TRIff^'P British Journal of Clinical ■^gJ^Jt pharmacology DOI:10.1111/j.l 365-2125.2012.04350.x Herb-drug interactions: an overview of systematic reviews Paul Posadzki, Leala Watson & Edzard Ernst Complementary Medicine, Peninsula Medical School, University of Exeter, Veysey Building, Salmon Pool Lane, Exeter, EX2 4SG, England Correspondence Dr Paul Posadzki PhD, MSc, BSc, Complementary Medicine, Peninsula Medical School, University of Exeter, Veysey Building, Salmon Pool Lane, Exeter, EX2 4SG, England. Tel.:+44 (0)13 9272 6043 Fax:+44 (0)13 9242 1009 E-mail: paul.posadzki@pcmd.ac.uk Keywords drug interactions, herbal medicine, safety, systematic reviews Received 7 March 2012 Accepted 27 April 2012 Accepted Article Published Online 1 June 2012 OBJECTIVES The aim of this overview of systematic reviews (SRs) is to evaluate critically the evidence regarding interactions between herbal medicinal products (HMPs) and synthetic drugs. METHODS Four electronic databases were searched to identify relevant SRs. RESULTS Forty-six SRs of 46 different HMPs met our inclusion criteria.The vast majority of SRs were of poor methodological quality.The majority of these HMPs were not associated with severe herb-drug interactions. Serious herb-drug interactions were noted for Hypericum perforatum and Viscum album.The most severe interactions resulted in transplant rejection, delayed emergence from anaesthesia, cardiovascular collapse, renal and liver toxicity, cardiotoxicity, bradycardia, hypovolaemic shock, inflammatory reactions with organ fibrosis and death. Moderately severe interactions were noted for Ginkgo biloba, Panax ginseng, Piper methysticum, Serenoa repens and Camellia sinensis.Jbe most commonly interacting drugs were antiplatelet agents and anticoagulants. CONCLUSION The majority of the HMPs evaluated in SRs were not associated with drug interactions with serious consequences. However, the poor quality and the scarcity of the primary data prevent firm conclusions. Introduction The prevalence of use of herbal medicinal products (HMPs) is high and continues to increase. This applies to the UK [1] as well as other parts of the world [2]. It is therefore important to be aware of the safety issues associated with the administration of HMPs [3-5]. HMPs contain pharmacologically active ingredients, some of which might interact with synthetic drugs [4] which, in turn, could endanger the health of patients [5-7]. The aim of this article is to provide an overview and critical evaluation of the evidence from systematic reviews (SRs) of herb-drug interactions. Methods Electronic literature searches were conducted in January 2012 to identify SRs of herb-drug interactions. The following electronic databases were used: MEDLINE and EMBASE (via OVID), AMED and CINHAL (via EBSCO) and Cochrane Database. Search terms were constructed using 'herbal medicine' and 'adverse events' terms and their derivatives and MeSH terms, and 'review' in the title of the article (details of the search strategy are presented in the appendix). Our own extensive departmental files were hand-searched. No restrictions of language or time of publication were imposed. Abstracts of reviews thus located were inspected © 2012 The Authors British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society ■r j Clin Pharmacol / 75:3 / 603-618 / 603 P. Posadzki etal. and those appearing to meet the inclusion criteria were retrieved for further evaluation by both authors. Systematic reviews were defined as articles that included an explicit and repeatable methodology.To get included, SRs had to focus on herb-drug interactions. If, for one specific HMP, multiply SRs were found, the most up-to-date, methodologically sound and independent one was included. Reviews of mixtures of more than one HMP and SRs of polyherbals were excluded. Non-systematic reviews and/or reviews pertaining to the effectiveness of HMPs were also excluded. The methodological quality of all SRs was assessed using the modified Oxman score [8].This is a validated tool that applies the following criteria for assessing the methodological quality of review articles: reporting of search methods and their comprehensiveness, repeatability of eligibility criteria, avoidance of selection bias and reliability of conclusions. These domains were scored as follows: 1 (fulfilled), 0 (partially fulfilled) or-1 (not fulfilled). A final result of 0 or below means the review has major flaws, 1 -2 minor flaws and 3-5 minimal or no flaws. Results Our searches generated 4366 articles, of which 4320 had to be excluded (Figure 1 ).Thus 46 SRs met our inclusion criteria (Table 1) [9-54].The following herbs were considered to interact with synthetic drugs: Aloe vera, Boswellia serrata, Calendula officinalis, Camellia sinensis, Cassia senna, Caulo-phyllum thalictroides, Cinnamomum spp., Cimicifuga race-mosa, Cnicus benedictus, Commifora mukul, Crataegus spp., Crocus sativus, Curcuma longa, Echinacea spp., Total number of hits for electronic search (n=4356) Additional records identified through manual search (n= 10) Records screened (n=3227 ) w Excluded: polyherbals (n= 667); no herb-drug interactions (n=2380) Full-text articles assessed for eligibility (n=l80) Excluded - not SR (n-134) w Total number of articles included: (n=46) Figure 1 Flow diagram 604 / 75:3 / Br j Clin Pharmacol Table 1 Key data from the included SRs First author (year) Type of primary HMPs Overall Quality Country [Ref] data * (n) evaluated Drugs that interact Type of interactions Clinical outcomes Mechanism of action judgment of 5R Comment Armbruer (2012) RCTs, NRCT, CCT, USA [40] SRs, MAs, CR, CS, AS, in vitro Cinnamon (Cinnamomum spp.) 1. Antibiotics 2. Anticoagulants or antiplatelets 3. Antidiabetics Barrette (2012) RCTs, CCT, SRs, CR, USA [41] CS, AS, in vitro Black cohosh (Cimicifuga racemosa) Bäsch (2003) USA [9] Bäsch (2003) USA [10] Bäsch (2004) USA [11] Bäsch (2005) USA [42] Bitter melon (Momordica charantia) Antifungals Antilipaemics Antineoplastic agents Antiretroviral agents Cytochrome P450 metabolized agents 9. Anxiolytics 10. Oestrogens 11. Hepatotoxic agents 12. Immunosuppressants 13. Sympathomimetics 1. Antihistamines . Antihypertensives . Antilipemic agents . Antineoplastic agents . Antiseizures . OEstrogens . Hepatotoxic agents . Oral agents . Tamoxifen, raloxifene . Hypoglycaemics <10 Alfalfa (Medicago 1. Hypoglycaemics sativa) 2. Cholesterol lowering agents 3. Chlorpromazine <10 Thyme (Thymus 1. 5-fluorouracil vuigaris) RCTs, NRCT, CCT, SRs, MAs, OS, CR, CS, AS, in i/itro <100 Echinacea spp. Synergism with 11 3tandt, 4, 5t, 6tandt,7, 9t, ' 12tandt, 13*, Inhibition of It, 8, synergism with ; Synergism with Synergism with 1 and 2 Synergism with 1. Amoxicillin 2. Antineoplastic agents 3. Cytochrome P450-metabolized agents 4. Hepatotoxic agents 5. Hydrophilic agents Synergism with 2t, 3, 4, 5t and inhibition of 3 Increased risk of hypoglycaemia, bleeding (theoretical) Inhibited arachidonic acid release and thromboxane B2 formation; inhibition of HMG-CoA activity, inhibition of aminopyrine N-demethylation Gl upset Rhabdomyolysis, shock, and death (causality questioned) Only minor -4 concerns It is not clear how (or if) Only minor -4 olack cohosh interacts with concerns estrogens/estrogen receptors and/or progestins Lowered blood glucose concentrations Increased drug-induced ohotosensitivity, lowered blood glucose, total cholesterol or LDL n.k. Decreased hepatic Only minor -4 gluconeogenesis, increased concerns hepatic glycogen synthesis; increased pancreatic insulin secretion. Saponins may reduce Only minor 2 cholesterol absorption concerns Thymol increases the stratum corneum lipids fluidity and perturbing the barrier integrity of the epidermis Selective modulation of the catalytic activity of CYP3A at hepatic and intestinal sites Only minor concerns Only minor concerns Most interactions were theoretical, limited evidence in humans. Caution for patients with diabetes, autoimmune diseases, liver damage, and for patients using antiarrhythmic agents, antilipemics and anticoagulant or antiplatelet agents. Interaction data in this area were lacking. Caution for patients with known estrogen sensitive conditions, such as oreast cancer, uterine cancer or endometriosis; in patients on hormone replacement therapy, including tamoxifen or raloxifene; in epileptic oatients; in patients on antihypertensive medications; and in oatients with liver disease. Low quality and quantity of the available evidence regarding interactions. Caution for patients with diabetes Chlorpromazine was reported to increase drug-induced photosensitivity when taken in combination with alfalfa Thyme may decrease concentrations of thyroid hormone; caution for patients taking hepatotoxic agents Use cautiously in patients using cytochrome P450-metabolized agents or hepatotoxic drugs Table 1 Continued First author (year) Type of primary HM Ps Overall Quality Country [Ref] data *(n) evaluated Drugs that interact Type of interactions Clinical outcomes Mechanism of action judgment of 5R Comment Bäsch (2006) RCTs, CS, <10 Calendula 1. Sedatives Synergism with 1 and 2t n.k. Insufficient evidence to Only minor 0 Systemic effects in humans were not USA [12] comparison study, (Calendula determine concerns clear; caution for patients taking AS officinalis) 2. Antihypertensives pharmacodynamics/kinetics sedatives Bäsch (2004) RCTs, NRCT.CS, AS <10 Lavender 1. Sedatives, Synergism with 1, 2, 3 and n.k. Linalool binds to glutamate Only minor -4 Use cautiously in patients taking USA [13] (Lavandula 2. Anticoagulants, NSAIDs, 4* and increases GABA concerns sedatives, anticoagulants, angusti folia anti-platelet agents, concentrations* antiplatelet agents and Miller) 3. Anti-seizures anti-epileptic drugs 4. Cholesterol lowering agents* Bäsch (2004) RCTs, NRCTs, SR, <100 Boswellia 1. Leukotriene inhibitors Inhibition of 1 and n.k. Inhibition of lipoxygenase to Only minor -4 Use cautiously in patients taking USA [14] comparison study, (Bosweiiia 2. Anti-neoplastic agentst synergism with 2t produce 5-HETE, LTB4 and concerns leukotriene inhibitors in vitro serrata) HLEt Bäsch (2012) RCTs, NRCT, CCT, <100 Mistletoe (Viscum 1. Antidiabetic agents Synergism with 11, 2, Organ fibrosis and Mistletoe lectins agglutinate Serious concerns -4 Use cautiously in patients with USA [43] SRs, OS, cohort album) 2. Antihypertensives 3tandt, 4, 5, 6, death, cardiotoxicity, human erythrocytes and cardiovascular disease, uncontrolled study, CR, CS, 3. Antineoplastic agents inhibition of 7t oradycardia, react with hyperthyroidism, seizures, glaucoma CCS, AS, in vitro 4. Cholinergic agents hypovolaemic shock immunoglobulins and diabetics. 5. CNS depressants and CVD collapse, 6. Diuretics inflammatory 7. Immunosuppressants reaction 8. Thyroid hormones Bäsch (2012) RCTs, NRCT, CCT, <100 Hawthorn 1. Alpha agonists Inhibition of Itandt, 2t, Increased risk of Inhibition of thromboxane Only minor -4 Although possible safe co-administration USA [44] SRs, MA, CR, AS, (Crataegus spp.) 2. Anticoagulants and synergism with 3tandt, bleedingt A2 biosynthesist concerns of hawthorn and cardiac glycosides in vitro antiplatelets 4tandt, 5t, 6t, 7t, 8t has been suggested, close monitoring 3. Antihypertensives during dose titration is warranted. 4. Antilipaemic agents 5. ß-adrenoceptor blockers 6. Digoxin, digitoxin 7. Phosphodiesterase inhibitors 8. Vasodilators Bäsch (2012) RCTs, CCT, SRs, <100 Green tea 1. Analgesics Synergism with 1, 4t and Increased risk of toxic EGCG inhibits the IL-1 Some concerns -4 Use cautiously in patients taking USA [45] MAS, CR, AS, in (Camellia 2. Antiandrogens t, 6, 7, 9, 15, 16 effects, hypertensive oeta-induced activity and analgesics, antilipaemics, antiseizures, vitro sinensis) 3. Antiarthritics inhibition of 2, 8, 10, crisis;, impaired iron expression of antivirals, ß-adrenoceptor blockers, 4. Anticoagulants and 13, 14t, metabolism and cyclooxygenase-2 and nitric cytochrome P450-metabolized agents, antiplatelets microcytic anaemia, oxide synthase-2; caffeine hepatotoxic agents, hormonal agents 5. Antidepressants increased blood acts via blockade of and sedatives. 6. Antilipaemics oressure; ischaemic adenosine receptors, and 7. Antivirals stroke theoretically, may 8. Cytochrome antagonize the effects of P450metabolized agents adenosine 9. Hepatotoxic agents 10. Oestrogen 11. Hypertensives 12. Hypoglycaemics 13. Sedatives 14. P-glycoprotein modulators 15. Antiseizures 16. ß-adrenoceptor agonists o cu Q-N 7T Brendler (2006) RCTs, CS, AS <100 Devil's claw 1. Anti-arrhythmic agents Synergism with It, Decreased HR t Release of inflammatory Only minor 0 Use with anticoagulant and antiplatelet Germany [15] (Harpagophytum 2. Inotropic agents inhibition of 2* mediatorst; inhibition of concerns agents should be approached with procumbens) 3. Anticoagulant/antiplatelet arachidonic acid caution agents metabolism pathwayst Brendler (2012) RCTs, AS, in vitro <100 Noni (Morinda 1. Anti-angiogenic drugs Synergism with It, 2t, 3t, Decreased gastric Inhibition of copper-induced Only minor -4 Use cautiously in patients using warfarin Germany [46] citri folia) 2. Antibiotics 5t, 6, inhibition of 3, 7t transit timet, LDL oxidation; of Ras concerns or other anticoagulants, 3. Anticoagulants increased risk of oncogene function, cell antihypertensives or ACE inhibitors. 4. Antihypertensives hyperkalemia, transformation; of the 5. Anti-inflammatory agents tumour-promoting effect of 6. Hepatotoxic agents TNF-a, and activator 7. Immunosuppressants protein-1 transactivation. Ceurvels, (2012) CR, AS <10 Blue cohosh 1. Antidiabetic agents Synergism with 3 and 5 Coronary caulosaponin and Only minor -4 Use cautiously in patients who are USA [47] (Cauiophyiium 2. Cardiovascular drugs vasoconstriction, caulophyllosaponin, have concerns pregnant or breast-feeding; in patients thaiictroides) tachycardia, increase been shown to have labour who smoke or are quitting smoking 3. Nicotine in blood pressure, induction properties due to possible nicotine toxicity; and in diaphoresis, patients with diabetes 4. Oxytocin abdominal pain, 5. Cocaine vomiting and muscle weakness Ernst (2005) UK CRs <100 Ginkgo biioba 1. Paracetamol Inhibition of 1, 3, 4, 6 Haemorrhage, Inhibition of platelet Some concerns 5 Use cautiously in patients taking [16] (acetaminophen) oleeding, apraxia, aggregation anaesthetics, analgesics, anticoagulants 2. lisinopril death, haematoma, and antiplatelet agents 3. anaesthetics hyphaema, 4. aspirin oermanent 5. warfarin neurological deficit 6. ibuprofen Giles (2005) USA RCT, OLS, SR <100 Butterbur 1. Anticholinergics Synergism with 1 Increased liver enzyme Reduction of smooth muscle Only minor 1 Administration of butterbur with [17] (Petasites levels spasm; inhibition of concerns anticholinergics may not be advisable hybridus) lipoxygenase activity and down-regulation of leukotriene synthesist Keifer (2007) RCTs, AS, in vitro <10 Peppermint 1. Antibiotics Synergism with 1,t3,t 6,t n.k. Menthol and menthyl acetate Only minor 2 No documented interactions in humans. USA [48] (Mentha 2. Benzoic acid and inhibition of 2,t 4,t may inhibit concerns piperita) 3. Calcium channel blockers 5tand t CYP3A4-mediated 4. Ciclosporin nifedipine metabolism and 5. Cytochrome P450 increase felodopine metabolized agents concentrations 6. Oxytetracycline Nelsen (2002) RCTs, CS, in vitro <100 Red clover 1. Cytochrome Inhibition of 11, 2 and Alleviated GrRH, FSH Binding to estradiol receptors Only minor 1 Red clover may have synergistic effects USA [18] (Trifolium P450-metabolized agents synergism with 2 and LH (estradiol-a and estradiol-^) concerns with anticoagulants or antiplatelet pratense) 1 WRT anH AfPc concentrations agents; use cautiously in patients Z. nr\ 1 dllu \J\_ri taking hormonal agents Sweeney (2005) Case series, in vitro, <10 Dandelion 1. Ciprofloxacin Inhibition of It, synergism Inhibition of platelet Sesquiterpenes lactones may Only minor -4 Patients using antihypertensive and/or USA [19] AS (Taraxacum with 3t, 4t aggregationt act as anti-inflammatory concerns antidiabetic agents or insulin should be officinaie) 2. Hypoglycaemic drugs agents; lactones may monitored closely while using increase gastric acid dandelion. 3. Anticoagulants secretion; increased bile oroduction and release; 4. Cytochrome P450 1A2 and inulin may act to buffer 2E metabolized agents olood glucose concentrations o o *6 Table 1 Continued First author (year) Type of primary HMPs Overall Quality Country [Ref] data * in) evaluated Drugs that interact Type of interactions Clinical outcomes Mechanism of action judgment of 5R Comment Tiffany (2002) RCTs, SR, OS, AS < 00 Horse chestnut 1. Hypoglycaemic agents Synergism with 1t n.k. Inhibition of the normal Only minor 1 No documented interactions in humans. USA [20] seed extract increase of serum glucose concerns (Hippocastanaceae) concentrations Ulbricht (2003) CR, AS < 00 Chaparral (Larrea 1. Cytochrome P450 Inhibition of It Increased renal and Diminished platelet Only minor 2 Chaparral should be avoided in USA [21] tridentate) metabolized agents liver toxicity aggregation; decrease concerns combination with potentially (theoretically) olasma glucose hepatotoxic agents concentrations; blocked cellular respiration and exerted antioxidant effects; inhibited induction of ornithine decarboxylaset and t Ulbricht (2004) RCTs, NRCT, < 00 Belladonna 1. Cisapride Inhibition of 1, 2t Delayed Inhibition of the muscarinic Only minor -4 Avoid concomitant use with alcohol, USA [22] [22] OS, AS (Herbae puivis 2. Tacrine gastrointestinal actions of acetylcholine concerns anti-arrhythmics, antidepressants, standardisatus) transit time anticholinergic and drugs that interact with atropine Ulbricht (2005) RCT, CS, AS < 00 Lemon balm 1. Barbiturates Synergism with 1t, 2, Hypnosist, sedation Reduced pituitary and serum Only minor 0 Use cautiously in patients taking USA [23] (Melissa 2. Sedatives inhibition of 4t TSH concentrationst concerns hormonal agents and sedatives officinalis) 3. Nicotine and scopolamine 4. SSRIs Ulbricht (2005) RCTs, CS, AS < 00 Guggul 1. Propranolol Inhibition of 1, 2, Increased risk of Guggulsterones have been Only minor 1 Guggulipid should be used with caution USA [24] (Commifora 2. Diltiazem synergism with 3t, 5 bleeding reported to function as concerns in patients taking thyroid drugs. mukui) 3. Thyroid agents (theoretical) antagonists of the 4. Lipid-lowering agents farsenoid X receptor 5. Anticoagulants, antiplatelet agents Ulbricht (2005) RCTs CRs, in vitro < 00 Kava (Piper 1. Cytochrome P450 Inhibition of It, 2, 3t, and Coma, sedation, Kavalactones or kavapyrones Some 3 Anesthesiologists recommend stop USA [25] methysticum) substrates synergism with 5 lethargy, drowsiness may alter central GABA concerns taking kava 2-3 weeks prior to 2. Dopamine agonists and transmission, blocking ion surgery; patients with Parkinson's antagonists channels; inhibition of disease should avoid kava. Avoid 3. Monoamine oxidase thromboxane synthesis and combining kava with hepatotoxic inhibitors cyclooxygenase. agents. 4. Antiplatelet agents 5. Sedatives/CNS depressants Ulbricht (2006) RCTs, SRs, CR, CS, < 00 Saw palmetto 1. Androgenic drugs Inhibition of 1, synergism Severe intra-operative Inhibition of lipooxygenase Some -4 Use cautiously in patients with USA [49] AS, in vitro (Serenoa 2. Anti-androgenic drugs with 2, 3, 4, 6 and 10 and cerebral and cyclooxygenase; concerns hypertension, hormone-sensitive repens) 3. Anticoagulants and haemorrhage, exerted activity on estrogen conditions and bleeding disorders antiplatelets hypertension, receptors; stimulation of 4. Antibiotics nausea or vomiting macrophage phagocytosis 5. Antihypertensives and NK cell synthesis of 6. Anti inflammatory agents interferon-gammat 7. Cytochrome P450 metabolized agents 8. Metronidazole or disulfiram 9. Hormonal agents 10. Immunomodulators Ulbricht (2007) USA [27] RCTs, NRCT, CCT, SRs, MA, CRs, CS, AS Fenugreek (Trigoneiia foenum-graecum) Ulbricht (2007) USA [28] Ulbricht (2007) USA [50] Banaba (Lagerstroemia speciosa) RCTs, CR, AS, in vitro <100 Aloe vera Ulbricht (2008) USA [39] Ulbricht (2009) USA [29] Ulbricht (2009) USA [26] <100 Blessed thistle (Cnicus benedictus) Chia (Salvia hispanica) >100 Ginseng (Panax ginseng) Ulbricht (2009) RCTs, SR, CRs, AS, USA [35] in vitro, <100 Green-lipped mussei (Ferna canaliculus) Ulbricht (2009) USA [51] Review, NRCT, CS, AS, in vitro <100 Maitake mushroom (Grifoia frondosa) Anti-arrhythmic agents/cardiac glicosides/potassium depletings 2. Antidiabetic agents 3. Anticoagulants and antiplatelets 4. Antilipaemic agents 5. Laxatives 1. Hypoglycaemic agents Synergism with 2, 5 inhibition of 31 Increased INR, reduced ootassium levels, lowered LDL, TG, and total cholesterol t and t, improved insulin resistance* Synergism with 11 Synergism with 1, 6 and 7 1. Insulin 2. Oral hypoglycemic agents 3. Laxatives 4. Sevoflurane 5. Thyroid hormones 6. Topical hydrocortisone 7. Zidovudine 1. Antibiotics 2. Anticoagulant and antiplatelet agents 3. Antineoplastic agents 1. Anticoagulants and antiplatelets 2. Antihypertensives 3. Antioxidants 4. Cytochrome P450-metabolized agents 1. DHT 2. anticoagulant 3. antidepressants 4. antidiabetics 5. antilipaemics 6. calcium channel blockers 7. digoxin 8. diuretics 1. Anti-inflammatory agents Synergism with 11 and t, and corticosteroids 2t 2. Leukotriene receptor antagonists 1. Antidiabetic agents 2. Antineoplastic agents 3. Antiviral agents 4. Immunosuppressants Synergism with It, 2t, 3t and t Synergism with 11, 2,3 Synergism with 1, 4, 5,7 inhibition of 2, 7, 8 Potassium depletion, hypokalaemia, increased hypoglycaemic effect Increasing bleeding risk (theoretical) Lowered blood oressure Mania, headache, tremor, and insomnia, reduced blood glucose, HbAlc, plasma cholesterol, triglyceride, LDL, and NEFA; elevated HDL, LH, FSH; altered BP n.k. Synergism with 2tandt 3 n.k. Modulation of Only minor oeta-glucuronidase and concerns mucinase activities, DNA fragmentation by orotodiosgenin; ohosphorylation of insulin receptor, or activation of insulin signalling pathway Increase the rate of glucose Only minor uptake and decrease the concerns isoprenaline-induced glycerol release Anthraquinone glycosides act Only minor as laxatives; stimulation of concerns p cells Cnicin and arctigenin have Only minor exhibited cytotoxic activity concerns against some tumor cells via inhibition of cellular DNA, RNA or protein synthesist Increased levels of Only minor alphalinolenic acid, fibre, concerns orotein and magnesium 2 Use cautiously in patients taking antidiabetics and antilipemics Inhibition of platelet aggregation and CYP2D6 Some concerns Lagerstroemin may activate insulin receptors, use cautiously in diabetic patients Use cautiously in patients with diabetes or glucose intolerance. Avoid oral aloe latex in patients with renal insufficiency, cardiac disease, or electrolyte abnormalities -4 Limited evidence in humans 0 Caution is advised as high doses of omega-3 fatty acids in Chia are known to increase the risk of bleeding, use cautiously in patients taking antioxidants -4 Caution is advised about concomitant use with warfarin, oral hypoglycaemic agents, insulin, antilipaemics anti-arrhythmias hormonal agents diuretics Inhibition of lipoxygenase Beta-glucans are distributed to the liver and spleen with a prolonged half-life Only minor concerns Only minor concerns -4 Limited evidence in humans -4 Use cautiously in patients using antihypertensives, antidiabetic agents and immunomodulators. 0> O ö Table 1 Continued First author (year) Type of primary HMPs Overall Quality Country [Ref] data * (n) evaluated Drugs that interact Type of interactions Clinical outcomes Mechanism of action judgment of SR Comment Ulbricht (2010) RCTs, CCT, CS, AS, < 00 Reishi mushroom 1. Antibiotics Synergism with 11, 2, 3, Increased risk of bleeding Inhibitory activity on Only minor -4 Use cautiously in patients using USA [52] in vitro (Ganoderma 2. Anticoagulant and 5tandt, 6t and (theoretical) angiotensin converting concerns anti-inflamatory agents anticoagulants lucidum) antiplatelets inhibition of S enzyme t and antiplatelet agents 3. NSAIDs 4. Antidiabetics 5. Antineoplastic agents 6. Antiviral agents 7. Cardiovascular agents 8. Neurologic agents Ulbricht (2010) RCTs, CCTs, AS <10 Stevia (Stevia 1. Sodium monoketocholate Synergism with 1, 2, 3, 4t Decreased glucose levels Inhibition of oxidative Only minor 0 Use cautiously in patients using diuretics USA [30] rebaudiana) 2. Vasodilators and blood pressure, phosphorylation, ATPase concerns and antihypertensives 3. Diuretics inhibition of rotavirus activity, NADH-oxidase activity, succinate-oxidase 4. Calcium channel blockers activity, succinate dehydrogenase, and L-glutamate dehydrogenaset; inhibition of ketogenesis and [14C] CO2 production from [1-14C] palmitatet Ulbricht RCTs, OS, CRs, in < 00 Umckaloabo 1. Anticoagulant and Synergism with It, 3, 4; Cardiovascular Gallic acid may stimulate a Only minor -4 Use cautiously in patients using (2010)USA [37] vitro (Pelargonium antiplatelet agents inhibition of 5t complications, release of TNF, stimulate concerns anticoagulants or antiplatelet agents sidoides) 2. Cardiovascular agents hepatotoxicity, interferon activity and 3. Hepatotoxic agents increased risk of increase NK activity 4. Laxatives oleeding (theoretical), 5. Immunosuppressants laxative effect Ulbricht RCTs, CRs, AS, in < 00 Rosemary 1. Immunosupressants Synergism with 3, 4, 5t Increased risk of Inhibition of ACE, and Only minor -4 Use cautiously in patients using (2010)USA [34] vitro (Rosmarinus 2. Cytochrome and t bleeding, hypotension platelets aggregationt, concerns salicylates, cytochrome P450 officinaiis) P450-metabolized agents decreased fibronectin and metabolized drugs and anti-diabetic 3. Anxiolytics fibrint agents 4. Antibiotics 5. Anticoagulants or antiplatelets Ulbricht (2010) RCTs, NRCTs, in < 00 Spearmint 1. Nephrotoxic agents Synergism with 1t, 2t, n.k. Decreased expression of Only minor -4 Interactions in humans are hypothetical USA [32] jitro, AS (Mentha 2. Hepatotoxic agents inhibition of 3t cytochrome P450scc and concerns spicata, Mentha 3. Cytochrome cytochrome P450C17 viridis) P450-metabolized agents enzymes Ulbricht (2011) RCTs, SR, ET, OLS, < 00 Saffron (Crocus 1. SSRIs Synergism with 1, 2, 3, 4, n.k. Trans-crocin-4 may inhibit Only minor -4 Use cautiously in patients using USA [33] CS sativus) 2. MAOIs 5 and inhibition of 6t Abeta fibrillogenesis and concerns anticoagulants or antiplatelet agents, 3. Fertility agents and t platelet aggregationt hormonal agents, antidepressants and 4. Alzheimer's agents antihypertensives 5. Anti hypertensives 6. Anticoagulants or antiplatelets Ulbricht (2011) RCTs, SRs, CCTs, < 00 Senna (Cassia 1. Digoxin Synergism with It, 2, 3t, Lowered serum estrogen Decreased deoxycholic acid Only minor -4 Use cautiously in patients using USA [36] senna) 2. Anticoagulant and 4t concentrations and and biliary cholesterol concerns anticoagulant and antiplatelet agents antiplatelet agents ootassium levels; saturation 3. Antibiotics increased risk of excessive bleeding and 4. Antineoplastics gallstones T3 o QJ Q_ N 7T Ulbricht (2011) RCT, CCTs, CS, AS <100 Gymnema USA [38] (Gymnema sylvestre) Ulbricht (2011) RCTs.SRs, CCT, CS, <100 Turmeric USA [53] CR (Curcuma longa) 1. Antidiabetic agents 2. antilipaemic agents 1. Paracetamol (acetaminophen) 2. acetylcholinesterase inhibitors 3. amiloride 4. antibiotics 5. anticoagulants and antiplatelets 6. antidiabetic agents 7. antihypertensives 8. Anti-inflammatory agents 9. Antilipemic agents 10. Antineoplastic agents 11. Celecoxib 12. Cytochrome P450-metabolized agents 13. 14. 15. 16. 17. Vora (2012) USA[54] Chasteberry (Vitex agnus-castus) Whitten (2006) Australia [31] St John's wort (Hypericum perforatum) Synergism with 1, 2 Inhibition of It, 12tandt, 15t, 19, 21 synergism with 2t, 3t, 4t, 5t andt, 6, Standt, 9t, lOtandt, 11tandt, 13t, 14t, 15t, 17t, 18t, 19, 20t, 211, 23 . Erythromycin . Erythropoietin . Hormonal agents . NSAIDs . Norfloxacin 18. Oxaliplatin 19. P-glycoprotein-regulated drugs 20. Retinol 21. Talinolol 22. Taxol 23. Warfarin 1. Prolactin Synergism with doses) (low . Immunosupressants . Antiretrovirals . Hormonal therapy . CVD drugs . Anicancer drugs . CNS drugs . Antimicrobals Inhibition of 1, 2, 4, 5, 6 and 7 Hypoglycemia Increased risk of oleeding, transient hypotension, oradycardia, and vasodilation Reductions of serum TG, total Only minor cholesterol, VLDL and LDL concerns Diferuloylmethane is believed to be the principal oharmacological agent responsible for all interactions Only minor Constituents of chasteberry Only minor bind to dopamine-2 concerns receptors in the pituitary, thereby inhibiting prolactin secretiont Transplant rejection, unwanted oregnancy, mania, orofacial dystonia, delayed emergence from anaesthesia, CVD collapse Induction of CYP3A enzymes and/or intestinal P-glyco protein Serious concerns -4 Supervision is needed in diabetic patients -4 Use cautiously in patients using beta olockers or those with metabolic syndrome or increased risk of bleeding. Use cautiously in patients taking oral contraceptives or HRT or in patients taking dopamine agonists or antagonists. Avoid using in patients with hormone sensitive cancers or conditions, in patients who are pregnant or breastfeeding or in women undergoing in vitro fertilization. High doses of this HMP cause significant changes in pharmacokinetic measurements consistent with CYP3A induction. Avoid in transplant patients or those requiring anaesthesia. *Range of primary data. tBased on in vitro studies. tBased on animal studies. ACE, angiotensin-converting enzyme; AS, animal study; ATP, Adenosine triphosphate; BP, blood pressure; CAM, complementary and alternative medicine; CCS, case control study; CCT, controlled clinical trial; CNS, central nervous system; CR, case report; CS, case series; CVD, cardiovascular; CYP2D6, cytochrome CYP 2D6; DHT, dihydrotestosterone; EGSG, epigallocatechin gallate; ET, equivalence trial; FSH, follicle stimulating hormone; GABA, gamma-aminobutyric acid; GrRH, gonadotropin releasing hormone; HbAlc, haemoglobin Ale; HLE, human leucocyte elastase; HMG, CoA-hepatic 3-hydroxy-3-methylglutaryl reductase; HDL, high-density lipoprotein; HRT, hormone replacement therapy; INR, International Normalized Ratio; LH, luteinizing hormone; LDL, low-density lipoprotein; LTB4, leukotriene B4; MOAI, monoamine oxidase inhibitors; NADH, dehydrogenase; NEFA, non-esterified fatty acid; NK, natural killer cells; n.m., not mentioned; n.k., not known; NRCT, non-randomized controlled trial; OCPs, Oral contraceptives; OS, observational study; OLS, open label study; RCT, randomized controlled trial; RRC, retrospective review of cases; SSRIs, Selective serotonin re-uptake inhibitors; SR, systematic review; SRS, spontaneous reporting scheme; TG, triglicerides; TNF, tumour necrosis factor; TSH, Thyroid stimulating hormone; UCT, uncontrolled trial; VLDL, very low density lipoprotein; 5-HETE, 5-hydroxyeicosatetraenoic. □ o *6 Table 2 The found herb-drug interactions for each class of medication Class of medication Herb Type of interaction Synergism Antagonism Alzheimer's agents Saffron (Crocus sativus) X Anaesthetics Ginkgo (Ginkgo biloba) X Analgesics Ginkgo (Ginkgo biloba) Green tea (Camellia sinensis) x X Anti-arrhythmias Ginseng (Panax ginseng) x X Antibiotics Rosemary (Rosmarinus officinalis) Saw palmetto (Serenoa repens) St John's wort (Hypericum perforatum) X X X Anticoagulants and antiplatelet agents Ginkgo (Ginkgo biloba) Ginseng (Panax ginseng) Guggul (Commifora mukul) Lavender (Lavandula angustifolia Miller) Noni (Morinda citrifolia) Reishi mushroom (Ganoderma lucidum) Saw palmetto (Serenoa repens) Senna (Cassia senna) Turmeric (Curcuma longa) X X X X X X X X X Antidiabetics Aloe (Aloe vera) Cinnamon (Cinnamomum spp.) Fenugreek (Trigonella foenum-graecum) Ginseng (Panax ginseng) Gymnema (Gymnema sylvestre) Turmeric (Curcuma longa) X X X X X X Antihypertensives Black cohosh (Cimicifuga racemosa) Chia (Salvia hispanica) Mistletoe (Viscum album) Saffron (Crocus sativus) Stevia (Stevia rebaudiana) X X X X X Anti-inflamatory agents Aloe (Aloe vera) Saw palmetto (Serenoa repens) Reishi mushroom (Ganoderma lucidum) X X X Antilipaemics Alfalfa (Medicago sativa) Fenugreek (Trigonella foenum-graecum) Ginseng (Panax ginseng) Green tea (Camellia sinensis) Gymnema (Gymnema sylvestre) X X X X X Antineoplastics Black cohosh (Cimicifuga racemosa) St John's wort (Hypericum perforatum) Thyme (Thymus vulgaris) X X X Anti-oxidants Chia (Salvia hispanica) X Antiseizures Green tea (Camellia sinensis) Lavender (Lavandula angustifolia Miller) X X Antivirals Aloe (Aloe vera) Green tea (Camellia sinensis) Maitake mushroom (Grifola frondosa) St John's wort (Hypericum perforatum) X X X X Anxiolytics Rosemary (Rosmarinus officinalis) X ß-adrenoceptor blockers Green tea (Camellia sinensis) Guggul (Commifora mukul) Turmeric (Curcuma longa) X X X Cholinergic agents Butterbur (Petasites hybridus) Mistletoe (Viscum album) X X CNS depressants Kava (Piper methysticum) Mistletoe (Viscum album) X X Cytochrome P450-metabolized agents Echinacea spp. Green tea (Camellia sinensis) St John's wort (Hypericum perforatum) X X X X Dopamine agonists and antagonists Kava (Piper methysticum) X Diuretics Ginseng (Panax ginseng) Mistletoe (Viscum album) Stevia (Stevia rebaudiana) X X X Gastro protective agents Belladonna (Herbae pulvis standardisatus) X Hepatotoxic agents Echinacea spp. Green tea (Camellia sinensis) Noni (Morinda citrifolia) Umckaloabo (Pelargonium sidoides) X X X X 612 / 75:3 / Br j Clin Pharmacol Herb-drug interactions Table 2 Continued Class of medication Herb Type of interaction Synergism Antagonism Hormonal agents Chasteberry (Vitex agnus-castus) X Ginseng (Panax ginseng) X Green tea (Camellia sinensis) X Red clover (Trifolium pratense) X X Saffron (Crocus sativus) X Saw palmetto (Serenoa repens) X X Hypoglycaemics Alfalfa (Medicago sativa) X Bitter melon (Momordica charantia) X Immunomodulators Saw palmetto (Serenoa repens) X St John's wort (Hypericum perforatum) X Laxatives Umckaloabo (Pelargonium sidoides) X Leukotriene inhibitors Boswellia (Boswellia serrata) X Monoamine oxidase inhibitors Saffron (Crocus sativus) X Sedatives Calendula (Calendula officinalis) X Green tea (Camellia sinensis) X Lavender (Lavandula angustifolia Miller) X Lemon balm (Melissa officinalis) X Selective serotonin re-uptake inhibitors Saffron (Crocus sativus) X CNS, central nervous systerr Ganoderma lucidum, Ginkgo biloba, Grifola frondosa, Gymnema sylvestre, Harpagophytum procumbens, Herbae pulvis standardisatus, Hippocastanaceae, Hypericum perforatum, Lagerstroemia speciosa, Larrea tridentate, Lavandula angustifolia miller, Medicago sativa, Melissa officinalis, Mentha piperita, Mentha spicata/Mentha viridis, Momordica charantia, Morinda citrifolia, Panax ginseng, Piper methysti-cum, Pelargonium sidoides, Perna canaliculus, Petasites hybri-dus, Rosmarinus officinalis, Serenoa repens, Salvia hispanica, Stevia rebaudiana, Taraxacum officinale, Thymus vulgaris, Trifolium pretense, Trigonella foenum-graecum, Viscum album and Vitex agnus-castus. The following drugs interacted with HMPs (Table 2): anaesthetics [16], anti-arrhythmic agents [15,27], antibiotics [19, 34, 36, 39, 40, 42, 46, 48, 49, 52, 53], anticoagulants [13,15,16,18,24,26,27,29,33,34,36,37,39,40,44-46,49, 50,52,53],anticholinergics [17,22],antidepressants [25,26, 33,45], antidiabetics [26, 27, 38,40,43,47, 50-53], antihypertensives [16,29,33,41,43-46,49,53], anti-inflammatory agents [13, 16, 35, 46, 52, 53], antimicrobials [31], antineoplastics [11,14, 31, 36, 39-43, 51-53], antiplatelet agents [13,15, 24,25,27,29,33, 34,36,37,39,40,44,45,49,50,52, 53],anti-epileptic drugs [13,41,45],antivirals [31,40,45,51, 52], calcium channel blockers [24,26,30], cholesterol lowering agents [10,13,24,26,27,40,41,44,45,50,53],CYP-450 metabolized agents [18,21,25,29,32,34,40,42,45,48,49, 53],diuretics [26,30,43], hormonal agents [18,24,26,31,40, 41, 43, 45, 49, 53, 54], hypoglycaemics [9, 10, 19, 20, 28], immunnosupressants [31, 34, 37, 40, 43, 46, 48] laxatives [27,37,50], leukotriene inhibitors [14], sedatives [12,13,23, 25,45],selective serotonin re-uptake inhibitors [23,33] and vasolidators [30,44]. These interactions were thought to cause a wide variety of clinical outcomes such as altered hormone concentrations [18], apraxia, death, haematoma, hyphaema, permanent neurological deficit [16], bradycardia and vasodilation [53], cardiovascular complications, hepato-toxicity [37], coma, sedation, lethargy, drowsiness [25], coronary vasoconstriction, tachycardia, diaphoresis, abdominal pain, muscle weakness [47], gastrointestinal upset [41], haemorrhage, bleeding [34], increased body weight, diarrhoea, decreased blood haemoglobin and altered calcium serum concentrations, hypoglycaemia [10, 38], increased liver enzyme levels [17], mania, headache, tremor and insomnia [26], microcytic anaemia, ischaemic stroke [45], organ fibrosis and death, cardiotox-icity, hypovolaemic shock, inflammatory reaction [43], potassium depletion, hypokalaemia [50], rhabdomyolysis, shock and death [42], severe intra-operative and cerebral haemorrhage, hypertension, nausea or vomiting [49], transplant rejection, unwanted pregnancy, mania, orofacial dystonia, delayed emergence from anaesthesia, cardiovascular collapse [31]. Thirteen SRs were based on less than 10 primary reports [9-13,19,27-30,47,48,54], 32 were based on less than 100 primary reports [14-18, 20-25, 31-46, 49-53] and one SR was based on more than 100 primary reports [26].The SRs included human studies [9-11,16-18,23-27, 29, 31, 33, 34, 36-38,40-47,49-54], animal studies [12,13, 15, 19-24, 27-30, 32-35, 39, 40, 42-46, 48, 51-53] or in vitro experiments [14, 18, 19, 23, 25, 33-37, 39-46, 48, 51-53]. Some HMPs acted as inhibitors/antagonists [16, 21, 22, 31] while others acted as agonists/synergists [9-13, 17, 20, 28-30, 34-36, 38-40, 47, 50, 51, 54]. In nine Br j Clin Pharmacol / 75:3 / 613 P. Posadzki etal. Table 3 Quality ratings for included systematic reviews of HMPs Search Search Inclusion Bias Conclusions Study (year) [ref] methods? (a) comprehensive? (b) criteria? (c) avoided? (d) supported? (e) Sum Armbruer (2012) [40] -1 -1 -1 0 -4 Barrette (2012) [41] -1 -1 -1 0 -4 Bäsch (2003) [9] -1 -1 -1 0 -4 Bäsch (2003) [10] 1 1 0 1 2 Bäsch (2004) [11] -1 -1 -1 0 -4 Bäsch (2006) [12] 0 1 0 0 0 Bäsch (2004) [13] -1 -1 -1 0 -4 Bäsch (2004) [14] -1 -1 -1 0 -4 Bäsch (2005) [42] -1 -1 -1 0 -4 Bäsch (2012) [43] -1 -1 -1 0 -4 Bäsch (2012) [44] -1 -1 -1 0 -4 Bäsch (2012) [45] -1 -1 -1 0 -4 Brendler (2006) [15] 0 1 0 0 0 Brendler (2012) [46] -1 -1 -1 0 -4 Ceurvels (2012) [47] -1 -1 -1 0 -4 Ernst (2005) [16] 1 1 1 1 5 Giles (2005) [17] 0 1 0 1 1 Keifer (2007) [48] 1 1 0 1 2 Nelsen (2002) [18] 11 -1-11 1 Sweeney (2005) [19] -1 -1 -1 1 -4 Tiffany (2002) [20] 1 1 0 1 Ulbricht (2003) [21] 1 1 0 1 2 Ulbricht (2004) [22] -1 -1 -1 1 -4 Ulbricht (2005) [23] 0 1 0 0 Ulbricht (2005) [24] 0 1 0 1 1 Ulbricht (2005) [25] 1 1 1 1 3 Ulbricht (2006) [49] -1 -1 -1 1 -4 Ulbricht (2007) [27] 1 1 0 1 2 Ulbricht (2007) [28] 1 1 0 0 1 Ulbricht (2007) [50] 1 1 0 1 2 Ulbricht (2008) [39] -1 -1 -1 0 -4 Ulbricht (2009) [29] 0 1 0 0 0 Ulbricht (2009) [35] -1 -1 -1 0 -4 Ulbricht (2009) [26] -1 -1 -1 0 -4 Ulbricht (2009) [51] -1 -1 -1 0 -4 Ulbricht (2010) [52] -1 -1 -1 0 -4 Ulbricht (2010) [30] 0 1 0 0 0 Ulbricht (2010) [37] -1 -1 -1 0 -4 Ulbricht (2010) [34] -1 -1 -1 0 -4 Ulbricht (2010) [32] -1 -1 -1 0 -4 Ulbricht (2011) [33] -1 -1 -1 0 -4 Ulbricht (2011) [36] -1 -1 -1 0 -4 Ulbricht (2011) [38] -1 -1 -1 0 -4 Ulbricht (2011) [53] -1 -1 -1 0 -4 Vora (2012) [54] -1 -1 -1 0 -4 Whitten (2006) [31] 1 1 1 1 5 Scoring: each question is scored as 1, 0 or -1; A score of 0 or below means the review has major flaws, 1-2 minor flaws and 3-5 minimal or no flaws. 1 means that: (a) the review states the databases used, date of most recent searches and some mention of search terms; (b) the review searches at least 2 databases and looks at other sources; (c) the review states the criteria used for deciding which studies to include in the overview; (d) the review reports how many studies were identified by searches, numbers excluded and appropriate reasons for excluding them; (e) the conclusions made by the author(s) are supported by the data and/or analysis reported in the review. 0 means that the above mentioned criteria were partially fulfilled. -1 means that none of the above criteria was fulfilled. This is an operationalization of the Oxman criteria [8], adapted from reference [55], 614 / 75:3 / Br J Clin Pharmacol Herb-drug interactions Table 4 The most clinically important herb-drug interactions HMP Synthetic drug Clinical outcome Ginkgo Anticoagulants, anti-inflammatory agents, antihypertensives, anaesthetics Haemorrhage, apraxia, haematoma, hyphaema, permanent neurological deficit, death Ginseng Antidepressants, antidiabetics, anticoagulants, calcium channel blockers, cholesterol lowering agents, diuretics, hormonal agents Inhibition of platelet aggregation, reduced platelet adhesiveness, hypoglycaemia, changes in blood pressure and heart rate, mania, headache, tremor, insomnia Kava Antidepressants, antiplatelets, CYP-450 metabolized agents, sedatives Coma, sedation, lethargy, drowsiness St John's wort Antineoplastics, antimicrobials, antiretrovirals, hormonal agents, immunnosupressants Transplant rejection, unwanted pregnancy, delayed emergence from anaesthesia, CVD collapse SRs, HMPs acted both as inhibitors and synergists [14,15, 18,19,23-27,32,33,37,41 -46,48,49,52,53]. For 39 HMPs, only minor concerns were raised regarding interactions [9-15, 17-24, 27-30, 32-42, 44, 46-48, 50-54], five raised some concerns [16, 25, 26, 45, 49] and two raised serious concerns [31,43]. Only three SRs were of excellent methodological quality [16,25,31 ], 10 had minor deficits [10,17,18,20,21, 24,27,28,48,50] and 20 had major methodological flaws [9,11 -15,19, 22, 23, 26, 29, 30, 32-47,49, 51 -54] (Table 3). Conflicts of interest of the authors were mentioned in only one SR [31]. The source of funding was mentioned in only two SRs [20,21]. Discussion This article was aimed at providing an overview of SRs of herb-drug interactions. Forty-six SRs could be included. Thirty-nine of the HMPs submitted to SRs did not interact with drugs [9-20, 22-24, 27-30, 32-42, 44, 46-48, 50-54]. Eight HMPs had the potential for such interactions [21,25, 26, 31, 43, 45,49]. The interactions caused mostly mild to severe adverse effects (AEs). The HMPs implicated were ginkgo, ginseng, green tea, kava, mistletoe, saw palmetto and St John's wort (Tables 1,2 and 4). The most common interacting drugs were anticoagulants [13,15,16,18, 24,26,27,29,33,34,36,37,39,40,44-46, 49,50,52,53] and antiplatelet agents [13,15,24,25,27,29, 33,34,36,37,39,40,44,45,49,50,52,53].The most probable mechanisms of these interactions involve an inhibition of thromboxane synthesis and cyclooxygenase. Some herbs acted as inhibitors/antagonists of drugs [16, 21, 22, 31] whereas others acted as agonists/synergists [9-13,17,20, 28-30,34-36,38-40,47,50,51,54]. In nine SRs, there was a bimodal mode of action causing both antagonism and synergism [14,15,18,19,23-27,32,33,37,41 -46,48,49,52, 53]. The methodological quality of the included SRs was frequently inadequate (Table 3). Many of the articles that scored poorly on our quality rating were monograph-type publications which are not designed as typical systematic reviews. As these articles do contribute relevant information and are relatively frequent in the literature about herbal medicine, we decided to include them in our overview. Thirty-nine HMPs were reported not to interact with synthetic drugs. However, this information may be unreliable because of the frequently poor quality of the primary data that missed detection of herb-drug interactions and subsequent AEs. In 10 SRs, herb-drug interactions were hypothetical as the primary research was based on in vitro and/or animal studies. This overview suggests that the quality of research on herb-drug interactions is often wanting. It also reveals that there is still paucity of such investigations. As a consequence, therapeutic decisions can be hampered.To make progress in this area, we need more effective monitoring systems, better implementation of existing regulations, better quality of reporting and more reliable SRs. The present analysis has several limitations. Although comprehensive searches were conducted, there is no guarantee that all relevant SRs were located. Furthermore, any overview of SRs is susceptible to publication bias. As we only included SRs, our overview cannot provide information on HMPs for which no SR is available. Conclusion In conclusion, the majority of SRs revealed moderately severe or minor interactions between HMPs and drugs. Some HMPs, however, do interact with drugs posing severe health threats.Due to the limited quality and scarcity of the primary data, these conclusions should be treated with caution. Competing Interests There are no competing interests to declare. Br j Clin Pharmacol / 75:3 / 615 P. Posadzki etal. Appendix 1 Search strategy for MEDLINE (herb$ adj3 (capletS or capsuleS or compounds or creamS or decoctionS or drugS or essences or extracts or formulS or healS or InfusS or juiceS or medicS or mixtures or powderS or preparS or prescriS or product or products or remedS or supplements or tablets or tea or teas or therapS or tinctures or tisaneS or treatments)).ti,ab. HerbalS.ti.ab. (plants adj3 (capletS or capsuleS or compounds or creamS or decoctionS or drugS or essences or extracts or formulS or healS or herbS or InfusS or juiceS or medicS or mixtures or powderS or preparS or prescriS or product or products or remedS or supplements or tablets or tea or teas or therapS or tinctures or tisaneS or treatments)).ti,ab. (phytodrugS or phytomedS or phytopharmacS or phytotherS or phytochemical$).ti,ab. ((naturals or naturoS) adj3 (capletS or capsuleS or compounds or creamS or decoctionS or drugS or essences or extracts or formulS or herbS or InfusS or juiceS or medicS or mixtures or powderS or preparS or prescriS or product or products or remedS or supplements or tablets or tea or teas or therapS or tinctures or tisaneS or treatments)).ti,ab. (botanicals adj3 (capletS or capsuleS or compounds or creamS or decoctionS or drugS or essences or extracts or formulS or healS or herbS or InfusS or juiceS or medicS or mixtures or powderS or preparS or prescriS or product or products or remedS or supplements or tablets or tea or teas or therapS or tinctures or tisaneS or treatments)).ti,ab. (traditional adj3 (capletS or capsuleS or compounds or creamS or decoctionS or drugS or essences or extracts or formulS or herbS or InfusS or juiceS or medicS or mixtures or powderS or preparS or prescriS or product or products or remedS or supplements or tablets or tea or teas or tinctures or tisaneS)).ti,ab. (Chinese adj3 (capletS or capsuleS or compounds or creamS or decoctionS or drugS or essences or extracts or formulS or herbS or InfusS or juiceS or medicS or mixtures or powderS or preparS or prescriS or product or products or remedS or supplements or tablets or tea or teas or tinctures or tisaneS)).ti,ab. (EthnobotanS or pharmacognoS or EthnopharmacoS or ethnomedic$).ti,ab. (Ayur ved$ or AyurvedS or kampo or siddha or unani).ti,ab. (folk adj3 (capletS or capsuleS or compounds or creamS or decoctionS or drugS or essences or extracts or formulS or herbS or InfusS or juiceS or medicS or mixtures or powderS or preparS or prescriS or product or products or remedS or supplements or tablets or tea or teas or tinctures or tisaneS)).ti,ab. exp Ethnobotany/ exp Phytotherapy/ exp Plants, Medicinal/ exp Herb-Drug Interactions/ exp Plant Exudates/ exp Materia Medica/ exp Herbal Medicine/ 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 complicat$.ti,ab. (safe or safety or risk$).ti,ab. Side effectS.ti.ab. (tolerate or tolerability or tolerance or hypersensativS or aggravat$).ti,ab. (Adverse adj3 (effects or events or Interactions or outcomes or Reactions or responses)).ti,ab. (UnintenS adj3 (effects or events or Interactions or outcomes or Reactions or responses)).ti,ab. (Unwanted adj3 (effects or events or Interactions or outcomes or Reactions or responses)).ti,ab. (Unexpected adj3 (effects or events or Interactions or outcomes or Reactions or responses)).ti,ab. (UndesirS adj3 (effects or events or Interactions or outcomes or Reactions or responses)).ti,ab. (harmS adj3 (effects or events or Interactions or outcomes or Reactions or responses)).ti,ab. (ToxicS or AdulteratS or ContaminatS or PoisonS or hepatotoxic$).ti,ab. (Aftereffect or after effect).ti,ab. exp Drug Toxicity/ exp Drug Contamination/ 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 ReviewS .ti. 19 and 34 and 35 REFERENCES 1 Hunt KJ, Ernst E. Patients' use of CAM: results from the Health Survey for England 2005. Focus Altern Complement Ther 2010;15:101-3. 2 Merritt-Charles L. The prevalence of herbal medicine use among surgical patients in Trinidad. Focus Altern Complement Ther 2011; 16: 266-70. 3 Paul JH, Seaforth CE. Harmful plants in Caribbean folk medicine. Focus Altern Complement Ther 2011; 16:261 -5. 4 Ernst E. Possible interactions between synthetic and herbal medicinal products. Part 1: a systematic review of the indirect evidence. Perfusion 2000; 13:4-6. 5 Ernst E, Pittler MH, Wider B, Boddy K.The Desktop Guide to Complementary and Alternative Medicine, 2nd edn. Edinburgh: Elsevier Mosby, 2006. 6 Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs an updated systematic review. Drugs 2009; 69:1777-98. 7 Izzo AA, Di Carlo G, Borrelli F, Ernst E. Cardiovascular pharmacotherapy and herbal medicines: the risk of drug interaction. Int J Cardiol 2005; 98:1-14. 8 Oxman AD, Guyatt GH. Validation of an index of the quality of review articles. J Clin Epidemiol 1991; 44:1271 -8. 9 Bäsch E, Gabardi S, Ulbricht C. Bitter melon (Momordica charantia): a review of efficacy and safety. Am J Health Syst Pharm 2003;60:356-9. 10 Bäsch E, Ulbricht C, Harrison M, Sollars D, Smith M, Dennehy C, Szapary P. Alfalfa (Medicago sativa L.):a clinical decision support tool. J Herb Pharmacother 2003;3:69-90. 11 Bäsch E, Ulbricht C, Hammerness P, Bevins A, Sollars D. Thyme (Thymus vulgaris L), thymol. J Herb Pharmacother 2004; 4:49-67. 12 Bäsch E, Bent S, Foppa I, Haskmi S, Kroll D, Meie M, Szapary P, Ulbricht C, Vora M, Yong S. Marigold {Calendula officinalis L): an evidence-based systematic review by the Natural Standard Research Collaboration. J Herb Pharmacother 2006;6:135-59. 616 / 75:3 / Br j Clin Pharmacol Herb-drug interactions 13 Bäsch E, Foppa I, Liebowitz R, Nelson J, Smith M, Sollars D, Ulbricht C. Lavender (Lavandula angustifolia Miller). J Herb Pharmacother 2004; 4:63-78. 14 Bäsch E, Boon H, Davies-Heerema T, Foppo I, Hashmi S, Hasskarl J, Sollars D, Ulbricht C. Boswellia:an evidence-based systematic review by the Natural Standard Research Collaboration. J Herb Pharmacother 2004;4:63-83. 15 Brendler T, Gruenwald J, Ulbricht C, Bäsch E. Devil's Claw (Harpagophytum procumbens DC): an evidence-based systematic review by the Natural Standard Research Collaboration. J Herb Pharmacother 2006;6:89-126. 16 Ernst E, Canter PH, Thompson Coon J. Does Ginkgo biloba increase the risk of bleeding? A systematic review of case reports. Perfusion 2005; 18: 52-6. 17 Giles M, Ulbricht C, Khalsa KP, Kirkwood CD, Park C, Bäsch E. Butterbur: an evidence-based systematic review by the natural standard research collaboration. J Herb Pharmacother 2005; 5:119-43. 18 Nelsen J, Ulbricht C, Barrette EP, Sollars D,Tsouronis C, Rogers A, Bäsch S, Hashmi S, Bent S, Bäsch E. Red clover (Trifolium pratense) monograph: a clinical decision support tool. J Herb Pharmacother 2002;2:49-72. 19 Sweeney B, Vora M, Ulbricht C, Bäsch E. Evidence-based systematic review of dandelion (Taraxacum officinale) by Natural Standard Research Collaboration. J Herb Pharmacother 2005; 5: 79-93. 20 Tiffany N, Boon H, Ulbricht C, Bäsch E, Bent S, Barrette EP, Smith M, Sollars D, Dennehy CE, Szapary P. Horse chestnut:a multidisciplinary clinical review. J Herb Pharmacother 2002; 2:71-85. 21 Ulbricht C, Bäsch E, Vora M, Sollars D, Rogers A, Bäsch S, Smith M, Moffet H, Hammerness P. Chaparral monograph: a clinical decision support tool. J Herb Pharmacother 2003; 3: 121-31. 22 Ulbricht C, Bäsch E, Hammerness P, Vora M, Wylie J, Woods J. An evidence-based systematic review of belladonna by the Natural Standard Research Collaboration. J Herb Pharmacother 2004; 4:61 -90. 23 Ulbricht C, Brendler T, Gruenwald J, Kligler B, Keifer D, Abrams TR, Woods J, Boon H, Kirkwood CD, Hackman DA, Bäsch E, Lafferty HJ. Lemon balm (Melissa officinalis L.):an evidence-based systematic review by the Natural Standard Research Collaboration. J Herb Pharmacother 2005; 5: 71-114. 24 Ulbricht C, Bäsch E, Szapary P, Hammerness P, Axentsev S, Boon H, Kroll D, Garraway L,Vora M, Woods J.Guggul for hyperlipidemia: a review by the Natural Standard Research Collaboration. Complement Ther Med 2005; 13: 279-90. 25 Ulbricht C, Bäsch E, Boon H, Ernst E, Hammerness P, Sollars D, Tsourounis C, Woods J, Bent S. Safety review of kava (Piper methysticum) by the Natural Standard Research Collaboration. Expert Opin Drug Saf 2005; 4:779-94. 26 Ulbricht C, Bäsch E, Brigham A, Bryan K, Costa D, Dacey C, Foppa I, Giese N, Hawkins EB, Montalbano JK, Tanguay-Colucci S, Varghese M, Vora M, Weissner W. An evidence-based systematic review of ginseng interactions by the Natural Standard Research Collaboration. Natural Med J 2009;1:1-13. 27 Ulbricht C, Bäsch E, Burke D, Cheung L, Ernst E, Giese N, Foppa I, Hammerness P, Hashmi S, Kuo G, Miranda M, Mukherjee S, Smith M, Sollars D, Tanguay-Colucci S, Vijayan N, Weissner W. Fenugreek (Trigonella foenum-graecum L. Leguminosae): an evidence-based systematic review by the Natural Standard Research Collaboration. J Herb Pharmacother 2007; 7:143-77. 28 Ulbricht C, Dam C, Milkin T, Seamon E, Weissner W, Woods J. Banaba (Lagerstroemia speciosa L.): an evidence-based systematic review by the Natural Standard Research Collaboration. J Herb Pharmacother 2007; 7:99-113. 29 Ulbricht C, Chao W, Nummy K, Rusie E,Tanguay-Colucci S, lannuzzi CM, Plammoottil JB, Varghese M, Weissner W. Chia (Salvia hispanica): a systematic review by the Natural Standard Research Collaboration. Rev Recent Clin Trials 2009;4:168-74. 30 Ulbricht C, Isaac R, Milkin T, Poole EA, Rusie E, Grimes Serrano JM, Weissner W, Windsor RC, Woods J. An evidence-based systematic review of stevia by the Natural Standard Research Collaboration. Cardiovasc Hematol Agents Med Chem 2010; 8:113-27. 31 Whitten DL, Myers SP, Hawrelak JA, Wohlmuth H.The effect of St John's wort extracts on CYP3A: a systematic review of prospective clinical trials. Br J Clin Pharmacol 2006; 62: 512-26. 32 Ulbricht C, Costa D, Grimes Serrano JM, Guilford J, Isaac R, Seamon E, Varghese M. An evidence-based systematic review of spearmint by the natural standard research collaboration. J Dietary Suppl 2010; 7:179-215. 33 Ulbricht C, Conquer J, Costa D, Hollands W, lannuzzi C, Isaac R, Jordan JK, Ledesma N, Ostroff C, Grimes Serrano JM, Shaffer MD, Varghese M. An evidence-based systematic review of saffron (Crocus sativus) by the Natural Standard Research Collaboration. J Dietary Suppl 2011;8:58-114. 34 Ulbricht C, Abrams TR, Brigham A, Ceurvels J, Clubb J, Curtiss W, DeFranco Kirkwood C, Giese N, Hoehn K, lovin R, Isaac R, Rusie E, Serrano G, Varghese M, Weissner W, Windsor RC An evidence-based systematic review of rosemary (Rosmarinus officinalis) by the Natural Standard Research Collaboration. J Dietary Suppl 2010;7:351-413. 35 Ulbricht C, Chao W, Costa D, Nguyen Y, Seamon E, Weissner W. An evidence-based systematic review of green-lipped mussel (Perna canaliculus) by the Natural Standard Research Collaboration. J Dietary Suppl 2009; 6: 54-90. 36 Ulbricht C, Conquer J, Costa D, Hamilton W, Higdon ER, Isaac R, Rusie E, Rychlik I, Grimes Serrano JM, Tanguay-Colucci S, Theeman M, Varghese M. An evidence-based systematic review of senna (Cassia senna) by the Natural Standard Research Collaboration. J Dietary Suppl 2011; 8:189-238. 37 Ulbricht C, Abrams TR, Conquer J, Costa D, Serrano G, lovin R, Yen Nguyen RS, Rusie E, Tran D, Weissner W, Windsor RC An Br j Clin Pharmacol / 75:3 / 617 P. Posadzki etal. evidence-based systematic review of Umckaloabo (Pelargonium sidoides) by the Natural Standard Research Collaboration.] Dietary Suppl 2010; 7: 283-302. 38 Ulbricht C, Abrams TR, Bäsch E, Davies-Heerema T, Foppa I, Hammerness P, Rusie E,Tanguay-Colucci S, Taylor S, Varghese M, Weissner W, Woods J. An evidence-based systematic review of Gymnema (Gymnema sylvestre R. Br.) by the Natural Standard Research Collaboration. J Dietary Suppl 2011;8:311-30. 39 Ulbricht C, Bäsch E, Dacey C, Dith S, Hammerness P, Hashmi S, Seamon E, Vora M, Weissner W. An evidence-based systematic review of blessed thistle (Cnicus benedictus) by the Natural Standard Research Collaboration. J Dietary Suppl 2008;5:422-237. 40 Armbruester N, Bryan K, Costa D, Giese N, Gruenwald J, lovin R, Isaac R, Seamon E, Grimes Serrano JM, Tanguay-Colucci S, Ulbricht C, Weissner W, Windsor R, Yoon H, Zhang J. Cinnamon (Cinnamomum spp.). Natural Standard Professional Monograph. Available at http://www.naturalstandard.com/databases/ herbssupplements/all/cassia.asp (last accessed 21 January 2012), 1-70.2012. 41 Barrette EP, Bäsch E, Bent S, Burke D, Costa D, Foppa I, Giese N, Goble M, Grimes Serrano JM, Hammerness P, Mendoza V, Miranda M, Smith M, Ulbricht C Black cohosh (Cimicifuga racemosa [L] Nutt.). Natural Standard Professional Monograph. Available at http://www. naturalstandard.com/databases/herbssupplements/ all/cimicifuga.asp (last accessed 21 January 2012) 2012. 42 Bäsch E, Ulbricht C, Bäsch S, Dalton S, Ernst E, Foppa I, Szapary P, Tiffany N, Orlando CW, Vora M. An evidence-based systematic review of echinacea (E. angustifolia DC, E. pallida, E. purpurea) by the Natural Standard Research Collaboration. J Herb Pharmacother 2005; 5: 57-88. 43 Bäsch E, Conquer J, Dominguez R, Giese N, Grimes Serrano JM, Hackman D, Heller M, Isaac R, Joseph A, Linardakis N, McGarry M, Schadde S, Scully L, Seamon E, Shaffer M, Ulbricht C, Weissner W. Mistletoe (Viscum album L). Natural Standard Professional Monograph. Available at http://www.naturalstandard.com/databases/ herbssupplements/all/mistletoe.asp (last accessed 21 January 2012), 1-70. 2012. 44 Bäsch E, Dacey C, Ernst E, Foppa I, Grimes Serrano JM, Hammerness P, Kerbel B, Nummy K, Seamon E, Shaffer M, Tanguay-Colucci S, Vora M, Ulbricht C, Weissner W. Hawthorn (Crataegus laevigata^. oxyacantha^.monogy/i^C. pentagyna). Natural Standard Professional Monograph. Available at http://www.naturalstandard. com/databases/herbssupplements/all/crataegus.asp (last accessed 21 January 2012). 2012. 45 Bäsch E, Conquer J, Culwell S, Dacey C, Grimes Serrano JM, Guilford J, Hammerness P, Higdon ER, Jingst S, Kats J, McDermott YH, Rusie E, Ulbricht C, Weissner W, Windsor R. Green tea (Camellia sinensis). Natural Standard Professional Monograph. Available at http://www.naturalstandard.com/ databases/herbssupplements/all/camellia.asp (last accessed 21 January 2012). 2012. 46 Brendler T, Abrams TT, Brigham A, Bryan JK, Diem-Che W, Ceurvels J, Giese N, Grimes Serrano JM, Gruenwald J, Khanzada F, Lee DS, Markowitz JS, Seamon E, Weissner W. Noni (Morinda citrifolia). Natural Standard Professional Monograph. Available at http://www.naturalstandard.com/ databases/herbssupplements/all/noni.asp (last accessed 21 January 2012). 2012. 47 Ceurvels J, Davis M, Clubb J, Giese N, Goodfriend J, Tanguay-Colucci S, Weissner W. Blue cohosh (Caulophyllum thalictroides) Natural Standard Professional Monograph. Available at http://www.naturalstandard.com/ databases/herbssupplements/all/caulophyllum.asp (last accessed 21 January 2012). 2012. 48 Keifer D, Ulbricht C, Abrams TR, Bäsch E, Giese N, Giles M, DeFranco Kirkwood C, Miranda M, Woods J. Peppermint (Mentha piperita): an evidence-based systematic review by the Natural Standard Research Collaboration. J Herb Pharmacother 2007; 7: 91 -143. 49 Ulbricht C, Bäsch E, Bent S, Boon H, Corrado M, Foppa I, Hashmi S, Hammerness P, Kingsbury E, Smith M, Szapary P, Vora M, Weissner W. Evidence-based systematic review of saw palmetto by the Natural Standard Research Collaboration. J Soc Integr Oncol 2006; 4:170-86. 50 Ulbricht C, Armstrong J, Bäsch E, Bäsch S, Bent S, Dacey C, Dalton S, Foppa I, Giese N, Hammerness P, Kirkwood C, Sollars D,Tanguay-Colucci S, Weissner W. An evidence-based systematic review of Aloe vera by the Natural Standard Research Collaboration. J Herb Pharmacother 2007; 7: 279-323. 51 Ulbricht C, Weissner W, Bäsch E, Giese N, Hammerness P, Rusie-Seamon E, Varghese M, Woods J. Maitake mushroom (Grifola frondosa): systematic review by the Natural Standard Research Collaboration. J Soc Integr Oncol 2009;7:66-72. 52 Ulbricht C, Abrams TR, Bent S, Boon H, Costa D, Dacey C, Guilford J, Giese N, Grimes Serrano JM, Hackman DA, Scully L, Rusie E, Shaffer M, Varghese M, Vijarian N, Weissner W, Welch S, Wong D, Woods J. Reishi mushroom (Ganoderma lucidum): systematic review by the Natural Standard Research Collaboration. J Soc Integr Oncol 2010; 8: 148-59. 53 Ulbricht C, Bäsch E, Barrette E, Boon H, Chao W, Costa D, Higdon ER, Isaac R, Lynch M, Papaliodis G, Serrano J, Varghese A, Vora M, Windsor R, Woods J.Turmeric (Curcuma longa): an evidence-based systematic review by the natural standard research collaboration. Altern Complement Ther 2011;17:225-36. 54 Vora K, Dennehy C, Ulbricht C, Bäsch E,Vora M.Chasteberry (Vitex agnus-castus) natural standard professional monograph. Available at http://www.naturalstandard.com/ databases/herbssupplements/all/vitex-agnus-castus.asp (last accessed 21 January 2012). 2012. 55 Ernst E, Posadzki P, Lee MS. Complementary and alternative medicine (CAM) for sexual dysfunction and erectile dysfunction in older men and women: an overview of systematic reviews. Maturitas 2011; 70: 37-41. 618 / 75:3 / Br j Clin Pharmacol