In the search for cures for his ailments, man discovered many healing and toxic properties of plants. Some were found to cure certain diseases while others were found to exert dramatic effects on the body. Consequently, most natural products used today as medicines are derived from plants.peer-reviewe

Forte, John Stephen

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2          thechronic✱ill     No 4 Summer 2000How Safe areHerbal Products?John Stephen Forte BPharm (Hons), MSc (Lond.)In the search for cures for hisailments, man discoveredmany healing and toxicproperties of plants. Somewere found to cure certaindiseases while others werefound to exert dramaticeffects on the body1.Consequently, most naturalproducts used today asmedicines are derived fromplants.In recent decades, the growingawareness of the possible toxicity ofmodern medicinal products hascontributed to a rise in interest, on thepart of the general public, inalternative medicinal therapies. Thisphenomenon is also evident in Malta,as demonstrated by the increasingavailability of herbal remedies frompharmacies. Unfortunately, there existsa remarkably common belief amongsuppliers and users of herbal remediesthat the products are harmless becausethey are derived from a natural source.However there is a substantial body ofevidence to rebut this view2.The pharmacological activity andtoxicity of conventional medicines canbe attributed to a drug substance orcombination of substances, or to themetabolic products that are generatedin the body. Herbal medicines exerttheir activity and effects in very muchthe same way but little is known aboutthe kinetic behaviour of the bioactivecompounds in the plants. Howevercomplex the composition of a herbalmedicine may be, the active principlesare chemical entities that possesspharmacodynamic properties and mustobey the same pharmacokinetic rules asconventional medicines2.Toxicity of Herbal IngredientsPlants have evolved defencemechanisms against predation byanimals and pests. These includechemicals that make the plantsunpalatable or that poison or kill thepredators, and may therefore be thecause of toxicity in humans. Thus thecoexistence of beneficial and adverseeffects is as much a reality for plantproducts as it is for conventionalmedicines3.The toxic effects of phytochemicalsubstances are varied when consumedby mammals. The main target organsappear to be the liver and the kidneys,probably because of their role in themetabolism and elimination ofxenobiotics. Plant substances may alsopossess carcinogenic, teratogenic,mutagenic, or genotoxic properties thatincrease their toxic effects.The safety of herbal remedies is ofparticular importance since themajority of these products are self-prescribed and are used to treat minorand often chronic conditions. The long-term traditional use of a plant, even formany hundreds of years, does notnecessarily establish its safety. Themore subtle and chronic forms oftoxicity, such as carcinogenicity,mutagenicity and hepatotoxicity, maywell have been overlooked by previousgenerations but are of concernnowadays when assessing productsafety9.Herbal products are often the targetof criticism because of their uniquestatus when compared with othermedicines. Conventional medicinalproducts must undergo extensivepreclinical testing in laboratory animalsfor the evaluation of organ toxicity anddeath, tests for mutagenic andcarcinogenic activity, and reproductivetoxicity before they are administered tohuman beings in clinical trials.However, it is ironic to note that muchof the knowledge on the toxicity ofherbal products that has beenaccumulated over the years stems fromobserved poisonous and lethal effectsin man3.The difficulty with which the herbalactive principles may sometimes beisolated or identified means that thesource of toxicity may at times beunknown. Furthermore, errors in theidentification of the species of plant orplant parts and difficulty in thestandardisation of the content of activeprinciples may lead to toxicityespecially in self-medication.Adverse ReactionsThe inherent toxic properties ofherbal ingredients may be the cause ofadverse effects arising from theingestion or topical application ofherbal products. This is even more sowhen the products do not containadulterants or substituted ingredientsthat however may in themselves be thecause of adverse reactions8. Someherbal ingredients that may potentiallygive rise to adverse events as reportedin the literature are summarisedin Table I. Herbal products have traditionallybeen used to treat both adults andchildren. Although herbal remedies mayoffer a milder alternative to someconventional medicines, they must beused with caution in children andmedical advice should be sought if indoubt. Babies may be at a higher riskof toxic effects because they may begiven higher doses than adults perkilogram of body weight, they lackcertain drug metabolising anddetoxifying enzymes, and they mayreceive herbal ingredients from themother during lactation10. Chamomile, apopular remedy for teething pains inbabies, is known to contain allergenicsesquiterpene lactones and should beused with caution. The administrationof herbal teas to children is generallyunwise unless used according toKey words: herbal, toxicity, adverse reactions, interactionsNo 4 Summer 2000    thechronic✱ill         3Herb Adverse EffectGinkgo Gastric upset, headacheGinseng2 Mastalgia, vaginal bleeding, insomniaGolden Seal2 Gastric upsetGravel Root1 Genotoxic, carcinogenic, hepatotoxicGround Ivy2 Irritant to GIT, kidneysGuaiacum Allergenic, dermatitisHops2 Allergenic, dermatitisHorehound, White2 Dermatitis, irritant (plant juice)Horse-chestnut NephrotoxicHorseradish2 Allergenic, irritantHydrangea Dermatitis, irritant to GITHydrocotyle2 Phototoxic, dermatitisIspaghula Oesophageal obstruction, flatulence(if swallowed dry)Jamaica Dogwood2 Irritant, numbness, tremors (high doses)Juniper2 Irritant, abortifacientLady’s Slipper Allergenic, dermatitis, hallucinationsLiferoot1,2 Genotoxic, carcinogenic, hepatotoxicLiquorice2 Hyperaldosteronism (excessive ingestion)Lobelia2 Nausea, vomiting, diarrhoeaMaté2 Sleeplessness, anxiety, tremorMistletoe2 Hepatitis, hypotension, poisonousMotherwort2 Phototoxic dermatitisNettle2 IrritantParsley Irritant, hepatitis, phototoxic, abortifacient(excessive ingestion)Pennyroyal2 Irritant, nephrotoxic, hepatotoxicPilewort1 IrritantPlantain2 Allergenic, dermatitis, irritantPleurisy Root2 Dermatitis, irritant, cardiac activityPokeroot2 Mitogenic, toxic, nausea, vomiting, crampPrickly Ash, Southern2 Toxic to animalsPulsatilla1,2 Allergenic, irritantQueen’s Delight1,2 Irritant to GITRed Clover2 OestrogenicRhubarb2 Purgative, irritant to GITRosemary ConvulsionsSage Toxic, convulsantSassafras1,2 Carcinogenic, genotoxicScullcap2 HepatotoxicitySenega Irritant to GITSenna2 Purgative, irritant to GITShepherd’s Purse2 IrritantSkunk Cabbage2 Itch, inflammationSquill2 Irritant, cardioactiveSt John’s Wort2 PhototoxicTansy1,2 Severe gastritis, convulsionsThyme Irritant to GITWild Carrot2 Phototoxic, dermatitisYarrow2 Allergenic, dermatitisYellow Dock2 Purgative, irritant to GITTable I: Potential Adverse Effects of Herbal Ingredients (adapted from Newall et al., 1996)Herb Adverse EffectAgnus Castus2 Allergic reactionsAlfalfa Systemic lupus erythematosus syndromeAloes2 Purgative, irritant to GITAngelica Phototoxic dermatitisAniseed Contact dermatitisApricot1,2 Cyanide poisoning (seed)Arnica1 Dermatitis, irritant to GITArtichoke Allergenic, dermatitisAsafoetida2 Dermatitis, irritantBayberry Carcinogenic to ratsBlue Flag2 Nausea, vomiting, irritant to GIT and eyes(fresh root)Bogbean2 Purgative, vomiting (in large doses)Boldo2 Toxicity, irritantBoneset2 Dermatitis, cytotoxicBorage1,2 Genotoxic, carcinogenic, hepatotoxicBroom2 Cardiac depressantBuchu2 Irritant to GIT, kidneyCalamus1 Carcinogenic, nephrotoxic, convulsionsCapsicum IrritantCascara2 Purgative, irritant to GITCassia Allergenic, irritantCelery Phototoxic, dermatitisCereus Irritant to GIT (fresh juice)Chamomile2 Allergic reactionsChaparral2 Dermatitis, hepatotoxicCinnamon Allergenic, irritantClove IrritantCohosh, Black2 Nausea, vomiting (high doses)Cohosh, Blue2 Irritant to GIT (seeds)Cola2 Sleeplessness, anxiety, tremorColtsfoot1,2 Genotoxic, carcinogenic, hepatotoxicComfrey1,2 Genotoxic, carcinogenic, hepatotoxicCorn Silk2 Allergenic, dermatitisCowslip AllergenicDamiana2 Convulsions (one report with high dose)Dandelion Allergenic, dermatitisEchinacea Allergenic, irritantElecampane Allergenic, irritantEucalyptus2 Nausea, vomitingEvening Primrose Oil Mild indigestion, increased risk of epilepsy(in schizophrenics on phenothiazines)Eyebright Mental confusion, raised intraocular pressure(tincture)Feverfew2 Allergenic, dermatitisFrangula2 Purgative, irritant to GITFucus2 HyperthyroidismGarlic Irritant to GIT, dermatitisprofessional advice9.The chemistry and pharmacology ofa number of herbs are poorlydocumented and their use in pregnancyshould be avoided. In addition to theherbs indicated in Table I, other herbsthat should be used with caution inpregnancy include Avens, Burdock,Calendula, Devil’s Claw, Euphorbia,Fenugreek, Gentian, Hawthorn, BlackHorehound, Meadowsweet, Myrrh,Passionflower, Poplar, Northern PricklyAsh, Raspberry, Uva-Ursi, Vervian, andWillow. Some of the herbs are reputedto be abortifacient or to affect themenstrual cycle although no recentclinical or experimental data exists.Others are oxytocic, demonstrateuterine activity or are uterinestimulants, demonstrate hormonalactivity, or are inherently toxic9.As is the case with conventionalmedicines, the serious and lethaladverse effects of some herbalingredients may arise as a result ofmisuse or abuse of preparations or dueto a lack of knowledge regarding thesubstances. The abuse of herbalproducts as alternatives to street drugsis an area of concern. This is evidencedby the use of Ephedra as an alternativeto 4-methyl-2-dimethoxyamphetamine(MDMA, ‘Ecstasy’) because of itseuphoric effect6. In fact, the UnitedKingdom (UK), United States ofAmerica (USA) and Canada have issuedwarnings against the use or supply ofEphedra-containing herbal foodsupplements4,5. The Food and DrugAdministration of the USA has alsoordered the removal from the market ofpreparations containing Ephedra, aloneor in combination with St John’s Wort,that were promoted as herbalalternatives to fenfluramine andGIT - Gastrointestinal tract        1 Not recommended for internal use         2 Herbal ingredients best avoided or used with caution during pregnancy.4          thechronic✱ill     No 4 Summer 2000Drug Herb InteractionAlprazolam Kava Excessive sedation may result with concomitantuse.Corticosteroids, Echinacea, Immunostimulating effects of the herbsCyclosporin Astragalus, may offset immunosuppressive effects ofLiquorice, the drugs.Alfalfa SproutsDigoxin Additive effects possible with herbs containingcardiac glycosides.Hawthorn Hawthorn purportedly potentiates digoxin.Liquorice Liquorice may cause hypokalaemia, hencepredisposing the patient to toxic effects ofdigoxin.Foxglove Plantain may be adulterated with Foxglove,hence elevating blood levels of digoxin.Siberian Ginseng, The herbs may interfere with digoxinKyushin assays.Uzara root Uzara root may exert additive digoxin-typecardiac effects.Diuretics Sodium-sparing The herbs may offset antihypertensive(e.g. hydrochloro- herbal aquaretics effects of the drugs.thiazide, furosemide) (e.g. Dandelion,Uva-Ursi)Gossypol Gossypol may exacerbate hypokalaemiasecondary to the drugs.Hypoglycaemics Karela Karela has been shown to decrease dosage(e.g. sulphonylureas) requirements for chlorpropamide.Iron Tannin-containing The herbs may interact with iron, henceherbs (e.g. Chamomile, inhibiting iron absorption.Feverfew, St John’s Wort)Levothyroxine Horseradish, Kelp The herbs may suppress thyroid function,complicating thyroid function.Nonsteroidal Herbs irritant to GIT Additive GIT irritation may be encounteredanti-inflammatory (e.g. Gossypol, with concomitant use.drugs Uva-Ursi)Phenelzine Ginseng, Yohimbine, Concomitant use with the herbs may result(and other MAO Ephedra in insomnia, headache and tremulousness.inhibitors)St John’s Wort, The herbs may have MAO inhibitor activityLiquorice and should not be used concomitantly withknown MAO inhibitors.Phenobarbitone Thujone-containing The herbs may lower seizure threshold,herbs (e.g. hence increasing anticonvulsant dosageWormwood, Sage) requirements.Gamolenic The herbs lower seizure thresholds andacid-containing herbs may increase anticonvulsant dosage(e.g. Evening requirements.Primrose Oil, Borage)Phenytoin Same as for phenobarbitone.Shankhapulshpi Shankhapulshpi may shorten the half-life anddiminish effectiveness of phenytoin.Spironolactone Liquorice Liquorice may offset the effects ofspironolactone.Warfarin Garlic, Ginger, The herbs may augment the anticoagulantGinkgo, Feverfew effect of warfarin.Ginseng Ginseng may decrease the effectiveness ofwarfarin.Table 2: Summary of Drug-Herb Interactions of CommonlyUsed Drugs  (adapted from Miller, 1998)GIT - Gastrointestinal tract      MAO - Monoamine oxidasemedical practitioner or a pharmacist12.The mechanism of a drug-herbinteraction may be difficult to identifywhen there is insufficient knowledge ofthe pharmacological activity of theherbal product. However, it is possibleto predict potential interactions on thebasis of known herbal constituents andtheir reported pharmacological actionand documented side effects9. Examplesof known or potential drug-herbinteractions are summarised in Table II.It should be emphasised that manydrug interactions are harmless andmany of those that are potentiallyharmful occur only in a smallproportion of patients and may thenvary in severity from patient topatient6.ConclusionThe ultimate benefit that theconsumer will derive from the use ofherbals depends on the correct use ofproducts of acceptable quality. This maybe achieved if there is adequate controlof the manufacture of herbal productsto ensure that the correct standardisedbotanical ingredients are used and tominimise the problem of toxicityassociated with adulteration,substitution, misidentification andcontamination of products13.Different standards of regulatorycontrol of herbal products exist invarious countries. When preparationsare sold without appropriate orcomplete labelling and productinformation, or when they are freelyavailable as unlicensed dietarysupplements, it becomes increasinglydifficult to enforce quality and safetyrequirements or to ensure that allincriminated products are withdrawnafter a drug alert8.The examples of herbal toxicity thatwere presented in this brief discussionare not intended to undermine the roleof herbal medicines in pharmacotherapybut, rather, to demonstrate that naturalproducts are composed of chemicalsubstances that possess properties thatcan be therapeutic as well as toxic.Herbal medicines should be allowed tofind a niche in pharmacotherapy, notsolely as an alternative form of therapybut also to complement conventionaldrugs. ✱fentermine7. Furthermore, warningsagainst abuse of products containingKhat and Yohimbe as alternatives tostreet drugs were issued in the UK4.Drug-Herb InteractionsA recent circular from the MalteseHealth Division highlighted theinteractions between herbal remediescontaining Hypericum perforatum (StJohn’s Wort) and conventionalmedicines11. However, very few drug-herb interactions have been reported inthe medical literature when comparedwith reports of interactions betweenconventional drugs. The low incidenceof reporting of interactions with herbs,in itself, neither confirms their safetyin use nor suggests that the incidenceis indeed low. Most of the interactionsare not recognised by patients whoself-medicate and are not reported to aNo 4 Summer 2000    thechronic✱ill         5References1. Samuelsson G. Drugs of Natural Origin.Stockholm: Swedish Pharmaceutical Press;1992.2. De Smet P.A.G.M. Drugs used in non-orthodoxmedicine. In: Dukes M.N.G., editor. Meyler’sSide-Effects of Drugs. Amsterdam: ElsevierScience Publishers; 1992.3. Sheehan D.M. Herbal medicines,phytoestrogens and toxicity: Risk:benefitconsiderations. Proceedings of the Society forExperimental Biology and Medicine 1998:217:379-385.4. WHO. Warning of herbal products sold asalternatives to abuse drugs. WHO DrugInformation 1997: 11:252.5. WHO. Ephedrine in food supplements. WHOPharmaceuticals Newsletter 1997: 9/10:3-4.Out of theShadows:Services for Personswith Epilepsy in MaltaDr Janet Mifsud BPharm (Hons), PhD (QUB) Senior Lecturer, Department of Clinical Pharmacology and Therapeutics University of Malta  email: janmif@um.edu.mtEpilepsy is the most common neurological disorder in clinicalpractice and it is a generic term used to define a variety ofseizure disorders. A seizure is a disturbance in the electricalactivity of the brain.   There are more than 20 differentepilepsies and syndromes, according to recent internationalreclassification of symptoms by the International LeagueAgainst Epilepsy.  These seizures affect awareness, producebrief loss of muscle control and may involve sensorydistortions.  Early diagnosis is crucial.  Children and adultswith undiagnosed seizures risk developing a more severe,more difficult to treat condition with consequent poorprognosis and increased medical costs.Twenty percent of cases developbefore the age of five and 50 % developbefore the age of 25.  It is alsoincreasingly associated with the elderly.In about 70% of cases there is noknown cause.  Of the remaining 30%,the most frequent causes include headtrauma, brain tumour and stroke,poisoning, alcoholism and followinginfections such as meningitis or viralencephalitis.  All people inherit varyingdegrees of susceptibility to seizures.The genetic factor is assumed to begreater when no specific cause can beidentified.  Modern treatment withdrugs can achieve full or partial controlof seizures in about 85% of cases.  Yetsocial, educational and employmentstigmas persist world-wide, even herein Malta.The World Health Organisationestimates there are 40 to 50 millionpeople with epilepsy throughout theworld and, in many countries, remains astigmatising condition surrounded bymystical beliefs and social taboos.  Inaddition, there are a number of socialand economic factors which willinfluence the outcome of seizurecontrol in persons with epilepsy andlack of data relating to the number ofpersons with this disability will hinderprogress in allocating medical, support,educational  and employment resourcesfor persons with epilepsy and theircareers.Local associationsOver the last three years theEpilepsy Society of Malta and MaltaCaritas Epilepsy Association have been6. U.S. Department of Health and HumanServices. FDA statement on street drugscontaining botanical ephedrine. HHS News1996: April 10:1.7. WHO. Herbal “Fen-Phen”: Warning concerning“natural” anti-obesity alternatives. WHOPharmaceuticals Newsletter 1997: 11/12:2-3.8. Forte J.S., Raman A. Regulatory issuesrelating to herbal products - Part 2: Safetyand toxicity. Journal of Medicinal Food 2000:3(1):41-57.9. Newall C.A., Anderson L.A., Phillipson J.D.Herbal Medicines: A Guide for Health-careProfessionals. London: The PharmaceuticalPress; 1996.10. Huxtable R.J. The harmful potential of herbaland other plant products. Drug Safety 1990:5(supplement 1):126-136.11. Health Division, Malta. Importantinteractions between St John’s Wort(Hypericum perforatum) preparations andprescribed medicines. DH Circular 2000: 69/2000(March 13).12. D’Arcy, P.F. Adverse reactions and interactionswith herbal medicines: Part 2. Druginteractions. Adverse Drug Reactions andToxicological Reviews 1993: 12:147-162.13. Forte J.S., Raman, A. Regulatory issuesrelating to herbal products - Part 3: Qualityand its determination. Journal of MedicinalFood 2000: 3(1):59-69.14. Miller L.G. Herbal medicines: Selected clinicalconsiderations focusing on known orpotential drug-herb interactions. Archives ofInternal Medicine 1998: 158:2200-2211.

Adverse reactions and interactions with herbal medicines: Part 2. Drug interactions. Adverse Drug Reactions and Toxicological Reviews

Department of Health and Human Services. FDA statement on street drugs containing botanical ephedrine.

Drugs of Natural Origin.

Drugs used in non-orthodox medicine.

Ephedrine in food supplements.

Fen-Phen”: Warning concerning “natural” anti-obesity alternatives.

Herbal medicines, phytoestrogens and toxicity: Risk:benefit considerations.

Herbal Medicines: A Guide for Health-care Professionals.

Herbal medicines: Selected clinical considerations focusing on known or potential drug-herb interactions.

Important interactions between St John’s Wort (Hypericum perforatum) preparations and prescribed medicines. DH Circular 2000: 69/ 2000(March 13).

Regulatory issues relating to herbal products - Part 2: Safety and toxicity.

Regulatory issues relating to herbal products - Part 3: Quality and its determination.

The harmful potential of herbal and other plant products. Drug Safety

Warning of herbal products sold as alternatives to abuse drugs. WHO Drug Information

How safe are herbal products?

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How safe are herbal products?

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