia botanica con una maggior concentrazione di piante medicinali.  Raccolti i dati sui residui per le cinque flore, gli autori le hanno poi comparate a coppie usando l’indice di correlazione di Pearson ed hanno identificato tre famiglie sovrapponibili dominanti in quattro flore su cinque: Asteraceae, Apiaceae e Lamiaceae (da notare che le quattro flore congruenti appartengono tutte all’ecozona Olartica, e l’unica non congruente alla regione Neotropicale).

Sull’onda di questa prima pubblicazione, vari autori hanno applicato la regressione lineare all’analisi comparativa di varie Flore, nel tentativo di duplicare e completare il lavoro di Moerman.

Allo stesso tempo sono state avanzate delle critiche e proposti dei miglioramenti alle tecniche statistiche.  La regressione lineare ad esempio soffre di alcune debolezze: non è adatta a generare ipotesi confutabili, tende a favorire i taxa più numerosi, perché pone un limite massimo ai residui: una famiglia con 10 specie non potrà mai avere uno scarto >10, mentre una famiglia con 100 specie potrebbe avere uno scarto di 100.  Inoltre la regressione lineare presuppone che il rapporto tra  numero di specie medicinali e numero di specie totali (SM/ST) sia lineare, ma questo presupposto non è necessariamente giustificato.  Per finire, la suddivisione in taxa usata da Moerman e colleghi permette una comparazione discreta (la spp. x appartiene/non appartiene alla famiglia y) e non continua tra le specie, e in questo modo non riflette bene la prossimità filogenetica, oltre ad essere legata alla parziale convenzionalità della classificazione tassonomica, in modo che la stessa analisi darebbe risultati differenti a seconda di un approccio tassonomico da lumpers o da splitters.

Bennett e Husby nel 2008 hanno testato la resi di Moerman nella Flora equadoriana usando il metodo binomiale, metodo che a loro parere avrebbe permesso di generare dati utili per testare ipotesi, anche se considera comunque il rapporto SM/ST come lineare.  Più di recente Weckerle e colleghi nel 2011 hanno studiato la Flora medicinale campana comparando i metodi della regressione lineare e quello binomiale ad un approccio Bayesiano, che considera il rapporto SM/ST come una variabile random, e tutte i taxa sopraspecifici come pari, prescindendo dalle suddivisioni tassonomiche, evitando quindi il problema del favorire taxa più numerosi.

Altro problema, discusso da Bletter e in altri articoli, come quello ben descritto da Meristemi, è quello dell’origine dei dati tassonomici: solo un lavoro di analisi filogenetica specifico e quindi lungo e costoso, permetterebbe una comparazione basata su un rapporto continuo di vicinanza filogenetica.
Nonostante le grandi difficoltà, mi pare assodato che i dati in letteratura indicano che il clustering tassonomico esiste, e si può quantificare. Per quanto questo dato sia importante ed intrigante, ci rimane da porci una domanda ancora più rilevante per le possibili implicazioni pratiche: quali sono le ragioni per cui i gruppi umani tendono ad usare più di frequente certe specie piuttosto che altre?  La risposta non è scontata, se alcuni autori hanno risposto che i raggruppamenti rispondono solo a criteri di tipo simbolico, mentre altri propongono approcci più o meno radicalmente adattazionisti.

Secondo Moerman la segregazione in gruppi è dovuta per lo meno a due ordini di ragioni legati tra loro: il primo ha a che vedere con la   correlazione tra filogenesi e fitochimica, per cui gli esseri umani riconoscerebbero, grazie alle loro proprietà organolettiche, piante contenenti gruppi chimici specifici (in particolare composti amari, aromatici e piccanti), e quindi, grazie al fatto che i percorsi metabolici si conservano nelle linee evolutive vicine, tenderebbero a riconoscere specie appartenenti a taxa correlati.  Il secondo ordine ha a che vedere con la trasmissione del sapere etnobotanico. La proposta di Moerman è che le flore medicinali analizzate si assomigliano perché i gruppi umani, nelle loro trasmigrazioni nel corso della storia dal paleolitico in poi, hanno portato con se un sapere tradizionale che hanno trasmesso alle generazioni successive, tramandando di fatto l’utilizzo di certe specie o taxa piuttosto che altri. Leonti e colleghi hanno poi parlato di trasmissione non di un sapere definito e specifico ma della trasmissione di un set di criteri di scelta di vario tipo: organolettici, morfologici, ecologici, simbolici.

Questo set di criteri avrebbe permesso l’adattamento del sapere tradizionale all’esplorazione di nuove regioni biogeografiche dove le specie medicinali o addirittura le famiglie più usate in precedenza non fossero presenti o importanti.  Alla base del clustering tassonomico esisterebbe quindi il legame tra le capacità percettive dell’uomo, la fitochimica delle piante, il parallelismo tra filogenesi e fitochimica, oltre a vari fattori culturali e sistemi cognitivi. Le Asteraceae verrebbero scelte perché conterrebbero principi attivi amari facilmente riconoscibili al gusto.  Tutto questo non ci porta ancora alla conclusione che la selezione sia significativa dal punto di vista dell’attività biologica delle piante.  Non va poi dimenticato che altri autori ritengono questo paradigma troppo ambizino, e ritengono che le ragioni per le quali le piante vengono preferite potrebbero essere di altro ordine, ad esempio la loro disponibilità nelle vicinanze delle abitazioni. In questo senso le Asteraceae verrebbero scelte perché si adattano bene a condizioni di crescita in ambiente ruderale e sono quindi facilmente disponibili all’uso.

Nella prossima puntata vorrei concentrarmi sul problema della definizione e quantificabilità del concetto di sapere tradizionale.

Uomo e piante 8/dimoltialtri

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Dopo un lungo periodo piuttosto congestionato che mi ha impedito di buttare giù alcunchè per il blog, provo a rintrecciare le fila del discorso sul rapporto uomo e piante. L’ultima e lontana puntata la potete ritrovare qui,  e da questa puntata potete rintracciare le altre sei già disseminate.  Mi ero fermato ad un punto cruciale, avendo tentato di dare una visione d’insieme della teoria chemioecologica dell’origine dell’uso delle piante (debitore per questo interesse ai testi di Johns e della Etkin), e essendomi lasciato da affrontare il capitolo più specifico sulla medicina “botanica” vera e propria.  Riprendo da qui, in parte riassumento quanto già detto ed in parte tentando di capire se questi ragionamenti possano illuminare la storia della medicina antica, e come.

Introduzione

Il filo che lega i primi post di questa serie alla seconda, che lega cioè i fenomeni chemioecologici adattivi tra uomo e piante allo sviluppo della medicina, è certamente sottile.  Indubbiamente l’ipotesi coevolutiva, con tutti i suoi limiti, fornisce una chiave interpretativa fertile – una buona euristica – per iniziare a rispondere alla domanda dalla quale siamo partiti: “come si giustifica la predominanza delle piante nelle farmacopee umane?”.  Essa propone che i rapporti tra uomini e piante si sono inizialmente sviluppati seguendo percorsi biologici di adattamento, simili a quelli che caratterizzano i rapporti tra piante ed altri animali, o tra piante e piante.[1]

D’altro canto, se volessimo estendere questo ragionamento all’intreccio sempre più complesso di pratiche, saperi, mediazioni simboliche ed istituzioni che caratterizzano la medicina come pratica culturale elaborata,[2] ci troveremmo di fronte ad ostacoli evidenti.  L’ipotesi coevolutiva, infatti, può “spiegare” solo in maniera limitata il sapere dell’uomo sulle piante medicinali; ci suggerisce la presenza di un legame “intrinseco” o “biologico”, ma questo legame non riesce, da solo, a dar ragione delle molteplici attività ed indicazioni terapeutiche attribuite, nel corso della storia, ai rimedi vegetali; è anzi probabile che possa giustificare direttamente solo gli utilizzi delle piante per parassitosi ed infezioni intestinali, più strettamente legati alla teoria dei tre livelli trofici.[3]

E’ invece ipotizzabile che l’interiorizzazione dei rapporti con le tossine vegetali [4] abbia costituito, per i primi gruppi umani, solo una base  sulla quale aggregare successive ulteriori  acquisizioni culturali di sapere farmacologico, aprendo la strada verso un utilizzo vieppiù complesso della chimica vegetale
Seguendo questa linea di ragionamento, si può tracciare una ideale (ed idealizzata) successione di momenti evolutivi[5].

Breve storia dei nostri primi rapporti con le piante

Le prime sperimentazioni

I primi rapporti complessi tra esseri umani e piante potrebbero avere avuto luogo come semplice interazione senza mediazioni culturali e senza riflessioni consapevoli da parte degli individui.  Un esempio potrebbe essere l’associazione mnemonica che avviene quando al consumo di una pianta succede un cambiamento immediatamente percepibile nello stato dell’organismo. Questa sorta di apprendimento automatico potrebbe avere avuto luogo solo per piante con effetti molto marcati e subitanei, come nel caso di piante velenose e/o farmacologicamente molto attive. Queste sono in effetti le protagoniste della farmacologia classica, le piante anestetiche, analgesiche, psicoattive, stimolanti, e ancora le piante cardiotoniche e diuretiche; ma anche piante con evidenti ed immediati effetti sul tratto gastrointestinale, un apparato sul quale le sostanze ingerite hanno un effetto spesso immediato e precedente all’assorbimento nella circolazione sistemica, sia per la sua caratteristica di essere un diaframma con il mondo esterno, sia per I meccanismi fortemente reattivi ad esso associati, posti a difesa della salute dell’organismo)[6].

Nei piccoli gruppi egalitari di cacciatori e raccoglitori del paleolitico,[7] precedenti alla rivoluzione agricola, e di solito costituiti da individui ben nutriti e in salute, le minacce per la salute derivavano principalmente da infezioni a lunga latenza, malattie croniche infettive della pelle e problemi parassitari, ferite e traumi derivati da incidenti familiari, di caccia e di guerra, mentre è improbabile che le infezioni acute e virulente, le diarree infettive, le epidemie, ecc., giocassero un ruolo rilevante, viste le ridotte dimensioni dei gruppi.[8] Infanticidio ed abbandono degli anziani erano probabili metodi di controllo della salute e della stabilità del gruppo.

Secondo molti storici  é probabile che l’origine delle malattie fosse sempre immaginata come esterna al corpo e con effetti non limitati all’individuo malato ma riverberati su tutto il gruppo di appartenenza. Inoltre, vista la ridotta complessità formale di queste società e la poca o assente stratificazione e specializzazione di ruoli, le attività di cura erano quasi esclusivamente intraprese all’interno della famiglia o della medicina popolare collettiva, non gestite da esperti con conoscenze esoteriche, e le terapie erano solitamente empiriche e magiche (piante ed incantesimi) o comportamentali (digiuno, reclusione, riposo).

Rapporti causa-effetto

É stato proposto che in questo contesto sociale le osservazioni empiriche e le associazioni consapevoli di tipo causa-effetto avrebbero iniziato a sovrapposi e ad arricchire il sostrato sopra descritto di risposte automatiche e di comportamenti appresi attraverso l’uso non mediato delle piante.  Questo utilizzo più consapevole delle piante è ad esempio evidente nel modo più sofisticato con il quale gli esseri umani, rispetto ad altri animali, usano le piante antelmintiche ed amebicide: eseguono infatti l’esame delle feci prima e dopo l’utilizzo per riconoscere e verificare  l’attivitá delle piante.  Uno strumento cognitivo di questo tipo potrebbe spiegare, ci dice Johns, l’utilizzo delle piante per il trattamento delle malattie più semplici (pensate e trattate in maniera naturalistica) come fratture, slogature, e soprattutto ferite ed infezioni della pelle, nel qual caso l’utilizzo di piante astringenti e antisettiche é aperto ad una verifica fattuale semplice e diretta [magari usare degli esempi]. Altri casi nei quali questa spiegazione potrebbe funzionare comprendono i disturbi della funzione sessuale, o ancora febbre, raffreddore, tosse, diarrea, mal di testa, ecc.

Malattie molto più complesse ed episodi più drammatici, che ponevano a rischio la stabilità e coesione del gruppo, erano invece al di là delle possibilità di comprensione naturalistica, per la mancanza di concetti di fisiologia e patologia, di statistica, di microbiologia. Le risposte offerte erano spesso di tipo soprannaturale, magico-religioso. D’altro canto, seppure non in grado di comprendere I meccanismi eziopatologici, gli individui potevano riconoscere gli schemi secondo I quali si organizzavano I sintomi, le ricorrenze, e le risposte dei quadri sintomatologici ai rimedi, quindi una dimensione empirica era pur sempre possibile, e poteva guidare, almeno in linea di principio,le scelte terapeutiche.  Naturalmente poteva anche succedere che le attività di certe piante, empiricamente osservabili, venissero sfruttate all’interno di un quadro esplicativo di tipo naturalistico, ma non perché agissero sulle cause della malattia o sui sintomi, ma perché rispondevano alle aspettative degli individui. Johns porta l’esempio dell’uso da parte degli Zuni di un trattamento emetico per trattare le gastralgie in genere; l’opinione di Johns è che questo utilizzo derivi dall’esperienza comune raccolta nei secoli sui disturbi di stomaco causati da intossicazioni alimentari. In questi casi, ma solo in questi, l’uso dell’emetico ha senso perché elimina le sostanze tossiche e quindi il disagio di stomaco. In caso di gastralgie derivate da altri problemi il trattamento non ha senso, ma potrebbe avere un certo effetto psicosomatico per il fatto di rispondere alle aspettative.

É comunque un fatto che in queste società il guaritore agiva sia nel campo naturalistico sia nel campo spirituale, in maniera sacra ed olistica, trattando sia l’individuo sia il gruppo. In un setting soprannaturale avrebbe agito come sciamano,[9] chiaroveggente, incantatore, divinatore e/o prete; in un setting naturalistico come specialista empirico: esperto di piante, specialista in ossa e legamenti, ostetrica, specialista in denti.

Tentativi di spiegazione più complessi

Il salto di qualità vero e proprio, che necessita di un livello di spiegazione diverso, arriva però con la nascita dei primi agglomerati urbani della rivoluzione neolitica, e con la conseguente crescente complessità delle società.  Il neolitico portò agricoltura ed allevamento, maggior sedentarietà ed aumento del cibo disponibile, e un surplus che si rese disponibile per lo scambio commerciale.  In risposta a questi cambiamenti la società si stratificò e divenne più gerarchizzata, alcuni gruppi di individui concentrarono nelle proprie mani più potere, più ricchezza e maggior capacità decisionale. Alcuni di questi si specializzarono in medicina e religione, dando inizio ad un primo contrasto tra sapere medico popolare e pubblico e sapere medico colto, arcano ed esoterico. La stratificazione favori un maggior pluralismo di forme di cura ed un maggior scetticismo rispetto alle terapie.

Contemporaneamente la popolazione umana aumentò e gli sviluppi dovuti ad allevamento, urbanizzazione e commercio elevarono il carico di malattie e favorirono le epidemie. L’agricoltura migliora infatti la quantità di calorie disponibili ma spesso, riducendo il ventaglio di nutrienti disponibili, porta ad elevata suscettibilità agli agenti patogeni.  Lo sviluppo dell’irrigazione facilitò con tutta probabilità la trasmissione dei patogeni per via orofecale, con aumento della mortalità infantile, mentre la creazione delle grandi vie commerciali favorì il trasporto di agenti patogeni a grandi distanze.[10] L’urbanizzazione più spinta portò ad un carico parassitario ed infettivo e a nuove malattie da contaminazione come tifo, malaria, ecc., mentre malattie ancora più esiziali (le esantematiche, il vaiolo, il colera, la sifilide) sarebbero arrivate solo più tardi.

Questi cambiamenti nella struttura della società e nella prevalenza delle malattie ebbe sicuramente effetti anche per la medicina. E’ probabile che le nuove malattie scardinarono e screditarono vecchi modi di gestire la salute e  vecchi rimedi, aprendo la strada a nuove concettualizzazioni, più sofisticate ed elaborate. Il maggior carico di malattie (più prevalenti, più diverse e più pervasive) creò inoltre la necessità di possedere un lessico specifico maggiore [11],mentre nuove necessità legate a problemi di fertilità spinsero alla ricerca di nuovi rimedi prima non necessari, ad azione contraccettiva, parturiente, galattagoga, emmenangoga ed abortiva.[12] L’aumento del carico di lavoro spinse probabilmente alla ricerca/offerta di tonici (fisici, psicologici, sessuali, della sorte). L’aumento di traumi e ferite causati dal lavoro agricolo e di allevamento, oltre che dalle attività di commercio e dalla guerra fece crescere le conoscenze in campo di cura delle ferite e riduzione dei traumi articolari.

Se per certe malattie, semplici e lineari nel loro decorso, è facile immaginare che l’uomo sia riuscito a scoprire dei rimedi vegetali secondo le modalità sopradescritte, ci sono patologie per le quali è improbabile se non impossibile che questo sia accaduto. Patologie complesse, dal lungo decorso rendono difficile associare un rimedio ad una riduzione dei sintomi, oppure semplicemente non rispondono ad alcun rimedio semplice. Gli esempi più classici sono le malattie cronico-degenerative, le malattie metaboliche, le neoplasie, l’invecchiamento e le patologie ad esso legate.

La fondamentale inevitabilità dei processi di senescenza e la morbidità e mortalità che questi comportano, in società dove ancora I soggetti incapaci di contribuire attivamente allo sforzo comune di sopravvivenza erano a rischio di perdita di status e ruolo sociale, contribuirono all’emergere di forti istanze esistenziali che stimolarono nuove riflessioni sui significati da dare alla morte, alla vecchiaia, a sofferenza e dolore, e alla ricerca di rimedi per lenire tali sofferenze ed angosce.

In gruppi umani più numerosi, nelle prime civiltà urbane con evidenti stratificazioni e gerarchie sociali, queste istanze  si legarono e vennero comprese all’interno di un più ampio contesto culturale, religioso e magico, che articolava il rapporto tra individuo, salute e malattia, e le strategie messe in atto per modificare questo rapporto.

In definitiva le istanze esistenziali si inserirono, ed in parte contribuirono a formare, un nascente sistema teorico e simbolico medico, adatto a capire e ad agire nel mondo, ed anche a motivare la ricerca di soluzioni terapeutiche [13], soluzioni che rivelano quindi inevitabilmente un inestricabile commistione della dimensione empirica, simbolica, rituale e magica. Questa commissione si rivela nel significato profondo assegnato alla Dottrina delle Segnature, alle caratteristiche organolettiche, morfologiche ed ecologiche delle piante medicinali.

Esempi di relazione tra sapere empirico e simbolico sono ad esempio le terapie usate nella medicina tradizionale in risposta all’”intrusione” di sostanze pericolose, spiriti maligni o “inquinamento sociale”  Queste terapie sono spesso di tipo naturalistico, indirizzate al tratto gastrointestinale e consistenti in digiuno, uso di rimedi emetici e lassativi (“eliminativi”), o amari.  Anche le piante dal sapore o dall’odore particolarmente forti (salienti dal punto di vista percettivo), sono state ritenute utili perché in grado di eliminare gli spiriti maligni responsabili della malattia; ne è testimonianza la grande importanza che ha l’utilizzo dei sensi chimici per la scelta dei rimedi in molte delle tradizioni colte, come nella medicina tradizionale cinese, nella medicina galenica,[14] nella tradizione medica indiana (Ayurveda, Unani-Tibb) e tibetana, ecc.  Qualche autore ha suggerito che il ruolo centrale che il tratto gastrointestinale ricopre nella maggior parte dei sistemi medici tradizionali[15] dia supporto alla teoria che il trattamento di parassitosi, infezioni o altri problemi gastrointestinali siano un tratto fondamentale associato alla nascita della medicina, e che si sia inestricabilmente associato ad istanze simboliche, che avrebbero “rivestito” un nocciolo empirico preesistente.

Voler vedere in una ricetta di medicina popolare, che associa l’uso di una pianta ad un rituale, esclusivamente il lato razionale, considerando spurio o comunque non rilevante il momento rituale o, d’altro canto, considerare rilevante solo questo ultimo aspetto eliminando a priori la possibilità che la pianta abbia una qualche azione, sono errori dovuti alla forzata ricerca di universali che tralascia i dettagli, che dissocia empirico e simbolico a priori.

Uso  delle piante nelle società tradizionali contemporanee: un utile parallelo

Di come si sia sviluppato l’uso delle piante medicinali nelle prime civiltà umane ci sarà tempo di parlare nei prossimi capitoli. Piuttosto, dopo questa analisi teorica rimaniamo disarmati di fronte ad un problema cruciale: la mancanza di dati oggettivi (scritti o iconografici) che possano confermare l’ipotesi fin qui descritta sulla preistoria della medicina delle piante. Questo fatto ci costringe ad usare dei parallelismi con l’utilizzo delle piante nelle società tradizionali del recente passato e contemporanee, nella speranza (e nella convinzione) che le forme di organizzazione della vita, gli usi e costumi e le pratiche mediche siano abbastanza simili a quelle delle prime comunità umane da darci un indizio su come siano andate le cose allora.

I dati etnografici indicano che le popolazioni con stile di vita ancora in transizione tra caccia-raccolta ed agricoltura, o nei primi stadi dell’agricoltura incipiente, usano solo una porzione limitata delle risorse vegetali a loro disposizione come medicine[16]. Le piante utilizzate a scopo medicinale si dispongono secondo uno schema non casuale e abbastanza stabile, sia se osservato all’interno di una cultura[17], sia se comparato tra culture geograficamente molto distanti[18, 19].  Tale somiglianza si può spiegare (secondo gli autori [19]) ipotizzando una convergenza tra filogenesi e fitochimica, tale per cui gli esseri umani scelgono piante appartenenti a gruppi tassonomici vicini perché portatori di corredi fitochimici simili e quindi probabilmente attivi sullo stesso tipo di patologie, oltre a fattori culturali e di trasmissione del sapere. I gruppi umani originali, nelle loro migrazioni per la conquista di nuovi territori, avrebbero portato con sé il proprio bagaglio di sapere medicinale, e lo avrebbero trasmesso alle nuove generazioni nei nuovi territori. Questo sapere “migrante” non consisterebbe semplicemente in una collezione di dati empirici,  ma dovrebbe essere inteso come un set dinamico di criteri di selezione delle piante, che comprende categorie morfologiche, organolettiche, ecologiche, simboliche e culturali in senso più ampio[20].

Secondo questa ipotesi la sperimentazione, la scoperta e l’acquisizione di nuovo sapere sulle piante (ad esempio la scelta di una nuova pianta per trattare un disturbo) e la percezione dell’efficacia delle piante stesse, si sarebbe costruita nei gruppi umani attraverso processi di analogia con le piante già conosciute, analogie basate sulla salienza percettiva delle piante, cioè sul sapore e sull’odore, sulle caratteristiche morfologiche,  oltre che su forme più astratte, simboliche e sociali, di categorizzazione (come ad esempio l’umoralismo, o la dottrina delle segnature).

E’ indubbio che il sapore delle piante giochi un ruolo apparentemente molto importante nella loro selezione e nella scelta della categoria nella quale farle ricadere. In uno studio su alcune popolazioni messicane tutte le piante medicinali culturalmente importanti risultarono essere aromatiche, e tutte le piante fortemente medicinali o salutari erano anche amare [21];  di converso, in altri studi, le piante esplicitamente non medicinali sono più spesso senza odore o sapore rispetto alle piante medicinali[22]. Nelle parole di un ricercatore: “le piante medicinali che sono più importanti per la comunità hanno aromi e sapori che sono rilevanti nella determinazione del loro utilizzo[23, 24] . Secondo alcuni questa rilevanza del gusto rifletterebbe un dato biologico basilare del rapporto chemioecologico piante-uomo: i sensi chimici sarebbero il ponte che unisce il nostro passato di primati foliovori al nostro presente di utilizzatori di piante medicinali, nel senso che ci permetterebbe di selezionare piante particolarmente ricche in composti attivi; e il raggrupparsi delle piante medicinali in pochi taxa sarebbe un semplice riflesso dell’abbondanza dei composti amari (o piccanti, o aromatici) in queste famiglie[25].

I processi adattivi richiamati all’inizio del capitolo riuscirebbero, secondo questa ipotesi, a costituire il sapere medicinale attraverso processi cognitivi universali[26] di esplorazione e scoperta guidati dalla percezione di gruppi fitochimici specifici; il gusto sarebbe un criterio chiave di classificazione, e la classificazione popolare delle piante non sarebbe arbitraria, bensì determinata almeno in parte dalla realtà biologica.

Questo modello di indagine e scoperta viene però criticato da chi [27] obietta che presumere l’esistenza di ruoli universali delle percezioni organolettiche nella selezione delle piante medicinali è prematuro. Secondo questi autori è difficile immaginare che una indagine empirica sul campo (un soggetto alla ricerca di piante) parta direttamente dai sapori[28], mentre è più realistico immaginare che le persone inizino ad esplorare le piante guardandosi intorno, osservando per prime le caratteristiche morfologiche; famiglie come le Asteraceae o le Lamiaceae potrebbero essere state favorite non per il contenuto fitochimico, bensì per la presenza di fiori ed infiorescenze peculiari e cospicue. Casagrande,[29] in un suo lavoro sul campo, ha riscontrato inoltre che il sapore non era, da solo, un fattore predittivo sufficiente né dell’importanza medicinale (percepita, emica) di una pianta, né del tipo di utilizzo della pianta stessa, e che quindi il sapore non sembrava giocare un ruolo importante nella trasmissione del sapere. Questa posizione si accorda bene con il modello bioculturale delle percezioni di Shepard[30], secondo il quale  le sensazioni devono essere intese come fenomeni bioculturali radicati nella fisiologia umana, ma anche costruiti attraverso le esperienze personali e la cultura. Intese in questo modo le percezioni organolettiche possono cambiare nel tempo e passando da una cultura all’altra, e con esse il legame tra sapore e uso medicinale delle piante.   Sempre secondo Casagrande é possibile che la prevalenza delle piante amare tra quelle medicinali rifletta semplicemente una sovrabbondanza di composti amari in natura[31], e la bassa specificità dei recettori per l’amaro non permetterebbe loro di riconoscere specifiche caratteristiche delle molecole, chimiche o farmacologiche [32].

Secondo questa posizione I sapori avrebbero giocato più un ruolo mnemonico che chemioecologico, e la combinazione di attributi delle piante con esperienza della malattia potrebbe spiegare l’esistenza di gruppi prototipici di piante usati per trattare gruppi specifici di malattie[33].

Questo non significherebbe, secondo Casagrande, che le piante usate dalle popolazioni nel passato e nel presente non siano efficaci, bensì che gli schemi di distribuzione del sapere non rappresentano un corrispondenza ottimale tra i bisogni basati sulle malattie e tutti i composti fitochimici disponibili[34], una conclusione raggiunta anche da Johnson in uno studio sui nativi nordamericani[35].

La correlazione storica tra certe piante e certi disturbi (ad esempio tra piante con forte salienza organolettica e disturbi del tratto gastrointestinale, una correlazione presente in tutte le culture e periodi storici) sarebbe quindi conseguente ad una categorizzazione mnemonica post-hoc (simile alla Dottrina delle Segnature[36]) ed anche ad un legame biologico euristico (perché I composti organolettici potrebbero essere indicatori di attività biologica).

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Note
[1] Inoltre contribuisce a guardare alla storia da una prospettiva eccentrica, da una visuale aliena, che non metta sempre al centro della storia umana l’uomo, ma ne riconosca le determinanti ambientali e contingenti. Come dice Hobhouse, (Hobhouse, Henry (2005) Seeds of Change. Counterpoint, Berkeley, USA, p.xiv) le piante sono una fonte inaspettata di cambiamento nella storia, spesso oscurata perché gli uomini erano troppo concentrati a guardare ai propri simili per accorgersene.
[2] Secondo Kleinmann (Kleinman, Arthur (1993) “What is specific to Western medicine?” In W.F. Bynum e Roy Porter (eds.) Companion Encyclopedia of the History of Medicine, Vol. 1 Routledge, London, UK, p.15) la medicina (intesa in senso lato, antropologico) può essere descritta come una struttura coerente di credenze sulla salute e l’istituzionalizzazione di pratiche terapeutiche. Le caratteristiche comuni a tutte le tradizioni sarebbero: la presenza di categorie attraverso le quali diagnosticare le malattie; la disponibilità di strutture narrrative che sintetizzino in problemi dei singoli individui in sindromi culturalmente significative; la possibilità di utilizzare metafore, idiomi ed altre forme simboliche centrali che portano alla costruzione di interpretazioni eziologiche della patologia così da legittimare azioni terapeutiche pratiche; l’esistenza di ruoli e carriere da guaritori; l’utilizzo di strategie retoriche che il guaritore utilizza per portare pazienti e familiari a cimentarsi con le attività terapeutiche; la disponibilità di una enorme varietà di terapie che combinano operazioni simboliche e pratiche, con l’intento di controllare I sintomi o le cause.
[3] Vedi il secondo post della serie Uomo e piante
[4] Evidente nella fisiologia umana – Vedi il sesto post della serie Uomo e piante
[5] Che si basa sulla combinazione dei dati archeologici con dati etnobotanici ed antropologici (Last, Murray “Non-western concepts of disease”. In Bynum, W.F., e Porter, Roy (1993) Companion Encyclopedia of the History of Medicine. Vol. 1 Routledge, London, UK, p. 634 ff. e bibliografia; Rothschild, H. (ed.) (1981) Biocultural Aspects of Disease, New York, Academic Press.
Johns
[6] cfr. Johns T. The origins of human diet and medicine. University of Arizona Press, 1999
[7] In mancanza di dati archeologici, la fonte più importante di inferenze sul passato sono le condizioni di vita odierne delle ultime popolazioni di cacciatori raccoglitori
[8] Vedi il quarto post della serie Uomo e piante
[9] Il fenomeno mondiale dello sciamanesimo è un modello molto antico (presente fin dal paleolitico) e particolare della figura del guaritore popolare, uno specialista del soprannaturale, del mondo invisibile dei poteri e delle forze divine dalle cui azioni distruttive la società deve essere protetta.
[10] E’ probabile che al contempo si osservasse una riduzione della mortalità adulta a causa dello sviluppo dell’immunità nei grandi gruppi urbani
[11] Logan, Dixon, 1994 op. cit
[12] l’impossibilità o l’impraticabilità dei tipici sistemi di controllo della popolazione tipici dei gruppi di cacciatori-raccoglitori a causa del ritmo troppo elevato di riproduzione nelle società agricole, insieme alla aumentata morbilità femminile a causa dell’elevato numero di parti e dell’anticipo del menarca (Logan, Dixon, 1994 op. cit)
[13] Un problema che non intendo qui pormi esplicitamente è quello di chiarire il legame e la relativa dipendenza o indipendenza delle teorie mediche da altre strutture concettuali proprie della società che le esprime. Capire cioè se le idee sulla malattia debbano essere comprese come sottosistemi del complesso ideologico dominante o se abbiano una loro indipendenza;  Cfr. Bynum e Porter 1993 op. cit.
[14] Galeno, Claudio De simplicium medicamentorum temperamentis ac facultatibus, ed. Kuhn, 11:379-892; 12:1-377
[15] Nella medicina Egiziana antica, centrale nella teoria patologica era la malattia denominata whdw, costituita da una “essenza putrefattiva” che dall’intestino passava al flusso sanguigno per arrivare ai tessuti, . Nei testi di medicina tibetana si racconta che la prima malattia sia stata l’indigestione, che venne curata con un rimedio offerto ai primi uomini da Brahma: acqua calda per indurre il vomito. L’utilizzo di emetici, purganti, espettoranti e sudorifici si ritrova nella medicina tradizionale in Africa, America, ed Europa, ed anche in contesti contemporanei (come la naturopatia).
[16] Heinrich, M, Ankli, A, Frei, B, Weimnn, C, Sticher, O (1998) “Medicinal plants in Mexico: Healers’ consensus and cultural importance”.  Soc. sci. Med. 47 (11):1859-1871; Saslis-Lagoudakis C.H., Klitgaard B.B., Forest F., Francis L., Savolainen V., Williamson E.M., Hawkins J.A. (2011) “The use of phylogeny to interpret cross-cultural patterns in plant use and guide medicinal plant discovery: An example from Pterocarpus (Leguminosae).” PLoSONE, 6(7): e22275
[17] Moerman D.E., Pemberton R.W., Kiefer D., Berlin B. (1999) “A comparative analysis of five medicinal floras.” J Ethnobiol 19(1):49-67; Pardo-de-Santayana M., Tardío J., Blanco E., Carvalho A.M., Lastra J.J., San Miguel E., et al. (2007) “Traditional knowledge of wild edible plants used in the northwest of the Iberian Peninsula (Spain and Portugal): a comparative study.” J Ethnobiol Ethnomed, 3, 27; Molares S., and Ladio A. (2009) “Chemosensory perception and medicinal plants for digestive ailments in a Mapuche community in NW Patagonia, Argentina.” J. Ethnopharmacol, 123(3), 397-406
[18] Leonti M., Ramirez F.R., Sticher O., Heinrich M. (2003) “Medicinal Flora of the Popoluca, Mexico: A botanical systematical perspective.” Econ Bot 57(2):218-230; Moerman D.E., Pemberton R.W., Kiefer D., Berlin B. (1999) “A comparative analysis of five medicinal floras.” J Ethnobiol 19(1):49-67; Treyvaud Amiguet V., Thor Arnason J., Maquin P., Cal V., Sanchez-Vindas P.,  Poveda Alvarez L (2006) “A regression analysis of Q’eqchi’ Maya medicinal plants from Souther Belize.” Econ Bot 60(1):24-38
[19] Le tre famiglie mediamente più utilizzate risultavano essere Asteraceae, Lamiaceae ed Apiaceae (Moerman D.E., Pemberton R.W., Kiefer D., Berlin B. (1999) “A comparative analysis of five medicinal floras.” J Ethnobiol 19(1):49-67;  Leonti M., Ramirez F.R., Sticher O., Heinrich M. (2003) “Medicinal Flora of the Popoluca, Mexico: A botanical systematical perspective.” Econ Bot 57(2):218-230; Treyvaud Amiguet V., Thor Arnason J., Maquin P., Cal V., Sanchez-Vindas P.,  Poveda Alvarez L (2006) “A regression analysis of Q’eqchi’ Maya medicinal plants from Souther Belize.” Econ Bot 60(1):24-38
[20] Leonti M., Ramirez F.R., Sticher O., Heinrich M. (2003) Op. cit.; Treyvaud Amiguet V., Thor Arnason J., Maquin P., Cal V., Sanchez-Vindas P.,  Poveda Alvarez L (2006) Op. cit.

[21] Heinrich, M, Ankli, A, Frei, B, Weimnn, C, Sticher, O (1998) “Medicinal plants in Mexico: Healers’ consensus and cultural importance”.  Soc. sci. Med. 47 (11):1859-1871; Leonti M., Ramirez F.R., Sticher O., Heinrich M. (2003) Op. cit.
[22] Reyes-Garcia V. (2010) “The relevance of traditional knowledge systems for ethnopharmcological research: theoretical and methodological contributions.” Journal of Ethnobiology and Ethnomedicine 6:32
[23] “Medicinal plants which are most important to the community have odors and flavors which are relevant in the determination of their use”  (Molares S., & Ladio A. (2009) “Chemosensory perception and medicinal plants for digestive ailments in a Mapuche community in NW Patagonia, Argentina.” Journal of Ethnopharmacology, 123(3), 397-406)
[24] Molares S., and Ladio A. (2009) “Chemosensory perception and medicinal plants for digestive ailments in a Mapuche community in NW Patagonia, Argentina.” J. Ethnopharmacol, 123(3), 397-406
[25] Pieroni A., Houlihan L., Ansari N., Hussain B., Aslam S. (2007) “Medicinal perceptions of vegetables traditionally consumed by South-Asian migrants living in Bradford, Northen England” J. Ethnopharmacol, 113:100-110
[26] Reyes-Garcia V. (2010) “The relevance of traditional knowledge systems for ethnopharmcological research: theoretical and methodological contributions.” Journal of Ethnobiology and Ethnomedicine 6:32
[27] Casagrande D.G. (2000) “Human taste and cognition in Tzeltal Maya medicinal plant use.” J Ecol Anthr. 4:57-69
[28] Brett propone che le persone alla ricerca di una nuova pianta medicinale inizierebbero la loro indagine selezionando piante che hanno un sapore simile a piante delle quali si sa che inducono effetti fisiologici simili a quelli che si intendono derivare dalla nuova pianta (Brett JA (1994) “Medicinal plant selection criteria among the Tzeltal Maya of Highland Chiapas, Mexico”. Ph.D diss., University of California).
[29] Casagrande D.G. (2000) Op. cit.
[30] Shepard G.H. (2004) “A sensory ecology of medicinal plant therapy in two Amazonian societies.” Am Anthr; 106:2, 252-266
[31] Akli, A, Sticher, O, and Heinrich M (1999) “Yucatec Maya medicinal plants versus nonmedicinal plants: Indigenous characterization and selection.” Human Ecology 27:557-580.  E in mancanza di studi sistematici non è ancora possibile supporre una sovrabbondanza di piante amare nelle Farmacopee rispetto alle Flore generali.
[32] D’altro canto recenti scoperte relative ai rcettori per l’amaro e per il pungente nel tratto gastrointestinale in aree extraorali sembrerebbe poter dare un razionale all’utilizzo di piante amare e pungenti in caso di disordini dell’alto tratto gastrointestinale (cfr Valussi 2011). Nonostante sia indubbio che i recettori per l’amaro non sono abbastanza selettivi per discriminare tra i differenti gruppi chimici in grado di stimolare una attivazione recettoriale, è probabile che alcune delle modificazioni fisiologiche dello stato gastrointestinale (motilità e secrezioni) secondarie all’ingestione di questi composti siano mediate dall’interazione con i recettori stessi. Vale a dire che la risposta fisiologica è al composto amaro in quanto composto che elicita una sensazione amara, a prescindere dalle sue caratteristiche chimiche. Da questo punto di vista uindi forse un ruolo per i composti organolettici può essere preservato.
[33] Casagrande D.G. (2000) Op. cit.; Pieroni A., Nebel S., Quave C., Munz H., Heinrich M. (2002) “Ethnopharmacology of liakra: traditional weedy vegetables of the Arbereshe of the Vulture area in southern Italy” J. Ethnopharmacol, 81:165-185
[34] Casagrande D.G. (2000) Op. cit.
[35] Johnson L.M. (2006) “Gitksan medicinal plants-cultural choice and efficacy.” J Ethnobiol Ethnomed 2:29
[36] Recentemente alcuni ricercatori hanno criticato l’opinione accettata che vede nella dottrina delle segnature una superstizione primitiva, proponendo che essa sia principalmente uno strumento usato per trasferire informazioni, in particolare nelle società preletterarie. Le segnature sarebbero quindi non uno strumento euristico per scoprire nuove attività in piante sconosciute, bensì attribuzioni post hoc utili a memorizzare le proprietà delle piante e quindi a disseminare l’informazione, e sono quindi utili anche al ricercatore moderno che si interroghi sulla conoscenza tradizionale. Cfr. Bennett, B.C., et al. 2007 op. cit

Digestive Functional Foods 5

Pubblicato il da

Ed eccoci alla penultima installazione (qui, qui, qui e qui le altre), dove andremo a vedere in qualche dettaglio il funzionamento dei recettori per l’amaro e per il pungente nel tratto gastrointestinale.

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Coevolution and gut sensorium
Since the discovery of secretin, the first gut hormone, by Bayliss and Starling, the idea that the gastrointestinal tract had luminal chemo-sensitivity became a serious hypothesis, and since then it has become an integral part of the model of neurohumoral control of gastrointestinal function. It implies the idea that the gastrointestinal mucosa has a sensory role via tastant-sensing cells distributed in the gastric antrum or duodenal mucos. These cells can interact with luminal nutrients and release hormones in an endocrine or paracrine manner to transfer information about luminal nutrient content to other organs, including the brain, via endocrine or subepithelial neurons and vagal pathways.[1]

The gastrointestinal tract can thus be seen as a sense organ that has coevolved with some phytochemicals (nutrients, toxins, and stimulants such as bitter or pungent compounds), and which allows the detection of these phytochemicals and the appropriate response to them, like vomiting, aversion, regulation of appetite and satiety, alteration of stomach and intestinal motility and secretions. It also allows us to integrate this local information with higher level neurohumoral messages, and to command dietary, digestive, metabolic responses, and alarm responses in case of toxins.[2]

Much recent research has focused on identification of the cell types and specific receptors involved in this sensory mechanism. Particularly important are the enteroendocrine cells of the gastrointestinal tract.[3]

Enteroendocrine cells in oral cavity and gastrointestinal tract

They act as primary chemoreceptors by releasing signaling molecules in response to changes in the luminal environment, showing at least two levels of action:
• transduction of luminal factors by release of signaling molecules, with paracrine actions on neighboring enterocytes, pivotal for digestion and food intake control.
• integration of sub-epithelial neurons, in particular receptors at afferent terminals in vagal and spinal pathways, providing an important link in the afferent transfer of information from gut surface to nervous system.


Enteroendocrine cells comprise cells producing cholecystokinin (CCK) (in duodenum and jejunum), glucagon-like peptide 1 (GLP-1) or peptide YY (PYY) (in ileum and colon), and also histamine and serotonin-producing[4] enterochromaffin-like cells.[5] These last ones are the predominant enteroendocrine cells, and they play a very important role in the regulation of gastrointestinal secretions, motility and visceral pain, mainly via serotonin secretion (involved in peristalsis, gastric motility and postprandial pancreatic secretion).[6]

These data give experimental support to the hypothesis that odor and taste are important clues for recognizing and classifying medicinal plants cross-culturally[7]. This hypothesis has been formalized by Shepard[8] when he proposed “sensory ecology” as a new theoretical framework for a cross-cultural understanding of sensation. “…[S]ensory ecology would be equally interested in cross-cultural variation and similarities and should incorporate physiological understandings and cultural constructions of sensory perceptions within a broad biocultural model addressing human-environment interactions”.

Let’s now have a look at the most important receptor families: bitter and pungent.

Bitter receptors
In Homo and in mammals, the capacity to detect the presence of toxic substances is strongly associated with the development of bitter receptors (taste receptor type 2 — TAS2R) in the oral cavity, an evolutionary-conserved mechanism to prevent ingestion of bitter-tasting compounds which are very often dietary toxins (e.g. alkaloids, saponines, etc.). This explains the fact that bitter is one of the few innate sensations universally recognized as disgusting and inducing aversive reactions.[9]

Bitter taste receptors were thought to have only gustatory functions, and to be limited to the oral cavity, but in the last 10 years there have been various reports of the presence of the receptors in extraoral sites, with non-gustatory functions. In particular TAS2Rs are well expressed in the gastrointestinal (endocrine cells in the mucosa of the gastric antrum and fundus, duodenum and gastroendocrine cells),[10] where they could regulate metabolic and digestive functions,[11] and possibly prevent the absorption of toxic compounds swallowed despite the bitter-detecting mechanisms in the mouth.[12]

While some TAS2R appear to be high selective, these are not the only ones linked to bitter sensations; there is evidence of  less specific receptors that respond to relatively high concentrations of several unrelated bitter ligands, a mechanism which might explain how few receptors mediate the perception of numerous bitter compounds. This mechanis might have evolved to protect organisms from ingesting any of an enormous set of unrelated chemical  potentially toxic compounds.

Some of the chemical characteristics of compounds which act as agonists at bitter receptors[13] are the presence of⁠:
• phenyl-β-D-glucopyranosides (their affinity decreased approximately 200-fold when the phenyl group was replaced by a methyl moiety)
• glicoside formed by an aglycon attached to a gluco- or mannopyranose moiety in the β-glycosidic configuration.
• aglycons with one or two aromatic rings (stronger agonist properties than a methyl group)
• compounds containing an –N=C=S group.

Some of the secondary plant metabolites with agonist activity[14] are:
• aristolochic acid
• cyclohexamide
• naphthalaldehydic acid
• naphthoic acid
• nitrolnaphthalene
• papavarine
• picrotin
• picrotoxinin
• piperonylic acid
• quinacrine
• salicin
• strychnine
• α-thujone

Moving from the realm of molecules to that of plants, let us take as an example a very common weed, Dandelion (Taraxacum officinale). The sesquiterpene lactones of the eudesmanolide and germacranolide type unique to Taraxacum are intensely bitter; the elicited sensation of bitterness correlates well with the potentially poisonous nature of sesquiterpene lactones, often highly irritating for the nose and throat mucosa (hence the name sneezeweed given to many of the plants containing these substances) and cytotoxic. Although the lactones of the eudesmanolide type do not seem to posses toxic activity, they still elicit the bitterness response.

Effects of the stimulation of bitter receptors
The ingestion of relevant quantities of bitter substance will provoke a delay in gastric emptying in the subjects, followed by nausea and at times emesis.[15] Lower doses of bitters are still perceived as disgusting and this perception helps to fix the offensive food in the memory; the elicited chain of reactions is too weak to provoke emesis, but still strong enough to elicit a biliary stimulation.[16]

The activation of TAS2R in the gastrointestinal tract promotes the release of GI peptides via the protein gustducin – in particular CCK, and perhaps also PYY and GLP-1 – that can in turn activate neural reflexes.[17]
The stimulation of CCK secretion in turn triggers the release of digestive enzymes from the pancreas and the emptying of bile salts from the gallbladder into the duodenum, which then induce protein and fat digestion. CCK release also regulates gastrointestinal motility, and gastric acid secretion, induces reflex inhibition of gastric emptying (although it does not significantly impair antral motility),[18] and causes satiation by stimulating vagal afferent endings by activating CCK-1 or CCK-A receptors.[19]
Since CKK secretion is also influenced by a transcription factor (SRBEP) that is a key regulator of lipid metabolism, and since a diet rich in vegetables is usually both low in cholesterol and higher than normal in bitter substances, CKK activity seems aimed at reducing the absorption of the bitter compounds (reduced appetite, delayed gastric emptying) and of maximizing the absorption of complex carbohydrates and of low levels of essential fatty acids and fat-soluble vitamins (stimulation of gall-bladder contractions, increase in bile acid excretion).[20]
Stimulation of these receptors seems also to modulate glucose homeostasis, helping in the regulation of glucose and insulin levels.[21]

Pungent receptors
Pungency, like bitterness, is universally recognized as aversive, causing sensations of burning and pain.
A set of ion channels (Transient Receptor Potential channels — TRP channels) expressed in the gut responds to a varied class of pungent compounds. It includes the vanilloid channel TRPV1 which responds to capsaicine, piperine, allicin,[22] camphor and endocannabinoids,[23] the melastatin channel TRPM8 which responds to menthol and 1,8-cineole,[24] and the TRPA1 channel (highly expressed in human enterochromaffin cells) which responds to mustard oil, methyl salicylate, eugenol and cinnamaldheyde.[25]


After ingestion, these compounds act at esophageal level first, and then at gastric and duodenal level, stimulating gastric secretions with a general digestion-enhancing effect. Piperine increases pancreatic activity and reduces the intestinal transit time, while TRPA1 stimulation at duodenal level seems to mediate the release of CCK.[26]
Capsaicin activates TRPV1 receptors in the duodenum, which can also be activated and sensitized by acid. This activation stimulates gastrin secretion,[27] evokes dyspeptic symptoms (acutely, while if used chronically it reduces them) and affects gastric sensorimotor function.[28] At low dosages it stimulates the secretions of various gut peptides, in particular of calcitonin gene-related peptide (CGRP), which in turn stimulates microcirculation and protection of gastric mucosa from irritant compounds.[29]
The TRPA1 agonists cause 5-HT release in enterochromaffin cells and promote contraction of isolated strips of intestine via the 5-HT3 receptor. These results suggest that TRPA1 acts as a sensor molecule in enterochromaffin cells for the regulation of gastrointestinal functions. It stimulates vagal afferents and enteric nerves, which results in various gastrointestinal reactions, such as vomiting and peristaltic reflux.[30]
Allyl isothiocyanates, TRPA1 agonists, inhibit gastric ulcer formation in a similar but stronger fashion than the TRPV1 agonists (capsaicin and piperine) by modulating prostaglandin synthesis.[31]
Essential oils, and in general molecules capable of stimulating olfactory receptors, have been known for a long time to be able to produce physiological effects such as salivation, increasing appetite, etc. as part of the cephalic phase of motility and secretions of the gastrointestinal tract.[32]
It is therefore possible to envisage that a local stimulation of the tastant and olfactant receptors can act on afferent neurons (mainly of the vagus) with an effect on the CNS, on intrinsic efferent nerve fibers, with effect on the enteric nervous system, and on the rate of secretion of various peptides; which can then have effects on various systemic events, like mucosal proliferation, secretory processes, gastrointestinal motility, glucose homeostasis, etc.[33] This consequently affects functional disturbances of the gastrointestinal tract, like early satiety, sensation of fullness and meteorism, epigastric pain, abdominal cramps, nausea, motility disorders.

——————————————————————————————————————
[1] Kitamura, A., Torii, K., Uneyama, H., and Nijima, A. (2010) “Taste and health: Nutritional and physiological significance of taste substances in daily foods: Role played by afferent signals from olfactory, gustatory and gastrointestinal sensors in regulation of autonomic nerve activity”. Biol. Pharm. Bull, 33(11) 1778–1782; Dockray GJ. (2003) “Luminal sensing in the gut: an overview”. J Physiol Pharmacol.;54(Suppl 4):9–17; Rozengurt N, Wu S, Chen MC, et al. (2006) “Co-localization of the a-subunit of gustducin with PYY and GLP-1 in L cells of human colon”. Am J Physiol Gastrointest Liver Physiol.; 291:G792–G802
[2] Dockray 2003 Op. Cit.; Rozengurt. E. (2006) “Taste receptors in the gastrointestinal tract. I. Bitter taste receptors and alpha-gustducin in the mammalian gut”. Am J Physiol Gastrointest Liver Physiol; 291(2):G171-7
[3] Wu, S. V., Rozengurt, N., Moon Yang, Young, S.H., Sinnett-Smith, J., and Rozengurt, E. (2002) “Expression of bitter taste receptors of the T2R family in the gastrointestinal tract and enteroendocrine STC-1 cells”. PNAS, 99 (4):2392–2397
[4] Dockray 2003 Op. Cit.; Flemstrom, G. and Sjoblom, M. (2005) “Epithelial cells and their neighbors. II. New perspectives on efferent signaling between brain, neuroendocrine cells, and gut epithelial cells”. Am J Physiol Gastrointest Liver Physiol, 289: G377–G380
[5] Sternini, C. (2007) “Taste receptors in the gastrointestinal tract. IV. Functional implications of bitter taste receptors in gastrointestinal chemosensing”. Am J Physiol Gastrointest Liver Physiol, 292: G457–G461
[6] Nozawa, K., Kawabata-Shoda, E., Doihara, H., Kojima, R., Okada, H., Mochizuki, S., Sano, Y., Inamura, K., Matsushime, H., Koizumi, T., Yokoyama, T., and Ito, H. (2009) “TRPA1 regulates gastrointestinal motility through serotonin release from enterochromaffin cells” PNAS, 106(9):3408-3413
[7] Gollin L (2004) “Subtle and profound sensory attributes of medicinal plants among the Kenya Leppo`Ke of east Kalimatan, Borneo”. Journal of Ethnobiology, 24(2):173-201; Leonti M, Sticher O, Heinrich M (2002) “Medicinal plants of the Popoluca, México: organoleptic properties as indigenous selection criteria”. Journal of Ethnopharmacology, 81, 307-315; Pieroni A, Torry B (2007) “Does the taste matter?: taste and medicinal perceptions associated with five selected herbal drugs among three ethnic groups in West Yorkshire, Northern England”. Journal of Ethnobiology and Ethnomedicine, 3:21.
[8] Shepard GH (2004) “A sensory ecology of medicinal plant therapy in two Amazonian societies”. American Anthropologist, 106:2, 252-266.
[9] Scott K. (2005) “Taste recognition: food for thought”. Neuron, 48: 455– 464; Meyerhof, W., Behrens, M., Brockhoff, A., Bufe, B., & Kuhn, C. (2005) “Human bitter taste perception”. Chem senses; 30 Suppl 1(suppl 1), i14-5.
[10] Wu et al. 2002 Op. Cit.
[11] Behrens M, Meyerhof W (2010) “Oral and extraoral bitter taste receptors”. Results Probl Cell Differ.; 52:87-99
[12] Kidd, M., Modlin, I.M., Gustafsson, B.I., Drozdov, I., Hauso, O., and Pfragner, R. (2008) “Luminal regulation of normal and neoplastic human EC cell serotonin release is mediated by bile salts, amines, tastants, and olfactants”. Am J Physiol Gastrointest Liver Physiol, 295: 260 –272
[13] Meyerhof, Behrens, Brockhoff, Bufe, & Kuhn, 2005 Op. Cit.
[14] Meyerhof, Behrens, Brockhoff, Bufe, & Kuhn, 2005 Op. Cit.
[15] Wicks D, Wright J, Rayment P, Spiller R. (2005) “Anticipatory physiological regulation in feeding biology: Cephalic phase responses” Eur J Gastroenterol Hepatol., 17(9):961-5
[16] Powers MA, Schiffman SS, Lawson DC, Pappas TN, Taylor IL. (1990) “The effect of taste on gastric and pancreatic responses in dogs.” Physiol Behav; 47(6):1295-7.
[17] Rozengurt 2006 Op. Cit.
[18] Wicks D, Wright J, Rayment P, Spiller R. (2005) “Impact of bitter taste on gastric motility”. Eur J Gastroenterol Hepatol;17(9):961-5
[19] Sternini 2007, Op. Cit.
[20] Jeon, T.-I., Zhu, B., Larson, J.L., and Osborne, T.F. (2008) “SREBP-2 regulates gut peptide secretion through intestinal bitter taste receptor signaling in mice”. The Journal of Clinical Investigation; 118(11):3693-3700
[21] Dotson CD, Zhang L, Xu H, Shin Y-K, Vigues S, et al. (2008) “Bitter Taste Receptors Influence Glucose Homeostasis”. PLoS ONE, 3(12): e3974
[22] Salazar H, Llorente I, Jara-Oseguera A, García-Villegas R, Munari M, Gordon SE, Islas LD, Rosenbaum T. (2008) “A single N-terminal cysteine in TRPV1 determines activation by pungent compounds from onion and garlic”. Nat Neurosci;11(3):255-61
[23] Venkatachalam K, Montell C (2007) “TRP channels”. Annu. Rev. Biochem. 76: 387–417
[24] Behrendt HJ, Germann T, Gillen C, Hatt H, Jostock R. (2004) “Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay”. Br. J. Pharmacol. 141 (4): 737–45
[25] Nilius B, Owsianik G, Voets T, Peters JA (2007) “Transient receptor potential cation channels in disease”. Physiol. Rev; 87 (1): 165–217
[26] Purhonen AK, Louhivuori LM, Kiehne K, Kerman KE, Herzig KH. (2008) “TRPA1 channel activation induces cholecystokinin release via extracellularcalcium”. FEBS Lett; 23;582(2):229-32
[27] Kidd M, Hauso Ø, Drozdov I, Gustafsson BI, Modlin IM. (2009) “Delineation of the chemomechanosensory regulation of gastrin secretion using pure rodent G cells”. Gastroenterology;137(1):231-41
[28] van Boxel OS, ter Linde JJ, Siersema PD, Smout AJ (2010) “Role of chemical stimulation of the duodenum in dyspeptic symptom generation”. Am J Gastroenterol;105(4):803-11.
[29] Abdel-Salam OM, Szolcsányi J, Mózsik G. (1997) “Capsaicin and the stomach. A review of experimental and clinical data”. J Physiol Paris; 91(3-5):151-71
[30] Nozawa, et al. 2009 Op. Cit.
[31] Matsuda H, Ochi M, Nagatomo A, Yoshikawa M. (2007) “Effects of allyl isothiocyanate from horseradish on several experimental gastric lesions in rats”. Eur J Pharmacol. 30;561(1-3):172-81
[32] Kitamura 2010 Op. Cit.
[33] Sternini, C. (2007) “Taste Receptors in the Gastrointestinal Tract. IV. Functional implications of bitter taste receptors in gastrointestinal chemosensing”.  Am J Physiol Gastrointest Liver Physiol 292: G457–G461

“A proposito… non avresti un rimedio per le colichette?”

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Una review sistematica di Perry e collaboratori sulle coliche infantili (qui l’articolo scaricabile) mi offre il destro per trattare un argomento sfuggente ma sempre presente quando si lavora con mamme e bambini: le colichette

I risultati della review sulle terapie alternative per le coliche sono abbastanza chiare: i dati non sono sufficienti a dare indicazioni certe, anche se l’estratto di finocchio e la preparazione Colimil (contenente finocchio, camomilla e melissa) possono vantare risultati clinici positivi.

Vale però la pena sottolineare che l’ambiguità dell’entità Coliche Infantili rende più difficile progettare una review sistematica o una metanalisi veramente significativa. E’ probabile infatti che a questa etichetta fenomenologica corrispondano una molteplicità di eziologie, quella gastrointestinale rappresentando solo una tra le tante. Una review sistematica dei rimedi erboristici (da sempre mirati a problemi di spasmi intestinali) dovrebbe poter analizzare solo il sottoset di disturbi di chiara origine gastrointestinali, per poter valutare chiaramente l’efficacia dei rimedi.

Ma vediamo più nel dettaglio cosa si intenda per coliche (qui un resoconto di una conferenza del 2000, datata ma ancora utile per inquadrare il problema).

Nonostante siano apparentemente una delle tante evenienze dei disturbi spastici intestinali, le “coliche” dell’infante (piuttosto comuni: 17-25% dei neonati secondo alcuni autori, 10-30% secondo altri) sfuggono ad una definizione precisa, e da qualche anno non sono più considerate necessariamente associate a disturbi gastrointestinali, ma definite come “parossismi di pianto e irritabilità inspiegabili che durano per più di 3 ore al giorno, per più di 3 giorni alla settimana, che continua da più di 3 settimane”.

Sappiamo da alcuni dati che le crisi tendono a ridursi e cessare intorno ai 4 mesi di età, ma il 30% dei bimbi piange fino ai 3 anni, ed il 10% fino ai 4-5 anni (qui una review).
Secondo una ricerca britannica a due settimane di vita ne soffrono il 43% degli infanti che allattano al biberon ed il 16% di quelli che allattano al seno. A 6-7 settimane la percentuale dei bambini allattati al biberon scende al 12% e quella degli allattanti al seno sale al 31%.

Alcuni autori hanno proposto che esse siano una normale distribuzione del pianto nell’infante, altri invece vedono nelle coliche una condizione patologica (qui, qui, e qui) ed identificano alcune cause probabili (in grassetto), ed altre meno corroborate:
1. Iperperistalsi/dismotilità gastrointestinale
2. Allergie alle proteine del latte vaccino
3. Intolleranza al lattosio
4. Disturbo della relazione infante-genitore
5. Anormale risposta neurofisiologica a normali input esogeni ed endogeni
6. Alterazioni ormonali
7. Fumo durante la gravidanza
8. Alterazioni nella microflora intestinale del neonato

E’ possibile che tra questi fattori si instaurino dei circoli viziosi, ad esempio le coliche possono far nascere il dubbio alla madre di non essere capace di allattare, questo la può mettere in crisi e mettere in crisi la sua relazione con l’infante, con peggioramento della situazione. Oppure il pianto causa una eccessiva ingestione di aria che causa gonfiore e dolore, e via dicendo.

Una proposta di eziopatogenesi che tenta di unire alcune delle cause proposte vorrebbe che certi neonati siano predisposti all’intolleranza verso le proteine del latte e ad una dismotilità intestinale con ipersensibilità/iperalgesia nelle prime settimane di vita. Questi processi porterebbero a stress ed alterazione delle percezioni, con una interpretazione anormale (dolore) di normali input (gonfiore addominale).

La realtà è che non si sà individuare una causa unica (dato questo che viene mimetizzato dal pomposo termine “disturbo idiopatico”), che probabilmente siamo di fronte ad un disturbo multifattoriale, o forse a diversi disturbi raggruppati in maniera artificiale. .

L’approccio migliore, secondo Lucassen e collaboratori è ricordare che: non si conosce la causa ma la condizione è benigna e non è associata a condizioni più gravi; che passerà dopo i tre mesi o poco dopo, e se non passa certamente scemerà; che non è legata ad errori nell’allattamento, e non ha senso passare dalla formula normale al latte di soia; e che in definitiva nessuno degli approcci farmacologici sembra utile più della semplice rassicurazione

Dieta
Nella review di Lucassen e collaboratori si propone di non parlare più di coliche dell’infante bensì di distinguere (secondo il modello di Carey) tra 1. pianto normale, 2. pianto eccessivo secondario (nell’ipotesi degli autori, secondario ad allergia a latte vaccino) e 3. pianto eccessivo primario (ovvero idiopatico, ovvero di cui non si conosce la causa).

Da questa review sistematica (criticata però in molto dei suoi punti, sia nel progetto che nella metodologia statistica utilizzata, vedi qui tre lettere al BMJ in risposta all’articolo pubblicato), si evidenzia che l’eliminazione delle proteine del latte vaccino è stata utile se al loro posto è stata usata una formula ipoallergenica, mentre la sostituzione con latte di soia e con formule a basso contenuto in lattosio sono dubbie; che il trattamento farmacologico con Diciclomina è stata efficace ma ha causato effetti collaterali severi, mentre quello con simeticone non ha mostrato di essere di beneficio.

Il suggerimento degli autori di tentare con una settimana di formula ipoallergenica non deve essere letto come universale: il latte ipoallergenico deve essere usato per i bimbi solo se sono allattati con il biberon, mentre in caso di allattamento al seno si avviserà la madre di non usare latticini. Inoltre la sostituzione non è vista come trattamento delle coliche infantili ma come diagnostica per discriminare tra pianto eccessivo primario e pianto eccessivo secondario all’allergia da latte vaccino.

In conclusione, è sensato modificare la dieta della madre in allattamento solo se fosse particolarmente ricca in cibi che causano flatulenza, come latticini, broccoli, cavoli e le altre brassicaceae, succo d’arancia; oppure se fosse ricca in caffeina.

E le piante?
Secondo la tradizione le piante possono dare una mano in alcuni casi di coliche, specialmente quando sia evidente un gonfiore addominale, o l’infante soffra di flatulenza. In questi casi le piante carminative sono l’approccio di elezione, in forma di infuso. Dato che molto spesso le piante carminative sono anche piante miorilassanti e rilassanti in genere, e dato che questi effetti sono tutti desiderabili, la classe delle piante aromatiche e ricche di olii essenziali è la più importante.
Ne menziono alcune delle più utilizzate con i bambini: Matricaria recutita, Melissa officinalis, Nepeta cataria, Lavandula vera. Più carminative le piante Mentha xpiperita, Foeniculum vulgare e Anethum graveolens. Se l’effetto tranquillizzante fosse particolarmente importante è possibile aggiungere Tilia spp.
Una combinazione in forma di infuso solubile contenente Matricaria recutita, Verbena officinalis, Glycyrrhiza glabra, Foeniculum vulgare e Melissa officinalis è stata testata in uno studio clinico prospettico in doppio cieco con placebo su bambini di tre settimane con coliche infantili; il dosaggio arrivava ad un massimo di 150 mL per dose, usata ad ogni episodio di colica, ma non più di tre volte al giorno. Dopo sette giorni di trattamento il punteggio sulla scala di miglioramento era migliore nel gruppo verum, e una maggior percentuale (57%) di bambini ha terminato lo studio senza coliche rispetto al placebo (26%).
Come detto all’inizio di questo post, la review sistematica di Perry, Hunt e Ernst (2010), che ha analizzato 15 studi clinici di qualità per un totale di 994 bambini, ha concluso che l’estratto di finocchio ed una formula contenente finocchio, melissa e camomilla mostrano efficacia in studi clinici controllati con placebo, di buona (ma non ottima) qualità.

Altre pratiche utili
Sempre in caso di chiara presenza di gas intestinali il massaggio sull’addome in senso orario con olio tiepido/caldo sembra utile, anche se non è chiaro se l’utilità derivi dall’azione specifica sul tratto gastrointestinale oppure su una azione tranquillizzante generale.

Tidbits: cannabis

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Nonostante parlare dell’utilizzo della Cannabis e dei suoi derivati come strumento per il trattamento del dolore cronico non sia più una eresia, rimane ancora difficile farlo con chiarezza e serietà e senza pregiudizi o stimmate apposte all’argomento. E’ quindi una buona notizia la pubblicazione di una review sul trattamento del dolore cronico, eseguita presso l’Università di Toronto.

La review ha considerato 18 studi clinici, diversi tipi di assunzione (cannabis fumata, estratti somministrati per via transdermica orale, analoghi del THC) e diversi tipi di dolore non legato a neoplasie (dolore neuropatico, fibromialgia, artrite reumatoide, dolore cronico di origine mista).

I risultati sono stati molto interessanti: la qualità degli studi esaminati è risultata in media eccellente (una rarità nel campo della ricerca su derivati vegetali), e 15 studi su 18 (l’83%) hanno mostrato risultati positivi per l’effetto analgesico. Un numero minore di studi ha mostrato effetti positivi sulla qualità del sonno, e comunque nessuno degli studi ha mostrato effetti collaterali particolarmente preoccupanti. I risultati migliori si sono visti con il dolore neuropatico, mentre gli effetti sono meno eclatanti per la fibromialgia e l’artrite reumatoide. Nonostante gli autori sottolineino che gli effetti, nei casi migliori, sono comunque risultati modesti, vale la pena ricordare che l’importanza di questi effetti va considerata nel contesto delle altre opzioni disponibili. Quando, come nel caso delle neuropatie, le altre opzioni (oppiacei, anestetici locali, antidepressivi) sono spesso non o poco utilizzabili o efficaci, anche una efficacia modesta è un’ottima notizia.

Rimane il fatto però che molti di coloro che utilizzano la Cannabis sativa come strumento terapeutico lo fanno non utilizzando farmaci a penetrazione transdermica orale (Sativex e simili) o i sistemi di evaporazione a basse temperature, bensì attraverso la combustione della pianta e resina secche. Di contro sono molti scarsi gli studi sugli effetti e l’efficacia della Cannabis assunta con l’inalazione del fumo.

Per questo è  interessante lo studio clinico randomizzato (e qui) sull’effetto analgesico della cannabis in casi di neuropatia cronica  eseguito da un gruppo di ricerca del McGill University Health Centre (MUHC) e della  McGill University.

I ricercatori hanno testato fumo di cannabis a tre livelli di THC: 2.5%, 6%e  9.4%. più un placebo allo 0%. I risultati sono stati anche in questo caso chiari: la dose di 25 mg al 9,4% di THC per tre volte al giorno per cinque giorni consecutivi ha portato ad una riduzione significativa dell’intensità media del dolore, la qualità del sonno è migliorata in maniera dose dipendente, l’ansia e la depressione si sono ridotte alla dose di THC pari al 9.4%

Oltre all’utilizzo della Cannabis e dei suoi derivati, i ricercatori da tempo cercano di utilizzare i cannabinoidi endogeni (endocannabinoidi), scoperti per l’appunto grazie alla ricerca sulla Cannabis, come farmaci. Il razionale è questo: lavorando sugli enzimi che degradano gli endocannabinoidi si cerca di aumentare la loro emivita aumentando quindi la loro azione ansiolitica e analgesica. Questa strategia ha funzionato per uno dei due endocannabinoidi principali, l’anandamide. Quando il suo enzima degradante, l’idrolasi delle ammidi degli acidi grassi (fatty acid amide hydrolase – FAAH) viene inibito i livelli di anandamide si elevano riducendo dolore ed infioammazione, e senza segnali di abituazione.

Diverso invece il discorso per quanto riguarda un altro endocannabinoide, il 2-arachidonilglicerolo (2AG), che sembrerebbe più promettente dell’anandamide, dato che la sua concentrazione cerebrale è naturalmente più elevata.  Infatti l’utilizzo di un bloccante selettivo dell’enzima che degrada il 2AG (la monoacilglicerolo lipasi – MAGL) porta ad un aumento dell’effetto analgesico di un fattore otto, effetto che però si riduce dopo sei giorni, e poirta a vari segnali di abituazione anche ad altre sostanze (THC e composti di sintesi con attività di legame ai recettori cannabinoidi CB1). Questi risultati implicano che a differenza dell’anandamide, il 2AG porta ad abituazione (e forse a dipendenza), probabilmente attraverso un meccanismo di downregolazione dei recettori CB1 in alcune aree del cervello.

Digestive Functional Foods 4

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Dopo il post monografico, torniamo ad analizzare il dato etnobotanico. Nel seguente spezzone tento di riassumere parte dei dati etnobotanici più recenti relativi all’utilizzo dei cibi funzionali tradizionali latu sensu nei disturbi gastroenterici, cercando, quando possibile, di limitarmi a disturbi non specifici (indigestione, gonfiore, dispepsia, ecc.), e cercando di trarre qualche indicazione di massima sulla eventuale segregazione rtassonomica dei rimedi. Come vedrete le conclusioni sono chiare (ma con vari caveat): esistono poche famiglie nelle quali si concentrano molti dei rimedi, e questi rimedi sono caratterizzati molto spesso dalla presenza di principi amari, pungenti e/o aromatici.  Buona lettura!

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Digestive Functional Foods in the ethnobotanical literature

The author compiled a non-systematic survey of FF plants used world-wide for digestive complaints, limiting, when possible, the analysis to plants used only for non specific gastrointestinal complaints, to remain coherent with the spirit of the FF definition. The plants listed were mainly used as digestives, appetite stimulants, antidyspepsics, carminatives, and antispasmodics. Plants with very specific activities (antiulcer) or with specific indications (IBS, etc.) were excluded, when possible.[1]

In a paper on edible plants of Palestine,[2] of the 103 edible plants, 64 (62 %) were used as food-medicines, and the two most important botanical families for food-medicines were Asteraceae and Lamiaceae.  This is in agreement with the findings of a similar study on food plant consumption in seven Mediterranean countries.[3]
Of the 78 alimentary species collected in Cyprus, 20 (25,6%) belonged to the Asteraceae, 7 each to Apiaceae and Brassicaceae, and 6 to the Lamiaceae. 40 were used only as food, and 37 (47,4%) as both food and medicine.[4]

In a study on Sicilian wild food plants, of the 188 food species recorded, 37 (19,6%) were used as both food and medicine, and of these 12 (32,4%) belonged to Asteraceae,  4 (11%) to Lamiaceae,  3 each to Brassicaceae and Apiaceae.[5]

In a review of plant foods as medicines in Mediterranean Spain, the authors found that  the percentage of edible plants used as medicines varied between 13,39 and 21,42 (17,52% on average), and that of spices and culinary herbs used as medicines varied between 5,74 and 9,25 (7% on average). All in all an average of around 24,5% of edible plants and spices were used as medicines.[6] Lamiaceae  and Asteraceae played major roles both in terms of recorded medicinal uses (146 the former and 57 the latter, of all 559 recorded uses) and of number of species used in medicinal treatments (42 the former and 29 the latter).

According to Rivera and coworkers, of the 145 wild gathered food species from Southern Spain, 81 (55,9%) are also used medicinally, and, more importantly, 61 (42%) are administered orally using the same plant part used in the culinary preparations.  This proportion was halved when examining   cultivated food species.[7]

In an ethnobotanical research in Kenya, the authors found that wild edible-medicinal plants represent  30,2% of all edible plants.⁠

The main datum that emerges from this exercise is the predominance of some taxa.

At a higher level the Family Asteraceae dominates with 41 citations of 25 different Genera, amongst which Matricaria, Sonchus and Artemisia are the most often cited.  The second Family by number of citations is that of Lamiaceae, with 24 citations of 16 different Genera, vastly dominated by Mentha and Ocimum.

Also important are the Apiaceae family with 12 citations of 12 Genera, Zingiberaceae (9 citations of 8 Genera) and Rutaceae (9 citations of 3 Genera, dominated by Citrus spp.).

As an aside, similar data emerge when we examine functional foods in general: a significant percentage, between 20 and 60% (average 40%) of edible wild plants is used in traditional societies as a medicine; and secondly, the family  Asteraceae seem to be the main source of medicinal plant species used by traditional societies (at least in the northern hemisphere) and one of the main sources of functional foods/medicinal foods/food medicines.[8]  Lamiaceae and Apiaceae are also very important in terms of number of species used.[9]
These taxa share a similar chemical make-up: they contain very salient organoleptic compounds, such as essential oils, resins and pungent compounds, and bitter compounds, mainly in the Asteraceae and Cucurbitaceae, usually showing low toxicity.

Similar results can be seen in wider reviews including medicinal plants stricto sensu:  still dominant is the triad of Asteraceae, Lamiaceae and Apiaceae, but with a high frequency of  Euphorbiaceae (8 citations of 4 Genera), Fabaceae (15 citations of 12 Genera) and Solanaceae: all families with a potentially more toxic chemical profile, containing irritant latex, toxic lectins and cyanide-producing molecules, often characterized by a strong bitter taste. ⁠.[10]

Bitters and Spices

The majority of the plants rich in essential oil and pungent compounds have been historically classified as spices.  For most of human history, spices have been a canonical example of a fluid entity shifting from the food to the medicine field: they were sold by grocers and spice merchants but also by apothecaries and physicians; they have been used extensively as ingredients in the preparations of dishes, usually accompanying and exalting the main food crops, while at the same time being consumed as infusions and decoctions, like many other medicinal plants. When used as foods, they were very rarely the main ingredient, and seldom provide high primary metabolite intake. Even when used as a medicine, their sensual, organoleptic quality played an important role, quite apart from their effective therapeutic quality.

In fact spices are more akin to medicinal foods that FF proper, and they were ascribed potent medicinal qualities well before empirical validations were available, most probably because they resemble the prototypical medicinal product: “they are specific (have unique and distinguishing tastes), small (in volume), and powerful (in the stimuli they emit and, in many cases, physiologic action)”.

The characteristic aroma and taste of spices is imparted by volatile essential oils and pungents (mono- and sesquiterpenes plus a few shikimic acid derivatives, plus thioethers in Alliaceae and isothiocyanates in Brassicaceae) and non volatile pungent compounds (mainly belonging to the acid amine group, like capsaicin in Capsicum and piperine in Piper).

Although very different from spices in term of economic and cultural importance, bitters too have a recognized place in many different cultures all over the world, in promoting the state of health. The almost universal use of bitter-tasting drinks as aperitif, digestives or fasting tools emphasizes this important role.[11]

Pungent, aromatic and bitter compounds do not exhaust the chemical variety of digestive FF, and their predominance cannot be taken without some caution. It is in fact probable that this predominance is due to many cultural, economical and social factors beyond the biological ones. Having said that, these compounds are extremely interesting because they seem to be able to act on gastrointestinal physiology before or even without systemic absorption, hence potentially with low toxicity profiles.
Moreover, in the last ten years research on gastrointestinal physiology has focused more and more on the health implications of tastants and olfactants, and this research has blended very well with the hypothesis of the coevolution of plant secondary compounds and human defense mechanisms.

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[1] Dufour DL and Wilson WM “Characteristics of ‘wild’ plant foods used by indigenous populations in Amazonia” in Etkin 1994, Op. Cit.; Vickers WT “The health significance of wild plants for the Siona and Secoya” in Etkin 1994, Op. Cit.; Price LL “Wild food plants in farming environment”s in Pieroni and Price 2006 Op. Cit.; Pieroni, A. and Quave, C. “Functional foods or food medicines? On the consumption of wild plants among Albanians and Southern Italians in Lucania”  in Pieroni and Price 2006 Op. Cit.; de Santayana, M.P., San Miguel, E., Morales, R. “Digestive beverages as a medicinal food in a cattle-farming community in Northen Spain (Campoo, Cantambria)”.  in Pieroni and Price 2006 Op. Cit.; Volpato and Godinez 2006 Op. Cit.; Vanderbroek, I.,  Sanca, S. “Food medicines in the Bolivian Andes (Apillapampa, Cochabamba Department)” in Pieroni and Price 2006 Op. Cit.; Ladio 2006 Op. Cit.; Ogoye-Ndegwa, C., Aagaard-Hansen, J. “Dietary and medicinal use of traditional herbs among the Luo of Western Kenya” in Pieroni and Price 2006 Op. Cit.; Eddouks, M. “Aspects of food medicine and ethnopharmacology in Morocco” in Pieroni and Price 2006 Op. Cit.; Curtin 1997, Op. cit.; Quave, C.L. and Pieroni, A “Traditional health care and food and medicinal plants use among historic Albanian migrants and Italians in Lucania, Southern Italy”. in Pieroni & Vandebroek 2007, Op. Cit.; Ceuterick, Vandebroek, Torry, & Pieroni Op. Cit; Van Andel, T and van’t Klooster, C. “Medicinal plant use by Surinamese immigrants in Amsterdam, The Netherlands: Results of a pilot market study”. in Pieroni & Vandebroek 2007, Op. Cit; Lundberg, P.C. “Use of traditional herbal remedies by Thai immigrant women in sweden” in Pieroni & Vandebroek 2007, Op. Cit; Vandebroek, I., Balick, M.J., Yukes, J., Duran, L., Kronenberg, F., Wade, C., Ososki, A.L., Cushman, L., Lantigia, R., Mejia, M., Robineau, L. “Use of medicinal plants by Dominican immigrants in New York City for the treatment of common health conditions: A comparative analysis with literatue data from the Dominican Republic” in Pieroni & Vandebroek 2007, Op. Cit; Manandhar, N.P. Plants and people of Nepal. Timber Oress, Oregon, USA, 2002; Ruffo, Birnie, Tengnas 2002 Op. Cit.; Germosen-Robineau, L Farmacopea vegetal caribena. Ed. Universitaria TRAMIL, ENDA-Caribe, 1998; Lewis, W.H., Elwin-Lewis, M.P.F. Medical Botany: Plants affecting human health 2nd edition. Wiley and sons, London, 2003; Williamson, E.M. (Ed.) Major herbs of Ayurveda. Churchill Livingstone, London, 2002; Williamson, Yongping Bao, Chen, Bucheli  2004, Op. Cit.; Akerreta, S., Cavero, R.Y., Lopez, V., Calvo, M.I. “Analyzing factors that influence the folk use and phytonomy of 18 medicinal  plants in Navarra”. Journal of Ethnobiology and Ethnomedicine 2007, 3:16; Lans, C. “Comparison of plants used for skin and stomach problems in Trinidad and  Tobago with Asian ethnomedicine” Journal of Ethnobiology and Ethnomedicine 2007, 3:3; Tilahun Teklehaymanot, Mirutse Giday “Ethnobotanical study of Medicinal plants used by people in Zegie peninsula, Northwestern Ethiopia” Journal of Ethnobiology and Ethnomedicine 2007, 3:12; Bussmann, Sharon and Lopez 2007 Op. Cit.; John Warui Kiringe “A Survey of Traditional Health Remedies Used by the Maasai of Southern Kaijiado District, Kenya” Ethnobotany Research & Applications, 2006 4:061-073;
[2] Ali-Shtayeh et al., 2008
[3] Hadjichambis ACH, Paraskeva-Hadjichambi D, Della A, Giusti M, DE Pasquale C, Lenzarini C, Censorii E, Gonzales-Tejero MR, Sanchez- Rojas CP, Ramiro-Gutierrez J, Skoula M, Johnson CH, Sarpakia A, Hmomouchi M, Jorhi S, El-Demerdash M, El-Zayat M, Pioroni A: Wild and semi-domesticated food plant consumption in seven circum-Mediterranean areas. International Journal of Food Sciences and Nutrition; 2008, 59 (5):383-414
[4] Della, Paraskeva-Hadjichambi, & Hadjichambis, 2006
[5] Lentini & Venza, 2007
[6] Rivera & Obón, 1996
[7] Rivera et al. 2005, cited in Leonti, S Nebel, Rivera, & M Heinrich, 2006
[8] Leonti, S Nebel, Rivera, & M Heinrich, 2006
[9] Ali-Shtayeh et al., 2008; Hadjichambis ACH, Paraskeva-Hadjichambi D, Della A, Giusti M, DE Pasquale C, Lenzarini C, Censorii E, Gonzales-Tejero MR, Sanchez- Rojas CP, Ramiro-Gutierrez J, Skoula M, Johnson CH, Sarpakia A, Hmomouchi M, Jorhi S, El-Demerdash M, El-Zayat M, Pioroni A: Wild and semi-domesticated food plant consumption in seven circum-Mediterranean areas. International Journal of Food Sciences and Nutrition; 2008, 59 (5):383-414; Della, Paraskeva-Hadjichambi, & Hadjichambis, 2006; Lentini & Venza, 2007; Rivera & Obón, 1996; Rivera et al. 2005, cited in Leonti, S Nebel, Rivera, & M Heinrich, 2006
[10] (Liu, et al., 2009; Long, et al., 2009; Kala, 2005; Muthu, et al., 2006; Pradhan & Badola, 2008; Bussmann & Sharon, 2006; Volpato, et al., 2009; Luziatelli, et al., 2010; Lulekal, et al. 2008; Yineger, Yewhalaw, & Teketay, 2008; Teklehaymanot & Giday, 2007; Mesfin, Demissew, & Teklehaymanot, 2009; Bhattarai, Chaudhary, & Taylor, 2006)
[11] Mills, SY, Bone, K Principles and Practice of Phytotherapy: Modern Herbal Medicine. Churchill Livingstone, 2000; Scarpa A,  Guerci A Actes du 2e Colloque European d‘Ethnopharmacologie et de  la 1 le Conférence internationale d‘Ethnomédecine, Heidelberg. 1993, 30-33; Johns 1990 Op. Cit.

Digestive Functional Foods 3

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Nella terza installazione digestiva ho deciso di scardinare l’ordine cronologico della discussione saltando ad una serie di minimonografie di piante con un certo bagaglio di letteratura sperimentale e clinica, e che, più o meno tirate per i tricomi, possono dirsi piante anche alimentari. Ci sarà tempo per ritornare a discorsi di ordine più teorico.

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Cynara cardunculus subsp. cardunculus Hayek — Asteraceae

Native to the Mediterranean area; the basal leaves were used as medicine as far back as ancient Roman times. It was used, as was characteristic of bitter remedies, primarily as a digestive and liver aid, to help stimulate the appetite, provide relief from nausea, stomach ache, flatulence, and a sense of fullness. More recently it has been described as liver protective, a choleretic, and a cholagogue. As with many members of the Asteraceae, it contains bitter-tasting sesquiterpene lactones, although the most characteristic and active compounds are caffeoylquinic acids (e.g. chlorogenic acid; 1,5-dicaffeoylquinic acid, neochlorogenic acid, criptochlorogenic acid, plus cinarine – 1,3-dicaffeoylquinic acid – only in hot acqueous extracts) and flavonoids.

Various experimental studies have shown promising choleretic and digestive activities of the dry extract of artichoke leaves. Total extract, fenolic acids and caffeoylquinic acids all show choleretic effects both in vitro1 and in vivo2 and they increases gastrointestinal peristalsis.3

These experimental studies are partly supported by clinical investigations that have shown that artichoke preparations may relieve digestive complaints (sensation of fullness, loss of appetite, nausea and abdominal pain) through an increase in the formation and flow of bile, probably mainly due to the presence of flavonoids and caffeoylquinic acids, but also via the bitter-tasting sesquiterpene lactones.4 In fact, the German Commission E approves the use of fresh or dried artichoke leaf for dyspeptic problems due to its choleretic action,5 and the ESCOP monograph reports as indications digestive disorders such as stomachache, nausea, emesis, sensation of fullness, flatulence.6

A post-marketing surveillance study reported by Held7 included 417 patients with hepatic and biliary tract disease treated for four weeks with artichoke leaf extract (1% caffeoylquinic acids, 1500 mg/day). In 65-77 % of patients, abdominal pain, bloating, meteorism, constipation, lack of appetite, and nausea were eliminated after one week, and in 52-82% of patients, after four weeks.

A mode of action study (a crossover, randomized, double blind clinical study, vs. placebo, with one-day treatment periods separated by an eight-day washout period) using an aqueous dry extract (4.5-5:1) on 20 subjects with acute or chronic metabolic disorders, showed that administration of six capsules (total weight 1.92 g) intraduodenally caused a peak increase (100 to 150 % compared to baseline) in bile one hour later, which lasted for three hours. The study inferred, but did not demonstrate, therapeutic benefit for dyspepsia. It suffered from many shortcomings: the study was too short, the sample size was small, it wasn’t conducted on subjects with dyspepsia, and the product was not delivered orally.8

A second post-marketing surveillance study included 553 subjects with dyspepsia, who were administered an average of 1.5 g of dry extract (3.8-5.5:1) for an average of 43.5 days. There was a clinically relevant reduction in dyspeptic symptoms for 71% of the subjects in 6 weeks of treatment (66% flatulence, 76% abdominal pain, 82% nausea and 88% emesis).9

Walker, Middleton, and Petrowicz reported an analysis of a patient subset from the initial survey by Fintelmann and Menssen with key symptoms of irritable bowel syndrome (n=279). These patients experienced significant reductions in symptoms (emesis 95%, nausea 85%, abdominal pain 75%).10

In a similar open study that lasted six months on 203 subjects suffering from dyspepsia, there was an average reduction (after 21 days) of 66% of the same range of symptoms. The global efficacy was evaluated by the physicians as being good or excellent in 85.7% of the cases.11

In a more recent double-blind, randomized controlled trial vs. placebo on 244 patients with

functional dyspepsia, the verum treatment (1920 mg dry extract/die) improved/reduced? symptoms and improved quality-of-life measures after six weeks.12

In an open, dose-ranging postal study, 454 healthy patients with self-reported dyspepsia were treated with a dry extract, at 320 or 640 mg daily. Both dosages reduced all dyspeptic symptoms, with an average reduction of 40% in global dyspepsia score.13 A subset analysis of the study, identifying post hoc 208 subjects suffering with IBS, showed a significant fall in disease incidence of 26.4% after 2 months.14

Thirty subjects with functional dyspepsia consumed an iced dessert with or without artichoke extract. The results show that ingestion of the dessert induces a reduction of symptom severity and range even without the extract, but that the presence of the extract intensifies the effects.15

A prospective cohort study on 311 patients with functional dyspepsia analyzed the efficacy of a commercial mixture of dry extracts of artichoke leaf (15% of chlorogenic acid – 150 mg per capsule), dandelion radix (Taraxacum officinalis – 2% of inulin), turmeric rhizome (Curcuma longa – 95% of curcumin) and rosemary (Rosmarinus officinalis) microencapsulated essential oil. After 60 days of treatment, a statistically significant gradual reduction in symptom severity was noted, and a global clinical response, defined as a 50% reduction in the total scores of all symptoms, was recorded in 38% of patients at 30 days.16

Taraxacum officinale G.H. Weber ex F. H. Wigg — Asteraceae

A perennial weed widely distributed in the warmer temperate zones of the Northern Hemisphere. Its roots and rhizomes have been used extensively since ancient times in Europe as a bitter tonic and for the treatment of various disorders such as dyspepsia, heartburn, spleen and liver complaints, hepatitis and anorexia.17

The intensely bitter-tasting compounds are sesquiterpene lactones of the eudesmanolide, guaianolide and germacranolide types18 (previously known as taraxacin) and are unique to Taraxacum. The drug contains also triterpene alcohols (taraxastane-type), phytosterols , lupane-type triterpene and hydroxycinnamic acids.19

In Germany, Commission E supports using Taraxacum officinale folia to treat loss of appetite, dyspepsia, bloating and flatulence, while radix with folia is recommended to treat disturbed bile flow, loss of appetite and dyspepsia.20

ESCOP recommends T. officinale radix for restoring hepatic and biliary function, dyspepsia and loss of appetite.21

Intragastric administration of an aqueous or 95% ethanol extract of the whole plant (dose non specified) to rats increased bile secretion by 40% in over 2 hours.22

Dandelion decoction administered by injection to dogs doubled the volume of bile secreted.23 A similar effect was observed following intraduodenal administration to rats.24

An herbal combination containing Calendula officinalis, Taraxacum officinale, Hypericum perforatum, Melissa officinale and Foeniculum vulgare reduced intestinal pain in 96% of 24 patients by the 15th day in an uncontrolled trial involving patients with chronic colitis. Defecation was normalized in patients with diarrhea syndrome.25

A prospective cohort study on 311 patients with functional dyspepsia analyzed the efficacy of a mixture of dry extracts of artichoke leaf, dandelion radix, turmeric rhizome and rosemary essential oil. After 60 days of treatment, a statistically significant gradual reduction in symptom severity was noted; and a global clinical response – defined as a 50% reduction in the total scores of all symptoms – was recorded in 38% of patients at 30 days.26

Silybum marianum (L.) Gaertn. — Asteraceae

Plant indigenous to North Africa, Asia Minor and southern Europe, have been used since ancient times for the treatment of gastrointestinal and hepatic complaints like anorexia,27 colic and abdominal cramps,28 and nausea.29

It is nowadays mainly known for its important hepatoprotective and hepartoregenerative activity but, being a bitter remedy, it shows classic digestive activity, although the clinical evidence is lacking (Commission E recognizes this by suggesting its use as a treatment of dyspeptic complaints). The seeds contain a complex mixture of flavolignans termed silymarin, which seems to be the main active principle ingredient?.30 Other important compounds are the flavonoids quercetin, dehydroksampferol and (+)-taxifolin, saponins, poliacetylenes and essential oils.

An experimental study has shown that intragastric administration of an acetone extract of fruit containing silybin increased the volume and dry mass of excreted bile in rats.31

Although there are no direct clinical data, Silybum marianum has been tested in a fixed preparation combining Iberis amara, Melissa officinalis, Matricaria recutita, Carum carvi, Mentha x piperita, Glycyrrhiza glabra, Angelica archangelica, Silybum marianum and Chelidonium majus. This preparation has shown a general activity on dyspepsia,32 in particular: a reduced acid output, increased mucin secretion, prostaglandin E(2) release and a decrease in leukotriene levels.33 A second study showed protection against the development of gastric acidity rebound/reflux? and inhibited the serum gastrin level in rats.34

Citrus limon (L.) Burmann fil. — Rutaceae

The rind has been used both in the West and in the East as a tonic digestive, strongly aromatic and slightly bitter, used in decoction and alcoholic extracts. In Traditional Chinese Medicine it is used to resolve gastrointestinal disorders such as abdominal and epigastric bloating, belching, nausea and emesis, inappetence and diarrhea, and in the West for colicky indigestions, abdominal bloating, slow digestion, and nervous dyspepsia. The juice has traditionally been used as a digestive, astringent, stomachic, antispasmodic and carminative, used for the treatment of inappetence, gastralgy, nausea, and gastric acid reflux.35

The epicarp is very rich in an essential oil dominated by monoterpenes (60-95%) in particular R(+)-limonene (up to 70%), and linear aldheides (citrals), but also characterized by photoactive furocoumarins (more than 5%).36 Also present are phenolic compounds, flavonoids, pectin and various organic acids from the juice.37

Lemon juice and extracts exert both indirect and direct actions on gastrointestinal activity. Particularly interesting are the indirect (cognitive and sensory mediated) ones.

It is well known that both lemon aroma and flavor are sialagogues, that is, that they influence the cephalic phase of digestion (salivation). In an interesting study comparing the effects of different visual stimuli, Christensen and Navazech show that there is a stronger response (a higher salivary volume) to visual stimuli of acidic (lemon juice) and pungent foods (pizza with hot peppers).38 Lemon odor and the introduction of lemon juice into the oral cavity both cause an increase in the volume of saliva, statistically higher than that caused by a non-stimulus (pure air or pure water).39 Moreover, according to Davenport, the lemon juice seems to be able to influence not only the quantity but also the quality (in terms of compositions) of the saliva, which becomes richer in proteins.40 This suggests that prior knowledge of the food items can modify the cephalic phase of digestion, and reinforces the thesis of a relationship between secondary metabolites and gastrointestinal physiology: the presence or the supposed presence of possibly hazardous substances (irritant, bitter, astringents, etc.) not only alters the salivary volume but increases the percentage of compounds like praline, which offer a certain degree of protection from irritant compounds such as tannins.

The study by Bauslaugh showed a relationship between salivation and gastrointestinal motility during olfactory stimulation,41 and it is well known that pepsinogen, gastrin and HCl secretions are influenced by cephalic stimulations,42 hence possibly by the organoleptic stimulation by lemon juice.

The palatability and the absence of gastrointestional adverse symptoms have already been tested in a commercial product containing lemon juice and various herb extracts.43

Apart from sensory, indirect activities, lemon juice can directly affect gastrointestinal secretions. 100 ml. of orange and lemon juice have shown very potent stimulant action on pancreatic secretion (higher output, higher bicarbonate content, higher enzymatic content), compared to other stimuli, and the peak response was observed earlier (60 minutes for the juice, 90 minutes for the other stimuli). In general the juice had a response quantitatively and qualitatively comparable to secretin.44

The fruit juice and some of its components (caffeic acid, ferulic acid, hesperidine, p-coumaric acid) show choleretic/cholagogue and antispasmodic action.45

The essential oil and many of its components are rubefacient46 and stimulant carminative;47 limonene is myorelaxant and antispasmodic at high doses, as are many of the other essential oil components: a-pinene, a-terpinene, bergapten, b-pinene, cariophillen, geraniol, mircene, nerale, terpinen-4-olo.48 Hence, they may? could play a role in the antispasmodic and carminative activity of lemon rind extract and lemon juice.

Pectin shows stomachic action and gastrointestinal protective activity.49

Foeniculum vulgare Mill. — Apiaceae

Commonly employed as a culinary herb and as a remedy to improve digestion in traditional systems of medicine; they have been used since ancient Roman and Egyptian times as a valuable warming carminative and aromatic digestive. Fennel has? also had a persistent/consistent reputation as an ingredient in “gripe water” and other remedies for infant colic.

Given in the form of a homemade tea or infusion, fennel is a useful standby for dyspepsia, bloating and flatulence, and poor appetite.50

It contains an essential oil mainly composed of trans-anethole (30-90%), (+)-fenchone (6-30%) and estragole (methylchavicol – ca. 5% ); and also contains flavonoids and coumarines.

Only a handful of modern clinical trials are reported in the literature, demonstrating – together with its widespread traditional use – a reduction in colic in babies, and a reduction in the symptoms of chronic colitis.

A randomized placebo-controlled trial tested a fennel seed oil emulsion, compared with placebo, on 125 infants, 2 to 12 weeks of age, diagnosed with colic. The emulsion eliminated colic in 65% of infants in the treatment group, compared to 23.7% of infants in the control group with an Absolute Risk Reduction (ARR) = 41%.51

A mixture containing chamomile (Matricaria recutita), fennel (Foeniculum vulgare) and lemon balm (Melissa officinalis) was found to have significant benefits in the treatment of infantile colic in a double-blind, placebo-controlled study on 93 breastfed infants, treated twice a day for 1 week. Crying time reduction was observed in 85.4% of subjects.52

However, two subsequent experimental studies in mice, while confirming the reduction of intestinal motility at dosages similar to those used in human trials, showed that the major contribution to the antispasmodic activity is due to Matricaria recutita and Melissa officinalis.53

In an uncontrolled clinical study twenty-four patients with chronic non-specific colitis were treated with a herb combination of Taraxacum officinale, Hipericum perforatum, Melissa officinaliss, Calendula officinalis and Foeniculum vulgare. As a result of the treatment, the spontaneous and palpable pains along the large intestine disappeared in 95.83 per cent of the patients by the 15th day of their admission to the clinic.54

Backed by weaker clinical evidence, but supported by very widespread and validated traditional use, are the indications for digestive complaints: dyspepsia with bloating and flatulence, poor appetite and indigestion.55

In animal studies, fennel has been shown to be antispasmodic, prokinetic and secretagogue.

Isolated trans-anethole reduced contractions of a rat diaphragm preparation;56 the essential oil seems able to reduce smooth muscle spasms in various in vitro models,57 but this activity seems concentration -dependent, with spasmogenic effect at lower doses, and spasmolytic at higher ones.58

The ethanol extract59 and the aqueous infusion show60 spasmolytic effects.

Intragastric administration of 24.0 mg/kg bw of the fruits increased spontaneous gastric motility in unanaesthetized rabbits.61

An aqueous extract of the fruits (10% p/v), administered to anaesthetized rats via gastric perfusion at 0.15 ml/minutes, significantly increased gastric acid secretions.62

The admixture of 0.5% fennel fruits to the diet of rats for 6 weeks reduced the food transit time by 12%,63 while the admixture of fennel fruits (0.5%) and mint (1%) for 8 weeks stimulated a higher rate of secretion of bile acids in rats, and a significant enhancement of secreted intestinal enzymes, particularly lipase and amylase.64

Melissa officinalis L. — Lamiaceae

A very popular traditional herb used in infusion for restlessness and dyspepsia, especially among children. It contains very low amounts of essential oil (0.02-0.37%), organoleptically characterized by the aldheydes geranial and neral, and 6% of rosmarinic acid.

There is a dearth of clinical research on the digestive activity of Lemon balm, and the only two existing clinical studies are based on formulas and not on the single herb extract.

A randomized, double-blind, placebo-controlled trial showed significant improvement of colic in babies given a chamomile, fennel and lemon balm preparation compared with babies given a placebo.65

A fixed commercial combination of extracts of Melissa officinalis, Mentha spicata and Coriandrum sativum was tested on 32 irritable bowel syndrome patients and compared to placebo for 8 weeks in a clinical study. The study shows that the combination reduces the severity and frequency of abdominal pain and of bloating better than placebo.66

There is little doubt that the ethanol fraction of the plant, and in particular the volatile oil component, is responsible for the antispasmodic activity of the herb. The ethanol extracts and the essential oil have shown inhibition of artificially-induced contraction of smooth muscles,67 but there are also contrasting data.68 The essential oil was more effective than its isolated components, but it has been observed that neral and geranial were more active than citronellal and β-cariophillen.69

Mentha xpiperita L. — Lamiaceae

Without doubt one of the most world-renowned aromatic plants, and the most important one in terms of annual production, both of the dried herb and essential oil. It has always been used in traditional learned and folk medicine as a carminative, antispasmodic, antiemetic and digestive, both in the West and in the East.

It contains a large amount of essential oil characterized by the presence of a monoterpene alcohol, menthol, which is responsible for many of the activities of the herb and for its characteristic aroma. It also contains flavonoid compounds and hydroxycinnamic compounds.70

Peppermint has also been the focus of a fair amount of good quality research, both experimental and clinical, that supports many of the traditional claims. In particular it has shown antispasmodic, carminative and choleretic activities.

The essential oil reduces intracolonic pressure.71 In an open study of 20 patients, peppermint essential oil used alongside a colonoscope relieved colonic spasms,72 and it had the same effect when administered with barium enemas.73

The essential oil is also able to reduce tension in hypertonic intestinal smooth muscles? in cases? of IBS.74

In healthy volunteers, intragastric administration of a dose equivalent to 180 mg peppermint oil, reduced intraesophageal pressure within 1-7 minutes of infusion.75

Oral administration of the essential oil delayed the gastric emptying time in healthy volunteers and in patients with dyspepsia,76 and it slowed small intestinal transit time in 12 healthy volunteers.77

A combination of essential oils (90 mg of peppermint and 50 mg of caraway in an enteric-coated capsule) was tested in various studies.

The combination produced smooth muscle relaxation of stomach and duodenum;78 in a double-blind, placebo-controlled multicentre trial with 45 patients it improved symptoms of dyspepsia, reducing pain in 89.5% of patients and improving Clinical Global Impression scores in 94.5% of patients.79

The same combination tested on 223 dyspeptic patients in a prospective, randomized, reference and double-blind controlled multicentre trial, significantly reduced pain,80 and tested on 96 outpatients with dyspepsia, significantly reduced pain by 40% and reduced sensations of pressure, heaviness and fullness.81

The formula was shown to be as effective as Cisapride in reducing both the magnitude and frequency of pain,82 and it had a relaxing effect on the gall bladder.83

In a systematic review of herbal medicines for functional dyspepsia, the authors found 17 randomized clinical trials, nine of which involved peppermint and caraway combination preparations. Symptoms were reduced by all treatments; 60- 95% of patients reported improvements in symptoms.84

The essential oil and fractions of it have been shown to have gastrointestinal smooth muscle relaxant activity and to inhibit spontaneous smooth muscle contractions both in vitro and in vivo.85 Some data are also available on the antispasmodic effects of the ethanol extract, as well as flavonoids isolated from the leaf.86

The carminative activity of peppermint is, in fact, probably due to a relaxing action on the gastrointestinal sphincters,87 and to a reduction of the volume of intestinal gas by the antimicrobial, anti-fermentative and antifoaming effects of the essential oil.88

Choleretic activity (increased bile secretion and increased synthesis of bile acids) has been demonstrated in animal models for the herb, various flavonoid fractions, flavomentin, the essential oil and menthol.89 The effect probably derives from the spasmolytic activity of menthol and other terpenes on the Oddi’s sphincter.90

The essential oil seems to be acting by interacting with smooth muscle Ca channels probably by inhibiting the influx of extracellular Ca ions without effects on their intracellular mobilization, and menthol has been isolated as the most important compound.91

The antiemetic and prokinetic effects of peppermint oil and of (-)-menthol are due at least partly to their binding to the 5-HT(3) receptor ion-channel complex, in a manner similar to that of ginger.92

Matricaria chamomilla L. — Asteraceae

It has been a highly popular family herb since antiquity, generally used for nervous excitability and digestive disorders, stomach cramping, dyspepsia and flatulence. This tradition of use notwithstanding, much of the research data concentrate on antinflammatory and vulnerary activity.

However, its antispasmodic and relaxant effects provide a theoretical basis for its use in gastrointestinal conditions, and the German Commission E approves chamomile for gastrointestinal spasms and inflammatory diseases of the gastrointestinal tract.

It contains an essential oil, flavonoids (in particular apigenin and its related flavonoid glycosides), and proazulenes (sesquiterpene lactones) including matricin, matricarin and desacetlymatricarin.93

Although a well-known and widely used herb, almost no substantial clinical research exists into the remedy’s use for digestive disorders, and only a few well designed clinical studies are available There are however some experimental studies pointing to antispasmodic activity of the plant and its constituents on smooth muscle.

In an open, multicentre study, 104 patients with gastrointestinal complaints (gastritis, flatulence and mild intestinal spasms) were treated for 6 weeks with an oral chamomile extract (standardized for 0.05% alpha-bisabolol and 0.15% apigenin-7-glucoside), with 44.2% of subjects self-reporting symptom free.94

In a double-blind study, a herbal decoction (150 mL/day containing Matricaria chamomilla, Verbena officinalis, Glycyrrhiza glabra, Foeniculum vulgare and Melissa officinalis) was tested for seven days on 68 healthy infants with colic. 57% of the infants experienced relief compared to 26% in the placebo group.95

In another trial – prospective, double-blind and randomized – a preparation containing chamomile extract and pectin was tested on children aged 6 months to 5.5 years with uncomplicated diarrhea. The preparation reduced duration and severity of diarrhea significantly faster than the placebo.96

Whole extracts and isolated components demonstrate a dose-dependent antispasmodic effect in vitro.97 The major activity was related to (-)-α-bisabolol, the cis-spiroethers,98 and the flavonoids (in particular apigenin).99 Bisabolol oxides A and B, the essential oil, other flavonoids and the small amount of coumarins were less active in vitro.100

The mechanisms for chamomile antispasmodic activity are still unclear. However, at least one mechanism has been proposed: the inhibition of cAMP- and cGMP-phosphodiesterases by flavonoids.101

Chamomile also increases production of bile by the liver.102

Cymbopogon citratus (DC.) Stapf. — Poaceae

An aromatic tropical grass, whose essential oil is characterized by the presence of citrals (up to 90%) and monoterpenes. It also contains triterpenoids and flavonoids. It has been traditionally deemed a carminative, a light sedative, an analgesic, an antiemetic and an antispasmodic.103

It is most frequently used as a remedy for gastrointestinal disorders, in particular stomachache, acids indigestion, abdominal cramps, diarrhea, and dyspepsia.104

There are, however, no clinical data available, and only a few experimental data showing that di essential oil is strongly antispasmodic and carminative.105

Aloysia citrodora Palau — Verbenaceae

Used in Latin America, USA and Europe as an aromatic ingredient in fruit salads, jams, cold drinks or as an infusion.106 The plant is rich in an essential oil dominated by citrals. It also contains flavonoids, phenolic acids and tannins.107

Various authors report its digestive,108 spasmolytic,109 stomachic,110 and carminative activity,111 and it has been used for gastrointestinal and spasmodic disorders, e.g. flatulence, dyspepsia, colic, nausea, etc.112

There are, however, no clinical data in support of these claims, but there are some experimental data.

The essential oil and many of its components are aperitive, analgesic/antinociceptive, and antispasmodic.113 . Cineole and borneol are choleretics and secretagogues.114

Chlorogenic acids could act synergistically with the essential oil as digestives, and vitexin shows an antispasmodic activity.115

Caceres reports of a clinical study (impossible to track down) which allegedly shows a positive effect of the plant on inappetence, slow digestion, gastralgy and emesis.116

Illicium verum, Hook. f. — Illiciaceae and Pimpinella anisum L. — Apiaceae

Both popular aromatic remedies: the first in China, where it is a component of the very famous five spice powder, together with cinnamon/cassia, cloves, fennel and Sichuan pepper; and the second in Europe and North America. Both are used quite often in food recipes (Star Anise in garam masala spice blends and the rice dish biriyani, and Aniseed in many flavored drinks)

These two fruits are deemed carminative and stomachic and they are taken internally in the treatment of abdominal pain and digestive disturbances. They are often included in remedies for indigestion, and they are believed to be effective for children’s digestive upsets, including colic pain.117 Some people chew the fruits after meals for better digestion. The essential oils are used as a stimulant, stomachic, carminative.

Star Anise is characterized by its essential oil content, particularly rich in prenylated C6-C3 compounds (phenylpropanoids: anethole and its analogues, estragole, eugenol), but contains also neolignans and sesquiterpenes in addition to several common flavonoids, diterpenoids and triterpenoids.118

Aniseed contains an essential oil whose major component is trans-anethole.

Their traditional use notwithstanding, there is no clinical evidence supporting it, but there are limited experimental data. The essential oil of Aniseed and trans-anethole both seem to act as antispasmodics in vitro and in vivo on animal models. They antagonize artificially-induced spasms and decrease the rate and extent of contractions of smooth muscle preparations,119 possibly via Ca-channel blockage and the NO-cGMP pathway.120 Many authors point to antispasmodic,121 carminative122 and digestive activities,123 suggesting use for abdominal colic, inappetence, dyspepsia, flatulence.

Zingiber officinale Roscoe — Zingiberaceae

Probably one of the oldest domesticated spices in human history. It has a prominent role in Asian systems of medicine where it is used for the treatment of dyspepsia, flatulence, colic, vomiting, diarrhea, spasms and to stimulate the appetite, but over the centuries has become part of western cuisine and pharmacopoea as well.124

The ginger rhizome contains an essential oil (1-4%) and a resin, known collectively as oleoresin. The chief constituents of the essential oil are the sesquiterpenes a-, and b-zingiberene, which are responsible for the characteristic aroma. The resin contains pungent phenolic compounds called gingerols, gingerdioles and gingerdiones, and their corresponding dehydration products known as shogaols.125

According to the studies, ginger exerts several effects in the gastrointestinal tract: secretagogue (saliva, bile, pancreatic juices, gastric juices), antiemetic, intestinal antispasmodic and gastric prokinetic.

It stimulates the flow of saliva, bile and gastric secretions.126 An extract containing the oleoresin and administered intraduodenally to rats produced an increase in the bile secretion, while the aqueous extract was not active. These results point towards the oleoresin as the active principle, and in fact it was shown that [6]- gingerol and [10]-gingerol were mainly responsible for the cholagogic effect.127 An oral dose of ginger enhanced rat pancreatic lipase, sucrase and maltase activity, and stimulated trypsin and chymotrypsin.128

The essential oil,129 a 95% ethanol extract,130 a hot water extract131 and of a formula containing ginger, Pinellia ternata, Citrus aurantium, Pachyma hoelen, and Glycyrrhiza glabra,132 were all shown to possess antispasmodic activity on intestinal smooth muscles.

The rhizome extract, shogaols and gingerols all increased gastric motility in animal models and in humans.

In a clinical study ginger, assumed before meals, increased number and frequency of contractions in the corpus and in the antrum, and frequency of contractions in the duodenum. Assumed after meals, it contributed to motility to a lesser degree.133

Ginger and a Japanese formula (Dai-Kenchu-To) containing ginger, Zanthoxylum fruit and ginseng root, both induced phasic contractions in the gastric antrum..134

Previous clinical data had shown that ginger did not affect the gastric emptying rate.135 There were suggestions, however, that this lack of activity was due to low dosage of ginger rhizome.

The prokinetic activity was confirmed in other in vitro and in vivo tests, that showed that ginger extract enhances the intestinal transit of charcoal meal and that it acts through a spasmogenic, dose-dependant cholinergic agonistic effect on the post-synaptic muscarinic M3 receptors in the stomach fundus. It also has a possible inhibitory effect on pre-synaptic muscarinic autoreceptors. At the same time it shows spasmolytic activity at the intestinal level (also possessed by 6-shogaol, 6-gingerol, 8-gingerol and 10-gingerol), probably through a Ca2 + antagonist effect.136

Various constituents found in Ginger, 6-, 8- and 10-gingerol, 6-shogaol, and galanolactone, act as serotonin receptor antagonists, which could explains the antispasmodic effects on visceral smooth muscle.137 They could exert their effect by binding to receptors in the signal cascade behind the 5-HT(3) receptor ion-channel complex, perhaps substance P receptors or muscarinic receptors.138

At the same time two compounds (10-shogaol and 1-dehydro-6-gingerdione), and particularly the whole lipophilic extract, have shown to partially activate the 5-HT(1A) receptor (20-60% of maximal activation).139

The serotonin receptor antagonist activity may partly explain the antiemetic effect of ginger, since these receptors do mediate peristalsis and emesis,140 and the constituents active on these receptors were also active as anticholinergic antiemetics, in the following descending order of potency: 6-shogaol> or= 8-gingerol>10-gingerol> or = 6-gingerol.141

Many clinical studies have shown the positive antiemetic effects (prevention and treatment of nausea) of Ginger and many of its constituents (shogaols, gingerols, zingerones) under different circumstances.142

A systematic review of six controlled studies found that Ginger was more effective than placebo in some studies of postoperative nausea and vomiting. Of the three studies conducted in postoperative nausea and vomiting, two suggested that Ginger was superior to placebo and equally as effective as metoclopramide, whereas one found no benefit.143

A recent Cochrane review on 20 trials concluded that Ginger might be of benefit in cases of nausea and emesis, but that the evidence to date was weak.144

Capsicum annuum L. — Solanaceae

A native American plant that has been exported all over the world and has conquered both the cuisine and the medicine of Europe, Africa and Asia, in a very interesting reverse spice journey.

Capsicum’s main active chemical group is that of the capsaicinoids, a group of pungent alkaloids whose prototype is capsaicin (8-methyl-N-vanillyl-6-nonenamide), which has been tested for its analgesic effect.145

The scientific evidence about capsicum and capsaicinoids and their effects on the gastrointestinal tract is rather contrasting. It is well known that capsaicin can interact with the vanilloid receptor VR1 and that this interaction can lead to direct and indirect effects. The interaction causes a selective impairment of the activity of nociceptive C-type fibers carrying pain sensations to the central nervous system, causing, on chronic dosage, analgesic and anti-inflammatory effects.146 These have been evaluated in patients suffering from heartburn147 and functional dyspepsia, with encouraging results.148

The data on gastric secretions and motility are less clear: some studies found a stimulation of gastric emptying149 and of secretions,150 others found no difference,151 and others even found a reduction in activity.152

The intake of red pepper has caused a reduced energy intake, suppression of hunger and increased satiety,153 an activity in line with a possible effect on the secretion of CCK.

Carica papaya L. — Caricaceae

A tropical plant original to the dry flatlands of Mesoamerica (South Mexico and Guatemala). The fruit is one of the most important fruits in the tropics and worldwide, and its fermented products are well known in the field of FF for its antioxidant properties.154 Its juice and jams made out of the fruit pulp are used also for digestive complaints (constipation, diarrhea, dyspepsia, enteritis), and it is supposed to possess carminative, cholagogue and digestive activities.155 It contains various proteolytic enzymes like papaine and chymopapaine; carotenoids, monoterpenoids; and organic acids.156

Papaine is a proteasis (similar to bromelin) with wide-range specificity, it hydrolyses polypeptides, amides and esters, particularly when used in an alkaline environment, and is used in digestive disorders; chymopapaine is very similar but less active. Although the mature fruit is less rich in papaine than the unripe one, the quantity is still sufficient to give a biological bases to the traditional digestive claims for the fruit and its derivatives.

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Note

1 ESCOP Monographs on the medicinal uses of plant drugs. Devon, European Scientific Cooperative on Phytotherapy, 2003

2 Preziosi P, Loscalzo B “L’azione sulla coleresi, sul colesterolo ematico e sulla lipoidosi colesterolica del principio attivo del carciofo e di sostanze ad esso correlate”. Fitoterapia. 1956; 27:666-72; Bombardelli E, Gabetta B, Martinelli EM, “Gas-liquid chromatographic and mass-spectometric investigation of Cynara scolymus extracts”. Fitoterapia. 1977; 48:143-152.

3 Lietti A. “Choleretic and cholesterol lowering properties of two artichoke extracts”. Fitoterapia. 1977; 48:153-58

4 Kraft K “Artichoke leaf extract–Recent findings reflecting effects on lipid metabolism, liver and gastrointestinal tracts”. Phytomedicine. 1997; 4 (4): 369-378; Wegener T, Fintelmann V. “Pharmacological properties and therapeutic profile of artichoke (Cynara scolymus L.)”. Wien Med Wochenschr. 1999;149(8-10):241-7.

5 Blumenthal M, Busse W, Hall T, Goldberg A, Gruenwald J, Riggins C, Rister S, eds. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Trans. S Klein. Austin, TX: American Botanical Council, 1998

6 ESCOP 2003 Op. Cit.

7 Held C “Artischoke bei Gallenwegsdyskinesien: Workshop “Neue Aspekte zur Therapie mit Choleretika.” Kluvensiek. 1991; 2: 9. Cited in Kraft 1997 Op. Cit.

8 Kirchhoff R, Beckers CH, Kirchhoff GM, Trinczek-Gartner H, Petrowicz O, Reimann HJ “Increase in choleresis by means of artichoke extract”. Phytomedicine. 1994; 1: 107-115

9 Fintelmann V. “Antidyspeptische und lipidsenkende Wirkungen von Artischockenextrakt: Ergenbnisse klinischer Untersuchungen zur Wirksamkeit und VertraNglichkeit von Hepar-SL forte an 553 Patienten”. Zeitschrift fur Allgemeinmedizin. 1997; 72 (Suppl. 2): 3-19. Cited in Kraft 1997 Op. Cit.; Fintelmann V, Menssen HG. “Aktuelle Erkenntnisse zur Wirkung von ArtischockenblaNtterextrakt als Lipidsenker und Antidyspeptikum”. Deutsche Apotheker-Zeitung. 1996; 136: 1405. Cited in Kraft 1997 Op. Cit.;

10 Walker AF, Middleton RW, Petrowicz O “Artichoke leaf extract reducessymptoms of irritable bowel syndrome in a post-marketing surveillance study”. Phytotherapy Research. 2001; 15 (1): 58-61

11 Fintelmann V, Petrowicz O Naturamed. 1998; 13:17-26

12 Holtmann G, Adam B, Haag S, Collet W, Grunewald E, Windeck T. “Efficacy of artichoke leaf extract in the treatment of patients with functional dyspepsia: a six-week placebo-controlled, double-blind, multicentre trial”. Aliment Pharmacol Ther. 2003 Dec;18(11-12):1099-105

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23 ESCOP 2003 Op. Cit.

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26 Sannia A. 2010 Op. Cit.

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150 Lippe ITH, Pabst MA, Holzer P. “Intragastric capsaicin enhances rat gastric acid elimination and mucosal blood flow by afferent nerve stimulation”. Br J Pharmacol 1989; 96: 91-100

151 Alfoldi P, Obal F, Toth E, Hideg J. “Capsaicin pretreatment reduces the gastric acid secretion elicited by histamine but does not affect the responses to carbachol and pentagastrin”. Eur J Pharmacol 1986; 123: 321-7; Rodriguez-Stanley et al. 2000 Op. Cit.; 14: 129-34; Park HJ, Na SK, Lee SI, Kang JK, Park IS. “The effect of red pepper and capsaicin on gastric emptying in human volunteers”. Gastroenterology 1998; 114: G3361

152 Alfoldi et al. 1986 Op. Cit.; Mozsik G, Debreceni A, Abdel-Salam OM, et al. “Small doses of capsaicin given intragastrically inhibit gastric basal acid secretion in healthy human subjects”. J Physiol (Paris) 1999; 93: 433-6.; Gonzalez R, Dunkel R, Koletzko B, Schusdziarra V, Allesher HD. “Effect of capsaicin-containing red pepper sauce suspension on upper gastrointestinal motility in healthy volunteers”. Dig Dis Sci 1998; 43: 11 165-71; Vazquez-Olivencia W, Shah P, Pitchumoni CS. “The effect of red and black pepper on orocecal transit time”. J Am Coll Nutr 1992; 11: 228-31; Horowitz M, Wishart J, Maddox A, Russo A. “The effect of chilli on gastrointestinal transit”. J Gastroenterol Hepatol 1992; 7: 52-6

153 Reinbach HC, Smeets A, Martinussen T, Møller P, Westerterp-Plantenga MS. “Effects of capsaicin, green tea and CH-19 sweet pepper on appetite and energy intake in humans in negative and positive energy balance”. Clin Nutr. 2009; 28(3):260-5

154 Aruoma OI, Hayashi Y, Marotta F, Mantello P, Rachmilewitz E, Montagnier L. “Applications and bioefficacy of the functional food supplement fermented papaya preparation”. Toxicology. 2010; 278(1):6-16. Epub 2010 Sep 24.

155 Duke et al. 2002 Op. Cit.; Caceres 1996 Op. Cit.

156 Williamson 2002 Op. Cit.

Digestive Functional Foods 2

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Nella seconda installazione mi concentro su due dati interessanti: l’importanza dei disturbi gastrointestinali nelle farmacopee tradizionali, e la predominanza di alcuni taxa nelle piante medicinali ad attività gastrointestinale: Asteraceae, Lamiaceae ed Apiaceae.
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Plants used for gastrointestinal complaints in the folk traditions
In analyzing the literature on traditional remedies, it is quite evident that there is a prevalence of plant remedies used for gastrointestinal complaints. In a comparison between indigenous and biomedical pharmacopoeias cited by Balick and Cox, and summarized data referring to 15 different geographical areas, it was shown that “indigenous plant remedies are focused more on gastrointestinal disorders then western Pharmacopoeas”. In fact, the main indication for plant-based remedies was gastrointestinal disturbances (accounting for 15% of the total), equal only to dermatological complaints.[1]

These data are confirmed by more recent research.
In the now famous paper by Etkin and Ross on Hausa folk medicinal knowledge, of the 781 recipes registered, 184 (23.5%) were used for gastrointestinal complaints. Limiting the analysis to the naturalistic maladies, the percentage rises to 32%.[2]
Amongst the most cited uses of the remedies of the Masai in Kenya, gastrointestinal indications play a major role: stomachache is cited 100% of the time, loss of appetite 92% and indigestion 45%.[3] In more recent study on Kenyan ethnobotany, plant remedies for stomach problems were cited 20% of the times.[4]
Very similar percentages are found in other African areas. The proportion of remedies used for treatment of gastrointestinal related disease are for instance high in most studies conducted in Ethiopia, going from 23%[5] to 35%.[6]

In a comparison of Mediterranean folk pharmacopoeias, the percentage of plants used for gastrointestinal complaints went from 31.2 in Uzbekistan, to 21.68 in Turkey, to 16.93 in Greece, to 10.6 in Italy.[7]
In an ethnobotanical survey of the western Pyrenees the plants were used primarily for gastrointestinal or RT disorders,[8] and a survey done in a Peruvian clinic showed that gastrointestinal problems were the second most important reason for patients to use plants.[9]
In the ethnobotany of the South West of the US, around 23.6% of the remedies are used for gastrointestinal disorders.[10]

According to two papers on Brazilian ethnomedicine, 22 to 30% of the medicinal plants were used for digestive disorders, the second most frequent use of all.⁠[11]
A very similar percentage is apparent in a study on Mexican ethnobotany, where roughly 30% of all plants were used to treat colics and stomachaches.[12]
According to Volpato and coworkers, almost 50% of the remedies used by Haitian immigrant to Cuba are intended to treat general gastrointestinal disorders, and about 20% are used as digestive and carminative.[13]
In Perù, 20.3% of the 402 medicinal plant species were used to treat gastrointestinal disturbances, the second most important indication of all,[14] and 6,68% of all plant mixtures (the highest percentage of all uses) was used to treat colic and intestinal problems.[15]
The use of medicinal plants for the treatment of gastrointestinal disorders has a high prevalence in other Andean societies as well.[16]

Many papers have recorded the very high percentage of plants used for gastrointestinal disorders in India, usually the most frequent use af all. The data vary between 25,3% for indigestion,[17] to 30% for stomach related disorders,[18] to 51,2% for generic gastrointestinal disorders.[19] Even when the indications are not the most important, the percentages are still very relevant, as in two recent studies reporting percentages of 9 and 18% for gastrointestional uses.[20]
In a review of remedies used in Pakistan, 16% of the plants were used for gastric problems.[21]
In a recent paper on Nepali remedies, 14,3% of plant species were taken for indigestion, and 10,7% were used as appetite stimulants.[22]
In East Timor the digestive uses were 4th by frequency, adding uo to 6,7%.[23]
⁠In an ethnobotanical study based in China, 40,52% of plants were used to treat gastrointestinal disorders.[24]

These data refer to medicinal plants but, even when selecting only those remedies that can be ascribed to the food-medicine continuum, this trend remains evident.[25] In a study in Mediterranean Spain, the functional or medicinal foods were used in great prevalence for gastrointestinal disorders (up to 20.4%),[26] and the same was true in a study in northwest Patagonia, where a great number of edible medicinal plants were used for gastrointestinal disorders.[27]

In Cuba viandas (starchy roots and tuber crops) and fruits, typical foods used also as medicinal resources, are particularly important for gastrointestinal distress. Viandas are usually boiled in water or milk and eaten as mashed vegetables (Xanthosoma spp., given as a stomachic, for gastritis and stomach ulcers), or grated and sun dried and eaten with milk (Maranta arundinacea, given to kids as a digestive).[28] Fruits are used as simple remedies to improve digestion (Carica papaya, Mangifera indica, Citrus sinensis for example), to prevent colic and “stomach congestion” in kids.[29]

Various reasons have been proposed to explain the prevalence of use for gastrointestinal disorders. Balick and Cox put forward reasons of saliency and of danger perception: the gastrointestinal ailments were, according to the authors, easily identifiable, contrariwise to, for example, tumors; and in traditional societies or in ancient periods of our history the main risks for people were infective diarrheas, gastrointestinal parasitic diseases, alimentary intoxications, etc., much more than cardiovascular diseases, CNS disturbances or neoplastic diseases.[30] Traditional pharmacopoeias are also probably quite conservative and tend to favor gastrointestinal remedies even when the prevalence of diseases has changed.[31]

This prevalence would also be partly explained by the ancient, pre-cultural link between plants and humans. Herbal remedies were (and still are) mainly used per os, thus human beings have “explored” the secondary metabolites sphere mainly through the gastrointestinal tract, which then has a pivotal role as a first diaphragm between the external world and its dangers (xenobiotics) and the internal physiology, and had to “measure itself” against plant constituents: those constituents that represented at the same time a health risk and a pharmacological opportunity.

If the thesis that man had to live in a world rich in alimentary toxins, and at times had to adapt and “learn” to use the same toxins to his own advantage; it is possible that he developed systems of detection, management and defense and that these systems are mainly present in the same gastrointestinal tract.[32]

In fact, according to Johns, the effects of wild foods on the gastrointestinal tract has probably been one of the primary factors in the evolution of medicine and of the use of medicinal foods. Because taste has always been the messenger of many chemical messages, it has been interpreted in many contextualized manners, so that even bitter and pungent tastes could be accepted or even desired.[33]

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Notes
[1] Balick, M., Cox, L. (1996) Plants, people, and culture: the science of ethnobotany. New York: Scientific American Library
[2] Etkin NL, e Ross PJ (1994) “Pharmacological implications of “wild” plants in Hausa diet”. In NL Etkin (ed.) Eating on the wild side: The pharmacological, ecological, and social implications of using noncultigens. Arizona University Press
[3] Kiringe, John Warui (2006) “A Survey of Traditional Health Remedies Used by the Maasai of Southern Kaijiado District, Kenya”. Ethnobotany Research & Applications; 4:061-073
[4] Bussmann, R. W. (2006) “Ethnobotany of the Samburu of Mt. Nyiru, South Turkana, Kenya”. Journal of ethnobiology and ethnomedicine, 2, 35. doi: 10.1186/1746-4269-2-35.
[5] Teklehaymanot, T., & Giday, M. (2007) “Ethnobotanical study of medicinal plants used by people in Zegie Peninsula, Northwestern Ethiopia.” Journal of ethnobiology and ethnomedicine, 3, 12. doi: 10.1186/1746-4269-3-12.
[6] Tessema T, Giday M, Aklilu N (2001) “Stacking and information on the medicinal plants of Ethiopia”. In National Biodiversity strategy and action plan project Medicinal plant Team, Addis Ababa: IBDA; 2001.
[7] Everest, A and Ozturk, E (2005) “Focusing on the ethnobotanical uses of plants in Mersin and Adana provinces (Turkey)”. Journal of Ethnobiology and Ethnomedicine, 1:6
[8] Akerreta, S, Cavero, RY, Calvo, MI (2007) “First comprehensive contribution to medical ethnobotany of Western Pyrenees” Journal of Ethnobiology and Ethnomedicine; 3:26
[9] Bussmann, RW, Sharon D, Lopez A (2007) “Blending traditional and western medicine: medicinal plant use among patients at the Clinica Anticona in El Porvenir, Peru”. Ethnobotany Research and Applications; 5:185-199
[10] Curtin, L.S.M. (1997) Healing herbs of the upper rio grande: Traditional Medicine of the South West. Revised and edited by Michael Moore. Western Edge Press
[11] Almeida, C. D. F. C. B. R., Amorim, E. L. C. de, Albuquerque, U. P. de, & Maia, M. B. S. (2006). “Medicinal plants popularly used in the Xingó region – a semi-arid location in Northeastern Brazil”. Journal of ethnobiology and ethnomedicine, 2, 15. doi: 10.1186/1746-4269-2-15; Albuquerque, U. P. de. (2006) “Re-examining hypotheses concerning the use and knowledge of medicinal plants: a study in the Caatinga vegetation of NE Brazil”. Journal of ethnobiology and ethnomedicine, 2, 30. doi: 10.1186/1746-4269-2-30.
[12] Estrada, E., Villarreal, J. a, Cantú, C., Cabral, I., Scott, L., & Yen, C. (2007) “Ethnobotany in the Cumbres de Monterrey National Park, Nuevo León, México”. Journal of ethnobiology and ethnomedicine, 3, 8. doi: 10.1186/1746-4269-3-8
[13] Volpato, G., Godínez, D., Beyra, A., & Barreto, A. (2009) “Uses of medicinal plants by Haitian immigrants and their descendants in the Province of Camagüey, Cuba”. Journal of ethnobiology and ethnomedicine, 5, 16. doi: 10.1186/1746-4269-5-16.
[14] Luziatelli, G., Sørensen, M., Theilade, I., & Mølgaard, P. (2010) “Asháninka medicinal plants: a case study from the native community of Bajo Quimiriki, Junín, Peru”. Journal of ethnobiology and ethnomedicine, 6(1), 21. doi: 10.1186/1746-4269-6-21.
[15] Bussmann, R. W., Glenn, A., Meyer, K., Kuhlman, A., & Townesmith, A. (2010) “Herbal mixtures in traditional medicine in Northern Peru”. Journal of ethnobiology and ethnomedicine, 6, 10. doi: 10.1186/1746-4269-6-10.
[16] Bussmann, R. W., & Sharon, D. (2006) “Traditional medicinal plant use in Loja province, Southern Ecuador”. Journal of ethnobiology and ethnomedicine, 2, 44. doi: 10.1186/1746-4269-2-44; Alexiades MN, Lacaze D. (1996) “FENAMADs program in traditional medicine: an integrated approach to health care in the Peru- vian Amazon”. In Balick MJ, Elisabetsky E, Laird SA (eds.) Medicinal Resources of the Tropical Forest Columbia University Press, New York:341-365; Arrázola S, Atahuachi M, Saravia E, Lopez A. (2002) “Diversidad floristica medicinal y potencial etnofarmacólogico de las plantas de los valles secos de Cochabamba Bolivia”. Revista Boliviana de Ecología y Conservación Ambiental; 12:53-85; Bastien J (1987) Healers of the Andes: Kallawaya Herbalists and Their Medicinal Plants University of Utah Press, Salt Lake City; Bastien J (1992) Drum and Stethoscope: Integrating Ethnomedicine and Biomedicine in Bolivia University of Utah Press, Salt Lake City
[17] Kala, C. P. (2005) “Ethnomedicinal botany of the Apatani in the Eastern Himalayan region of India”. Journal of ethnobiology and ethnomedicine, 1, 11. doi: 10.1186/1746-4269-1-11.
[18] Pradhan, B. K., & Badola, H. K. (2008) “Ethnomedicinal plant use by Lepcha tribe of Dzongu valley, bordering Khangchendzonga Biosphere Reserve, in North Sikkim, India”. Journal of ethnobiology and ethnomedicine, 4, 22. doi: 10.1186/1746-4269-4-22.
[19] Sajem, A. L., & Gosai, K. (2006) “Traditional use of medicinal plants by the Jaintia tribes in North Cachar Hills district of Assam, northeast India”. Journal of ethnobiology and ethnomedicine, 2, 33. doi: 10.1186/1746-4269-2-33.
[20] Ragupathy, S., & Newmaster, S. G. (2009) “Valorizing the “Irulas” traditional knowledge of medicinal plants in the Kodiakkarai Reserve Forest, India”. Journal of ethnobiology and ethnomedicine, 5, 10. doi: 10.1186/1746-4269-5-10; Ragupathy, S., Steven, N. G., Maruthakkutti, M., Velusamy, B., & Ul-Huda, M. M. (2008) “Consensus of the “Malasars” traditional aboriginal knowledge of medicinal plants in the Velliangiri holy hills, India”. Journal of ethnobiology and ethnomedicine, 4, 8. doi: 10.1186/1746-4269-4-8.
[21] Hayat, M. Q., Khan, M. A., Ahmad, M., Shaheen, N., Yasmin, G., & Akhter, S. (2008) “Ethnotaxonomical approach in the identification of useful medicinal flora of tehsil Pindigheb (District Attock) Pakistan”. Ethnobotany Research & Applications, 6, 035-062
[22] Kunwar, R. M., Nepal, B. K., Kshhetri, H. B., Rai, S. K., & Bussmann, R. W. (2006) “Ethnomedicine in Himalaya: a case study from Dolpa, Humla, Jumla and Mustang districts of Nepal”. Journal of ethnobiology and ethnomedicine, 2, 27. doi: 10.1186/1746-4269-2-27.
[23] Collins, S. W. M., Martins, X., Mitchell, A., Teshome, A., & Arnason, J. T. (2007) “Fataluku medicinal ethnobotany and the East Timorese military resistance”. Journal of ethnobiology and ethnomedicine, 3, 5. doi: 10.1186/1746-4269-3-5.
[24] Long, C., Li, S., Long, B., Shi, Y., & Liu, B. (2009) “Medicinal plants used by the Yi ethnic group: a case study in central Yunnan”. Journal of ethnobiology and ethnomedicine, 5, 13. doi: 10.1186/1746-4269-5-13.
[25] Ruffo, C.K., Birnie, A., Tengnas, B. (2002) Edible wild plants of Tanzania. RELMA, Kenya; Williamson, G.; Yongping Bao; Chen, K.; Bucheli, P. (2004) “Effects of Phytochemicals in Chinese Functional Ingredients on Gut Health” In Choon Nam Ong and B. Halliwell (eds.) Herbal and Traditional Medicine Molecular Aspects of Health. Lester Packer
[26] Rivera-Nunez D., Obion-de-Castro C (1993) “Plant food as medicine in Medittìerranean Spain” In Actes du 2e Colloque Européen d’Ethnophannacologie et de la 1 le Conference internationale d’Ethnomédecine, Heidelberg, 24-27 mars 1993;
[27] Ladio AH (2006) “Gathering of wild plant foods with medicinal use in a Mapuche community of Northwest Patagonia” in Pieroni A, & Price LL Eating and Healing: Traditional Food As Medicine, The Haworth Press.
[28] Volpato G, Godìnez D “Medicinal foods in Cuba: Promoting health in the household”, in Pieroni and Price 2006 Op. Cit.
[29] Volpato, Godinez 2006 Op. Cit.
[30] Balick and Cox 1996 Op. Cit.
[31] Rivera-Nunez, Obon-de-castro, 1993 Op. Cit.
[32] Johns 1990, Op. Cit.
[33] Johns, T (1994) “Ambivalence to the palatability factor in wild food plants”. In NL Etkin (ed.) Eating on the wild side: The pharmacological, ecological, and social implications of using noncultigens. Arizona University Press

Digestive Functional Foods 1

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Necessitato a fare un po’ di lavoro di background per un articolo prossimo venturo su cibi funzionali con attività digestiva, pubblico qui parte del materiale raccolto, in alcuni pezzi. La versione in italiano? Speriamo in tempi brevi :-).

Inizio con un volo d’uccello sui termini del discorso: i cibi funzionali.

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Functional foods and nutraceuticals
During the 1980s the Japanese Health Authorities identified special foods with extra-nutritional values as an important object of discussion, and in 1984 the Japanese Ministry of Education Science and Culture used the term “physiologically functional foods” or “functional foods” for the first time. In 1991, a formal category for alimentary items that had extra-nutritional activities was introduced: that of the “Foods for Specified Health Uses” (FOSHU), defined as: “foods with documented evidence of aiding specific physiological functions beyond whatever conventional nutrient exist in the food”.[1]

Around the time when the FOSHU system was under discussion in Japan, the term “nutraceutical” was introduced in the U.S., which included “any substance that may be considered a food or a part of a food and demonstrates to have a physiological benefit, or to provide medical or health benefits, including the prevention and treatment of protection against chronic  disease”,[2]  and which, although “produced from foods”, is  “sold in pills, powders, (potions) and other medical forms not generally associated with food[3] “.

Functional foods have been defined in many ways, but recent definitions describe them as: “products that have physiologic benefits beyond nutritive qualities, and are offered in the form of foodstuffs, including those that have been fortified or have ingredients reduced or removed”;[4] or as items that are: “similar in appearance to conventional foods, (…) consumed as part of a usual diet, and have demonstrated physiological benefits and / or reduce the risk of chronic disease beyond basic nutritional functions.”

Since then, many other terms have been used to describe the complex and multifaceted gray area of food-and-medicine: pharmafood, phytoceutical, phytonutrient, medicinal food, designer food, etc. However, functional food and nutraceutical remain the two most commonly encountered terms, and are often used interchangeably in the generalist news media. In fact one is the subset of the other, since by definition nutraceuticals are those functional foods that are transformed and offered in a pill or otherwise concentrated form, different from normal, common foodstuff.

Traditional functional foods
Although these two term have perhaps been around for 20 years, foods which are “good for your health” (Traditional or Folk Functional Foods) have been around for much longer. Medical historians have stressed the fact that the distinction between medicines and food was blurred and at times non-existent in ancient and preliterate societies, and that it was the advent of modern medicine which artificially constructed a defined hiatus between diet and therapy, food and medicine.[5]  Quoting Albala: ”most complex societies codify their foods investing in them a significance beyond satisfying hunger. In the West, at least since the ancient Greeks, this significance has been medical.”[6] Galen, following the Hippocratic spirit of preventive medicine of the Regimen, codified the age old belief that a good doctor should also be a good cook.[7] Boorde and Cogan could, in the middle of the 16th century, still hotly debate in favor of this belief, the first saying that: ”A good coke is halfe a physycyon. For the chefe physycke (the counseyll of a physycyon excepte) doth come from the kytchyn”,[8] the second referring to: ”cunning Cookes, or to the learned Physitian, who is or ought to be a perfect Cooke in many points”.[9]

The same can be said of ancient Chinese Medicine,[10] where the term Wei meant “taste” but carried all the potency of astronomical, political, ritual and medical theory association with the five agents (wood, fire, earth, metal, water), and the five flavors were to extend a framework of knowledge that had existed since/been constructed in early imperial times.[11]

Examples of FF are also available in contemporary times, both in pre-industrial societies and, although vanishing, in industrialized societies.[12] In the introduction to the collection of essays dedicated to medicinal foods, Pieroni and Price present some memories that could well be our own: the chestnut-meal polenta cooked in red wine as a cough remedy recalled by Pieroni[13] and the chicken soup used for colds cited by Price;[14] and  since the 1970s ethnobotanical literature has made it clear that the blurring of  boundaries between food and medicine is present in contemporary traditional societies, and that, as many studies have shown, non-cultivated wild gathered plants play an important role in the health benefits attributed to the Mediterranean diets.[15]

Ethnobotanists have pointed out that it would be more appropriate to talk about a continuum linking the opposite poles of medicines and foods in folk knowledge,[16] and Pieroni and Quave have come up with an often-cited mapping of this continuum, describing three other categories beyond those of food and medicine:[17]

  • Functional Foods: consumed as foods but acting beyond their basic nutritional function as food by providing protection or reducing the risk of chronic disease.
  • Folk Functional Foods: weedy species or foods eaten because they are healthy but with a general rather than unique and specific health action. Besides their main nutritional or denjoyment purposes they have other effects on body functions.[18]
  • Food medicines/Medicinal foods are ingested in a food context but are assigned specific medicinal properties; or they are consumed in order to obtain a specific medicinal action.

Some other plants are used multifunctionally, simultaneously used as food and medicines without any relationship between the two uses.[19]

It is, therefore, clear that, when talking about traditional functional foods, we need to go beyond the marketing hype, which often puts together (without blending them) the themes of the “natural” hence “safe” traditional food, with the scientific authority of biomedicine bestowed on the term functional.
Any research on this subject needs to be done across fields of research, combining historical, ethnobotanical and biomedical knowledge and insights, to avoid the fallacy of seeing FF as a mere container/vessel for phytochemicals, discounting the cultural construction of the objects of research.  Not only would this be methodologically incorrect, it would also  lead to an important mistake: namely, ascribing functional potential to a material simply due to the presence of an identified compound with known experimental activity; or, conversely, of choosing one compound as the sole element responsible for  the “medicinal” dimension of a food.

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Note
[1] Etkin, N.L. Edible medicines: An ethnopharmacology of food. The University of Arizona Press. 2006. p. 207; Dai Y, Luo X., “Functional food in China”. Nutr Rev. 1996 Nov; 54 (11 Pt 2):S21-3.
[2] DeFelice, S.L. “Preface”. In S.L. DeFelice (ed.) Nutraceuticals: Developing, Claiming, and Marketing Medical Foods. Pp. V-viii. Marcel Dekker, New York
[3] Recommendations for Defining and Dealing with Functional Foods, Report of the Bureau of Nutritional Sciences Committee on Fuctional Foods, Health Canada, 1996
[4] Etkin, N.L. 2006 Op. Cit. Pp. 207-208
[5] Etkin, N.L. Chapter 2: “Food in the history of biomedicine”. In N.L. Etkin 2006 Op. Cit. p. 207
[6] Albala, Kenneth “Dietary regime in the Renaissance”, in Malloch Room Newsletter, Jan. 1994,7: 1–2.
[7] Grant, M Galen on food and diet, London, Routledge, 2000, p. 62.; Powell, O Galen: On the properties of foodstuffs, Cambridge University Press, 2003
[8] Boorde, A The first boke of the introduction of knowledge and a compendyous regyment, ed. F J Furnivall, Early English Text Society, Extra Series, 10 London, Early English Text Society, 1870, p. 277; from the edition of 1547. As quoted in Andrew Wear, Knowledge and practice in English medicine, 1500–1680, Cambridge University Press, 2000, p. 170
[9] Cogan, T The haven of health: chiefely gathered for the comfort of students, and consequently of all those that have a care of their health, amplified upon five words of Hippocrates, written Epid. 6, Labor, cibus, potio, somnus, Venus .. . Hereunto is added a preservation from the pestilence, with a short censure of the late sicknes at Oxford of Thomas Cogan, London, printed by Henrie Midleton, for William Norton, 1584, p. 98, as cited in Wear, op. cit., note 2 above, p. 170.
[10] Unschuld, Paul U. Medicine in China: A History of Ideas. University of California Press, 1985; Unschuld, Paul U. Medicine in China: a history of pharmaceutics. Berkeley: University of California Press; Lo, Vivienne, and Penelope Barrett. “Cooking up fine remedies: on the culinary aesthetic in a sixteenth-century Chinese Materia Medica.” Medical History 49, no. 4 (2005): 395-422..
[11] Graham, A Disputers of the Tao, La Salle, ILL, Open Court, 1989, pp. 314–70
[12] Rivera-Nunez D., Obion-de-Castro C “Plant food as medicine in Meditterranean Spain” Actes du 2e Colloque  Européen  d’Ethnophannacologie  et  de  la 1 le Conf6rence  internationale  d’Ethnomédecine, Heidelberg, 24-27 mars 1993; Sandhu DS, Heinrich M. “The use of health foods, spices and other botanicals in the Sikh community in London”. Phytother Res. Jul 2005;19(7):633-42
[13] Pieroni A, & Price LL “Introduction” in Eating and Healing: Traditional Food As Medicine, The Haworth Press, 2006
[14] Pieroni and Price 2006 Op. Cit.
[15] Pieroni A, Nebel S, Quave C, Munz H, Heinrich M. “Ethnopharmacology of liakra: traditional weedy vegetables of the Arbereshe of the Vulture area in southern Italy”. Journal of Ethnopharmacology 2002, 81:165-185.; Bonet, M.A. and J. Vallés. “Use of non-crop food vascular plants in Montseny biosphere reserve (Catalonia, Iberian Peninsula)”. International Journal of Food Science and Nutrition; 2002. 53:225– 248; Rivera, D., C. Obon, C. Inocencio, M. Heinrich, A. Verde, J. Fajardo, and R. llorach. “The ethnobotanical study of local mediterranean food Plants as Medicinal Resources in Southern Spain”. Journal of Physiology and Pharmacology. 2005. 56 (S):97–114; Tardío, J., H. Pascual, and R. Morales. “Wild food plants traditionally used in the province of Madrid, Central Spain”. Economic Botany. 2005;  59:122– 136; Tardío, J., M. Pardo de Santayana, and R. Morales. “Ethnobotanical review of edible plants in Spain” Botanical Journal of the Linnean Society, 2006, 152, 27–71; The Local Food-Nutraceuticals Consortium “Understanding local Mediterranean diets: A multidisciplinary pharmacological and ethnobotanical approach”. Pharmacological Research. 2005; 52 (2005) 353–366
[16] Etkin, N.L. and P.J. Ross “Food as medicine and medicine as food: An adaptive framework for the interpretation of plant utilisation among the Hausa of northern Nigeria”. Social Science and Medicine. 1982; 16: 1559-1573; Johns, T. With bitter herbs they shall eat it. Tucson: University of Arizona Press. 1990; Grivetti, L.E. and B.M. Ogle “Value of traditional foods in meeting macroand micronutrients needs: The wild plant connection”. Nutrition Research Review. 2000; 13: 31-46; Ogle, B.M. and L.E. Grivetti “Legacy of the chameleon: Edible wild plants in the kingdom of Swaziland, southern Africa. A cultural, ecological, nutritional study. Part I–Introduction, objectives, methods, Swazi culture, landscape and diet”. Ecology of Food and Nutrition. 1985a; 16: 193-208; Ogle, B.M. and L.E. Grivetti “Legacy of the chameleon: Edible wild plants in the kingdom of Swaziland, southern Africa. A cultural, ecological, nutritional study. Part II–Demographics, species, availability and dietary use, analysis by ecological zone”. Ecology of Food and Nutrition. 1985b; 17: 1-30; Ogle, B.M. and L.E. Grivetti “Legacy of the chameleon: Edible wild plants in the kingdom of Swaziland, southern Africa. A cultural, ecological, nutritional study. Part III–Cultural and ecological analysis”. Ecology of Food and Nutrition. 1985c; 17: 31-40; Ogle, B.M. and L.E. Grivetti “Legacy of the chameleon: Edible wild plants in the kingdom of Swaziland, southern Africa. A cultural, ecological, nutritional study. Part IV–Nutritional values and conclusions”. Ecology of Food and Nutrition. 1985d; 17: 41-64
[17] Pieroni, A. e Quave, C. “Functional foods or food medicines? On the consumption of wild plants among Albanians and Southern Italians in Lucania” in A., Pieroni e L., Leimar Price (eds.) Eating and Healing, Haworth Press,  2006, p. 110
[18] Preuss, A. “Characterisation of functional food”. Deutsche Lebensmittel-Rundschau, 1999. 95:468-472
[19] Ceuterick, Melissa, Ina Vandebroek, Bren Torry, Andrea Pieroni “The Use of Home Remedies for Health Care and Well-Being by Spanish-Speaking Latino Immigrants in London: A Reflection on Acculturation” in Andrea Pieroni & Ina Vandebroek (eds.) Traveling cultures and plants: The ethnobiology and ethnopharmacy of human migrations. Bergham Books, New York, 2007