Herb–drug interactions: an overview of systematic reviews

Authors

  • Paul Posadzki,

    Corresponding author
    1. Complementary Medicine, Peninsula Medical School, University of Exeter, Veysey Building, Salmon Pool Lane, Exeter, EX2 4SG, England
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  • Leala Watson,

    1. Complementary Medicine, Peninsula Medical School, University of Exeter, Veysey Building, Salmon Pool Lane, Exeter, EX2 4SG, England
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  • Edzard Ernst

    1. Complementary Medicine, Peninsula Medical School, University of Exeter, Veysey Building, Salmon Pool Lane, Exeter, EX2 4SG, England
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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

Abstract

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. The 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 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, Caulophyllum thalictroides, Cinnamomum spp., Cimicifuga racemosa, Cnicus benedictus, Commifora mukul, Crataegus spp., Crocus sativus, Curcuma longa, Echinacea spp., 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 methysticum, Pelargonium sidoides, Perna canaliculus, Petasites hybridus, Rosmarinus officinalis, Serenoa repens, Salvia hispanica, Stevia rebaudiana, Taraxacum officinale, Thymus vulgaris, Trifolium pretense, Trigonella foenum-graecum, Viscum album and Vitex agnus-castus.

Figure 1.

Flow diagram

Table 1. Key data from the included SRs
First author (year) Country [Ref] Type of primary data * (n) HMPs evaluated Drugs that interact Type of interactions Clinical outcomes Mechanism of action Overall judgment Quality of SR Comment
  1. *Range of primary data. †Based on in vitro studies. ‡Based on animal studies.

  2. 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; HbA1c, haemoglobin A1c; 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.

Armbruer (2012) USA [40] RCTs, NRCT, CCT, SRs, MAs, CR, CS, AS, in vitro<100Cinnamon (Cinnamomum spp.)1. AntibioticsSynergism with 1, 2, 3and, 4, 5, 6and,7, 9, 10, 11, 12and, 13,Increased risk of hypoglycaemia, bleeding (theoretical)Inhibited arachidonic acid release and thromboxane B2 formation; inhibition of HMG-CoA activity, inhibition of aminopyrine N-demethylationOnly minor concerns−4Most 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.
2. Anticoagulants or antiplatelets
3. Antidiabetics
4. Antifungals
5. Antilipaemics
6. Antineoplastic agents
7. Antiretroviral agents
8. Cytochrome P450 metabolized agents
9. Anxiolytics
10. Oestrogens
11. Hepatotoxic agents
12. Immunosuppressants
13. Sympathomimetics
Barrette (2012) USA [41] RCTs, CCT, SRs, CR, CS, AS, in vitro<100Black cohosh (Cimicifuga racemosa)1. AntihistaminesInhibition of 1, 8, synergism with 2, 3, 4,GI upsetIt is not clear how (or if) black cohosh interacts with estrogens/estrogen receptors and/or progestinsOnly minor concerns−4Interaction data in this area were lacking. Caution for patients with known estrogen sensitive conditions, such as breast cancer, uterine cancer or endometriosis; in patients on hormone replacement therapy, including tamoxifen or raloxifene; in epileptic patients; in patients on antihypertensive medications; and in patients with liver disease.
2. Antihypertensives
3. Antilipemic agents
4. Antineoplastic agents
5. Antiseizures
6. OEstrogens
7. Hepatotoxic agents
8. Oral agents
9. Tamoxifen, raloxifene
Basch (2003) USA [9] CCTs, CRs<10Bitter melon (Momordica charantia)1. HypoglycaemicsSynergism with 1Lowered blood glucose concentrationsDecreased hepatic gluconeogenesis, increased hepatic glycogen synthesis; increased pancreatic insulin secretion.Only minor concerns−4Low quality and quantity of the available evidence regarding interactions. Caution for patients with diabetes
Basch (2003) USA [10] CS, CR<10Alfalfa (Medicago sativa)1. HypoglycaemicsSynergism with 1 and 2Increased drug-induced photosensitivity, lowered blood glucose, total cholesterol or LDLSaponins may reduce cholesterol absorptionOnly minor concerns2Chlorpromazine was reported to increase drug-induced photosensitivity when taken in combination with alfalfa
2. Cholesterol lowering agents
3. Chlorpromazine
Basch (2004) USA [11] RCT, SRS<10Thyme (Thymus vulgaris)1. 5-fluorouracilSynergism with 1n.k.Thymol increases the stratum corneum lipids fluidity and perturbing the barrier integrity of the epidermisOnly minor concerns−4Thyme may decrease concentrations of thyroid hormone; caution for patients taking hepatotoxic agents
Basch (2005) USA [42] RCTs, NRCT, CCT, SRs, MAs, OS, CR, CS, AS, in vitro<100 Echinacea spp. 1. AmoxicillinSynergism with 2, 3, 4, 5 and inhibition of 3Rhabdomyolysis, shock, and death (causality questioned)Selective modulation of the catalytic activity of CYP3A at hepatic and intestinal sitesOnly minor concerns−4Use cautiously in patients using cytochrome P450-metabolized agents or hepatotoxic drugs
2. Antineoplastic agents
3. Cytochrome P450-metabolized agents
4. Hepatotoxic agents
5. Hydrophilic agents
Basch (2006) USA [12] RCTs, CS, comparison study, AS<10Calendula (Calendula officinalis)1. SedativesSynergism with 1 and 2n.k.Insufficient evidence to determine pharmacodynamics/kineticsOnly minor concerns0Systemic effects in humans were not clear; caution for patients taking sedatives
2. Antihypertensives
Basch (2004) USA [13] RCTs, NRCT,CS, AS<10Lavender (Lavandula angustifolia Miller)1. Sedatives,Synergism with 1, 2, 3 and 4n.k.Linalool binds to glutamate and increases GABA concentrationsOnly minor concerns−4Use cautiously in patients taking sedatives, anticoagulants, antiplatelet agents and anti-epileptic drugs
2. Anticoagulants, NSAIDs, anti-platelet agents,
3. Anti-seizures
4. Cholesterol lowering agents
Basch (2004) USA [14] RCTs, NRCTs, SR, comparison study, in vitro<100Boswellia (Boswellia serrata)1. Leukotriene inhibitorsInhibition of 1 and synergism with 2n.k.Inhibition of lipoxygenase to produce 5-HETE, LTB4 and HLEOnly minor concerns−4Use cautiously in patients taking leukotriene inhibitors
2. Anti-neoplastic agents
Basch (2012) USA [43] RCTs, NRCT, CCT, SRs, OS, cohort study, CR, CS, CCS, AS, in vitro<100Mistletoe (Viscum album)1. Antidiabetic agentsSynergism with 1, 2, 3and, 4, 5, 6, inhibition of 7Organ fibrosis and death, cardiotoxicity, bradycardia, hypovolaemic shock and CVD collapse, inflammatory reactionMistletoe lectins agglutinate human erythrocytes and react with immunoglobulinsSerious concerns−4Use cautiously in patients with cardiovascular disease, uncontrolled hyperthyroidism, seizures, glaucoma and diabetics.
2. Antihypertensives
3. Antineoplastic agents
4. Cholinergic agents
5. CNS depressants
6. Diuretics
7. Immunosuppressants
8. Thyroid hormones
Basch (2012) USA [44] RCTs, NRCT, CCT, SRs, MA, CR, AS, in vitro<100Hawthorn (Crataegus spp.)1. Alpha agonistsInhibition of 1and, 2, synergism with 3and, 4and, 5, 6, 7, 8Increased risk of bleedingInhibition of thromboxane A2 biosynthesisOnly minor concerns−4Although possible safe co-administration of hawthorn and cardiac glycosides has been suggested, close monitoring during dose titration is warranted.
2. Anticoagulants and antiplatelets
3. Antihypertensives
4. Antilipaemic agents
5. β-adrenoceptor blockers
6. Digoxin, digitoxin
7. Phosphodiesterase inhibitors
8. Vasodilators
Basch (2012) USA [45] RCTs, CCT, SRs, MAs, CR, AS, in vitro<100Green tea (Camellia sinensis)1. AnalgesicsSynergism with 1, 4 and , 6, 7, 9, 15, 16 inhibition of 2, 8, 10, 13, 14,Increased risk of toxic effects, hypertensive crisis;, impaired iron metabolism and microcytic anaemia, increased blood pressure; ischaemic strokeEGCG inhibits the IL-1 beta-induced activity and expression of cyclooxygenase-2 and nitric oxide synthase-2; caffeine acts via blockade of adenosine receptors, and theoretically, may antagonize the effects of adenosineSome concerns−4Use cautiously in patients taking analgesics, antilipaemics, antiseizures, antivirals, β-adrenoceptor blockers, cytochrome P450-metabolized agents, hepatotoxic agents, hormonal agents and sedatives.
2. Antiandrogens
3. Antiarthritics
4. Anticoagulants and antiplatelets
5. Antidepressants
6. Antilipaemics
7. Antivirals
8. Cytochrome P450metabolized agents
9. Hepatotoxic agents
10. Oestrogen
11. Hypertensives
12. Hypoglycaemics
13. Sedatives
14. P-glycoprotein modulators
15. Antiseizures
16. β−adrenoceptor agonists
Brendler (2006) Germany [15] RCTs, CS, AS<100Devil's claw (Harpagophytum procumbens)1. Anti-arrhythmic agentsSynergism with 1, inhibition of 2Decreased HR Release of inflammatory mediators; inhibition of arachidonic acid metabolism pathwaysOnly minor concerns0Use with anticoagulant and antiplatelet agents should be approached with caution
2. Inotropic agents
3. Anticoagulant/antiplatelet agents
Brendler (2012) Germany [46] RCTs, AS, in vitro<100Noni (Morinda citrifolia)1. Anti-angiogenic drugsSynergism with 1, 2, 3, 5, 6, inhibition of 3, 7Decreased gastric transit time, increased risk of hyperkalemia,Inhibition of copper-induced LDL oxidation; of Ras oncogene function, cell transformation; of the tumour-promoting effect of TNF-a, and activator protein-1 transactivation.Only minor concerns−4Use cautiously in patients using warfarin or other anticoagulants, antihypertensives or ACE inhibitors.
2. Antibiotics
3. Anticoagulants
4. Antihypertensives
5. Anti-inflammatory agents
6. Hepatotoxic agents
7. Immunosuppressants
Ceurvels, (2012) USA [47] CR, AS<10Blue cohosh (Caulophyllum thalictroides)1. Antidiabetic agentsSynergism with 3 and 5Coronary vasoconstriction, tachycardia, increase in blood pressure, diaphoresis, abdominal pain, vomiting and muscle weaknesscaulosaponin and caulophyllosaponin, have been shown to have labour induction propertiesOnly minor concerns−4Use cautiously in patients who are pregnant or breast-feeding; in patients who smoke or are quitting smoking due to possible nicotine toxicity; and in patients with diabetes
2. Cardiovascular drugs
3. Nicotine
4. Oxytocin
5. Cocaine
Ernst (2005) UK [16] CRs<100 Ginkgo biloba 1. Paracetamol (acetaminophen)Inhibition of 1, 3, 4, 6Haemorrhage, bleeding, apraxia, death, haematoma, hyphaema, permanent neurological deficitInhibition of platelet aggregationSome concerns5Use cautiously in patients taking anaesthetics, analgesics, anticoagulants and antiplatelet agents
2. lisinopril
3. anaesthetics
4. aspirin
5. warfarin
6. ibuprofen
Giles (2005) USA [17] RCT, OLS, SR<100Butterbur (Petasites hybridus)1. AnticholinergicsSynergism with 1Increased liver enzyme levelsReduction of smooth muscle spasm; inhibition of lipoxygenase activity and down-regulation of leukotriene synthesisOnly minor concerns1Administration of butterbur with anticholinergics may not be advisable
Keifer (2007) USA [48] RCTs, AS, in vitro<10Peppermint (Mentha piperita)1. AntibioticsSynergism with 1,3, 6, and inhibition of 2, 4, 5and n.k.Menthol and menthyl acetate may inhibit CYP3A4-mediated nifedipine metabolism and increase felodopine concentrationsOnly minor concerns2No documented interactions in humans.
2. Benzoic acid
3. Calcium channel blockers
4. Ciclosporin
5. Cytochrome P450 metabolized agents
6. Oxytetracycline
Nelsen (2002) USA [18] RCTs, CS, in vitro<100Red clover (Trifolium pratense)1. Cytochrome P450-metabolized agentsInhibition of 1, 2 and synergism with 2Alleviated GrRH, FSH and LH concentrationsBinding to estradiol receptors (estradiol-α and estradiol-β)Only minor concerns1Red clover may have synergistic effects with anticoagulants or antiplatelet agents; use cautiously in patients taking hormonal agents
2. HRT and OCPs
Sweeney (2005) USA [19] Case series, in vitro, AS<10Dandelion (Taraxacum officinale)1. CiprofloxacinInhibition of 1, synergism with 3, 4Inhibition of platelet aggregationSesquiterpenes lactones may act as anti-inflammatory agents; lactones may increase gastric acid secretion; increased bile production and release; inulin may act to buffer blood glucose concentrationsOnly minor concerns−4Patients using antihypertensive and/or antidiabetic agents or insulin should be monitored closely while using dandelion.
2. Hypoglycaemic drugs
3. Anticoagulants
4. Cytochrome P450 1A2 and 2E metabolized agents
Tiffany (2002) USA [20] RCTs, SR, OS, AS<100Horse chestnut seed extract (Hippocastanaceae)1. Hypoglycaemic agentsSynergism with 1n.k.Inhibition of the normal increase of serum glucose concentrationsOnly minor concerns1No documented interactions in humans.
Ulbricht (2003) USA [21] CR, AS<100Chaparral (Larrea tridentate)1. Cytochrome P450 metabolized agentsInhibition of 1Increased renal and liver toxicity (theoretically)Diminished platelet aggregation; decrease plasma glucose concentrations; blocked cellular respiration and exerted antioxidant effects; inhibited induction of ornithine decarboxylase and Only minor concerns2Chaparral should be avoided in combination with potentially hepatotoxic agents
Ulbricht (2004) USA [22] [22] RCTs, NRCT, OS, AS<100Belladonna (Herbae pulvis standardisatus)1. CisaprideInhibition of 1, 2Delayed gastrointestinal transit timeInhibition of the muscarinic actions of acetylcholineOnly minor concerns−4Avoid concomitant use with alcohol, anti-arrhythmics,antidepressants, anticholinergic and drugs that interact with atropine
2. Tacrine
Ulbricht (2005) USA [23] RCT, CS, AS<100Lemon balm (Melissa officinalis)1. BarbituratesSynergism with 1, 2, inhibition of 4Hypnosis, sedationReduced pituitary and serum TSH concentrationsOnly minor concerns0Use cautiously in patients taking hormonal agents and sedatives
2. Sedatives
3. Nicotine and scopolamine
4. SSRIs
Ulbricht (2005) USA [24] RCTs, CS, AS<100Guggul (Commifora mukul)1. PropranololInhibition of 1, 2, synergism with 3, 5Increased risk of bleeding (theoretical)Guggulsterones have been reported to function as antagonists of the farsenoid X receptorOnly minor concerns1Guggulipid should be used with caution in patients taking thyroid drugs.
2. Diltiazem
3. Thyroid agents
4. Lipid-lowering agents
5. Anticoagulants, antiplatelet agents
Ulbricht (2005) USA [25] RCTs CRs, in vitro<100Kava (Piper methysticum)1. Cytochrome P450 substratesInhibition of 1, 2, 3, and synergism with 5Coma, sedation, lethargy, drowsinessKavalactones or kavapyrones may alter central GABA transmission, blocking ion channels; inhibition of thromboxane synthesis and cyclooxygenase.Some concerns3Anesthesiologists recommend stop taking kava 2–3 weeks prior to surgery; patients with Parkinson's disease should avoid kava. Avoid combining kava with hepatotoxic agents.
2. Dopamine agonists and antagonists
3. Monoamine oxidase inhibitors
4. Antiplatelet agents
5. Sedatives/CNS depressants
Ulbricht (2006) USA [49] RCTs, SRs, CR, CS, AS, in vitro<100Saw palmetto (Serenoa repens)1. Androgenic drugsInhibition of 1, synergism with 2, 3, 4, 6 and 10Severe intra-operative and cerebral haemorrhage, hypertension, nausea or vomitingInhibition of lipooxygenase and cyclooxygenase; exerted activity on estrogen receptors; stimulation of macrophage phagocytosis and NK cell synthesis of interferon-gammaSome concerns−4Use cautiously in patients with hypertension, hormone-sensitive conditions and bleeding disorders
2. Anti-androgenic drugs
3. Anticoagulants and antiplatelets
4. Antibiotics
5. Antihypertensives
6. Anti inflammatory agents
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<10Fenugreek (Trigonella foenum-graecum)1. Anti-arrhythmic agents/cardiac glicosides/potassium depletingsSynergism with 2, 5 inhibition of 3Increased INR, reduced potassium levels, lowered LDL, TG, and total cholesterol and , improved insulin resistanceModulation of beta-glucuronidase and mucinase activities, DNA fragmentation by protodiosgenin; phosphorylation of insulin receptor, or activation of insulin signalling pathwayOnly minor concerns2Use cautiously in patients taking antidiabetics and antilipemics
2. Antidiabetic agents
3. Anticoagulants and antiplatelets
4. Antilipaemic agents
5. Laxatives
Ulbricht (2007) USA [28] RCT, AS<10Banaba (Lagerstroemia speciosa)1. Hypoglycaemic agentsSynergism with 1n.k.Increase the rate of glucose uptake and decrease the isoprenaline-induced glycerol releaseOnly minor concerns1Lagerstroemin may activate insulin receptors, use cautiously in diabetic patients
Ulbricht (2007) USA [50] RCTs, CR, AS, in vitro<100 Aloe vera 1. InsulinSynergism with 1, 6 and 7Potassium depletion, hypokalaemia, increased hypoglycaemic effectAnthraquinone glycosides act as laxatives; stimulation of β cellsOnly minor concerns2Use cautiously in patients with diabetes or glucose intolerance.
2. Oral hypoglycemic agentsAvoid oral aloe latex in patients with renal insufficiency, cardiac disease, or electrolyte abnormalities
3. Laxatives
4. Sevoflurane
5. Thyroid hormones
6. Topical hydrocortisone
7. Zidovudine
Ulbricht (2008) USA [39] AS, in vitro<100Blessed thistle (Cnicus benedictus)1. AntibioticsSynergism with 1, 2, 3 and Increasing bleeding risk (theoretical)Cnicin and arctigenin have exhibited cytotoxic activity against some tumor cells via inhibition of cellular DNA, RNA or protein synthesisOnly minor concerns−4Limited evidence in humans
2. Anticoagulant and antiplatelet agents
3. Antineoplastic agents
Ulbricht (2009) USA [29] RCTs, AS<10Chia (Salvia hispanica)1. Anticoagulants and antiplateletsSynergism with 1, 2,3Lowered blood pressureIncreased levels of alphalinolenic acid, fibre, protein and magnesiumOnly minor concerns0Caution 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
2. Antihypertensives
3. Antioxidants
4. Cytochrome P450-metabolized agents
Ulbricht (2009) USA [26] RCTs, CR>100Ginseng (Panax ginseng)1. DHTSynergism with 1, 4, 5,7 inhibition of 2, 7, 8Mania, headache, tremor, and insomnia, reduced blood glucose, HbA1c, plasma cholesterol, triglyceride, LDL, and NEFA; elevated HDL, LH, FSH; altered BPInhibition of platelet aggregation and CYP2D6Some concerns−4Caution is advised about concomitant use with warfarin, oral hypoglycaemic agents, insulin, antilipaemics anti-arrhythmias hormonal agents diuretics
2. anticoagulant
3. antidepressants
4. antidiabetics
5. antilipaemics
6. calcium channel blockers
7. digoxin
8. diuretics
Ulbricht (2009) USA [35] RCTs, SR, CRs, AS, in vitro,<100Green-lipped mussel (Perna canaliculus)1. Anti-inflammatory agents and corticosteroidsSynergism with 1 and , 2n.k.Inhibition of lipoxygenaseOnly minor concerns−4Limited evidence in humans
2. Leukotriene receptor antagonists
Ulbricht (2009) USA [51] Review, NRCT, CS, AS, in vitro<100Maitake mushroom (Grifola frondosa)1. Antidiabetic agentsSynergism with 2and 3n.k.Beta-glucans are distributed to the liver and spleen with a prolonged half-lifeOnly minor concerns−4Use cautiously in patients using antihypertensives, antidiabetic agents and immunomodulators.
2. Antineoplastic agents
3. Antiviral agents
4. Immunosuppressants
Ulbricht (2010) USA [52] RCTs, CCT, CS, AS, in vitro<100Reishi mushroom (Ganoderma lucidum)1. AntibioticsSynergism with 1, 2, 3, 5and, 6 and inhibition of 8Increased risk of bleeding (theoretical)Inhibitory activity on angiotensin converting enzymeOnly minor concerns−4Use cautiously in patients using anti-inflamatory agents anticoagulants and antiplatelet agents
2. Anticoagulant and antiplatelets
3. NSAIDs
4. Antidiabetics
5. Antineoplastic agents
6. Antiviral agents
7. Cardiovascular agents
8. Neurologic agents
Ulbricht (2010) USA [30] RCTs, CCTs, AS<10Stevia (Stevia rebaudiana)1. Sodium monoketocholateSynergism with 1, 2, 3, 4Decreased glucose levels and blood pressure, inhibition of rotavirusInhibition of oxidative phosphorylation, ATPase activity, NADH-oxidase activity, succinate-oxidase activity, succinate dehydrogenase, and L-glutamate dehydrogenase; inhibition of ketogenesis and [14C] CO2 production from [1-14C] palmitateOnly minor concerns0Use cautiously in patients using diuretics and antihypertensives
2. Vasodilators
3. Diuretics
4. Calcium channel blockers
Ulbricht (2010)USA [37] RCTs, OS, CRs, in vitro<100Umckaloabo (Pelargonium sidoides)1. Anticoagulant and antiplatelet agentsSynergism with 1, 3, 4; inhibition of 5Cardiovascular complications, hepatotoxicity, increased risk of bleeding (theoretical), laxative effectGallic acid may stimulate a release of TNF, stimulate interferon activity and increase NK activityOnly minor concerns−4Use cautiously in patients using anticoagulants or antiplatelet agents
2. Cardiovascular agents
3. Hepatotoxic agents
4. Laxatives
5. Immunosuppressants
Ulbricht (2010)USA [34] RCTs, CRs, AS, in vitro<100Rosemary (Rosmarinus officinalis)1. ImmunosupressantsSynergism with 3, 4, 5 and Increased risk of bleeding, hypotensionInhibition of ACE, and platelets aggregation, decreased fibronectin and fibrinOnly minor concerns−4Use cautiously in patients using salicylates, cytochrome P450 metabolized drugs and anti-diabetic agents
2. Cytochrome P450-metabolized agents
3. Anxiolytics
4. Antibiotics
5. Anticoagulants or antiplatelets
Ulbricht (2010) USA [32] RCTs, NRCTs, in vitro, AS<100Spearmint (Mentha spicata, Mentha viridis)1. Nephrotoxic agentsSynergism with 1, 2, inhibition of 3n.k.Decreased expression of cytochrome P450scc and cytochrome P450C17 enzymesOnly minor concerns−4Interactions in humans are hypothetical
2. Hepatotoxic agents
3. Cytochrome P450-metabolized agents
Ulbricht (2011) USA [33] RCTs, SR, ET, OLS, CS<100Saffron (Crocus sativus)1. SSRIsSynergism with 1, 2, 3, 4, 5 and inhibition of 6 and n.k.Trans-crocin-4 may inhibit Abeta fibrillogenesis and platelet aggregationOnly minor concerns−4Use cautiously in patients using anticoagulants or antiplatelet agents, hormonal agents, antidepressants and antihypertensives
2. MAOIs
3. Fertility agents
4. Alzheimer's agents
5. Anti hypertensives
6. Anticoagulants or antiplatelets
Ulbricht (2011) USA [36] RCTs, SRs, CCTs,<100Senna (Cassia senna)1. DigoxinSynergism with 1, 2, 3, 4Lowered serum estrogen concentrations and potassium levels; increased risk of excessive bleeding and gallstonesDecreased deoxycholic acid and biliary cholesterol saturationOnly minor concerns−4Use cautiously in patients using anticoagulant and antiplatelet agents
2. Anticoagulant and antiplatelet agents
3. Antibiotics
4. Antineoplastics
Ulbricht (2011) USA [38] RCT, CCTs, CS, AS<100Gymnema (Gymnema sylvestre)1. Antidiabetic agentsSynergism with 1, 2HypoglycemiaReductions of serum TG, total cholesterol, VLDL and LDLOnly minor concerns−4Supervision is needed in diabetic patients
2. antilipaemic agents
Ulbricht (2011) USA [53] RCTs,SRs, CCT, CS, CR<100Turmeric (Curcuma longa)1. Paracetamol (acetaminophen)Inhibition of 1, 12and, 15, 19, 21 synergism with 2, 3, 4, 5 and, 6, 8and, 9, 10and, 11and, 13, 14, 15, 17, 18, 19, 20, 21, 23Increased risk of bleeding, transient hypotension, bradycardia, and vasodilationDiferuloylmethane is believed to be the principal pharmacological agent responsible for all interactionsOnly minor concerns−4Use cautiously in patients using beta blockers or those with metabolic syndrome or increased risk of bleeding.
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. Erythromycin
14. Erythropoietin
15. Hormonal agents
16. NSAIDs
17. Norfloxacin
18. Oxaliplatin
19. P-glycoprotein-regulated drugs
20. Retinol
21. Talinolol
22. Taxol
23. Warfarin
Vora (2012) USA [54] RCT<10Chasteberry (Vitex agnus-castus)1. ProlactinSynergism with 1 (low doses)n.k.Constituents of chasteberry bind to dopamine-2 receptors in the pituitary, thereby inhibiting prolactin secretionOnly minor concerns−4Use 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.
Whitten (2006) Australia [31] RCTs<100St John's wort (Hypericum perforatum)1. ImmunosupressantsInhibition of 1, 2, 4, 5, 6 and 7Transplant rejection, unwanted pregnancy, mania, orofacial dystonia, delayed emergence from anaesthesia, CVD collapseInduction of CYP3A enzymes and/or intestinal P-glycoproteinSerious concerns5High doses of this HMP cause significant changes in pharmacokinetic measurements consistent with CYP3A induction. Avoid in transplant patients or those requiring anaesthesia.
2. Antiretrovirals
3. Hormonal therapy
4. CVD drugs
5. Anicancer drugs
6. CNS drugs
7. Antimicrobals

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].

Table 2. The found herb–drug interactions for each class of medication
Class of medication Herb Type of interaction
Synergism Antagonism
  1. CNS, central nervous system.

Alzheimer's agents Saffron (Crocus sativus)x 
Anaesthetics Ginkgo (Ginkgo biloba) x
Analgesics Ginkgo (Ginkgo biloba) x
Green tea (Camellia sinensis)x 
Anti-arrhythmias Ginseng (Panax ginseng)xx
Antibiotics Rosemary (Rosmarinus officinalis)x 
Saw palmetto (Serenoa repens)x 
St John's wort (Hypericum perforatum) x
Anticoagulants and antiplatelet agents Ginkgo (Ginkgo biloba) x
Ginseng (Panax ginseng) x
Guggul (Commifora mukul)x 
Lavender (Lavandula angustifolia Miller)x 
Noni (Morinda citrifolia) x
Reishi mushroom (Ganoderma lucidum)x 
Saw palmetto (Serenoa repens)x 
Senna (Cassia senna)x 
Turmeric (Curcuma longa)x 
Antidiabetics Aloe (Aloe vera)x 
Cinnamon (Cinnamomum spp.)x 
Fenugreek (Trigonella foenum-graecum)x 
Ginseng (Panax ginseng)x 
Gymnema (Gymnema sylvestre)x 
Turmeric (Curcuma longa)x 
Antihypertensives Black cohosh (Cimicifuga racemosa)x 
Chia (Salvia hispanica)x 
Mistletoe (Viscum album)x 
Saffron (Crocus sativus)x 
Stevia (Stevia rebaudiana)x 
Anti-inflamatory agents Aloe (Aloe vera)x 
Saw palmetto (Serenoa repens)x 
Reishi mushroom (Ganoderma lucidum)x 
Antilipaemics Alfalfa (Medicago sativa)x 
Fenugreek (Trigonella foenum-graecum)x 
Ginseng (Panax ginseng)x 
Green tea (Camellia sinensis)x 
Gymnema (Gymnema sylvestre)x 
Antineoplastics Black cohosh (Cimicifuga racemosa)x 
St John's wort (Hypericum perforatum) x
Thyme (Thymus vulgaris)x 
Anti-oxidants Chia (Salvia hispanica)x 
Antiseizures Green tea (Camellia sinensis)x 
Lavender (Lavandula angustifolia Miller)x 
Antivirals Aloe (Aloe vera)x 
Green tea (Camellia sinensis)x 
Maitake mushroom (Grifola frondosa)x 
St John's wort (Hypericum perforatum) x
Anxiolytics Rosemary (Rosmarinus officinalis)x 
β-adrenoceptor blockers Green tea (Camellia sinensis)x 
Guggul (Commifora mukul) x
Turmeric (Curcuma longa) x
Cholinergic agents Butterbur (Petasites hybridus)x 
Mistletoe (Viscum album)x 
CNS depressants Kava (Piper methysticum) x 
Mistletoe (Viscum album)x 
Cytochrome P450-metabolized agents Echinacea spp. xx
Green tea (Camellia sinensis) x
St John's wort (Hypericum perforatum) x
Dopamine agonists and antagonists Kava (Piper methysticum)  x
Diuretics Ginseng (Panax ginseng) x
Mistletoe (Viscum album)x 
Stevia (Stevia rebaudiana)x 
Gastroprotective agents Belladonna (Herbae pulvis standardisatus) x
Hepatotoxic agents Echinacea spp. x 
Green tea (Camellia sinensis)x 
Noni (Morinda citrifolia)x 
Umckaloabo (Pelargonium sidoides)x 
Hormonal agents Chasteberry (Vitex agnus-castus)x 
Ginseng (Panax ginseng)x 
Green tea (Camellia sinensis) x
Red clover (Trifolium pratense)xx
Saffron (Crocus sativus)x 
Saw palmetto (Serenoa repens)xx
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 

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, hepatotoxicity [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, cardiotoxicity, 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 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].

Table 3. Quality ratings for included systematic reviews of HMPs
Study (year) [ref] Search methods? (a) Search comprehensive? (b) Inclusion criteria? (c) Bias avoided? (d) Conclusions supported? (e) Sum
  1. 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.

  2. 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.

  3. 0 means that the above mentioned criteria were partially fulfilled.

  4. −1 means that none of the above criteria was fulfilled.

  5. This is an operationalization of the Oxman criteria [8], adapted from reference [55].

Armbruer (2012) [40] −1−1−1−10−4
Barrette (2012) [41] −1−1−1−10−4
Basch (2003) [9] −1−1−1−10−4
Basch (2003) [10] 110−112
Basch (2004) [11] −1−1−1−10−4
Basch (2006) [12] 010−100
Basch (2004) [13] −1−1−1−10−4
Basch (2004) [14] −1−1−1−10−4
Basch (2005) [42] −1−1−1−10−4
Basch (2012) [43] −1−1−1−10−4
Basch (2012) [44] −1−1−1−10−4
Basch (2012) [45] −1−1−1−10−4
Brendler (2006) [15] 010−100
Brendler (2012) [46] −1−1−1−10−4
Ceurvels (2012) [47] −1−1−1−10−4
Ernst (2005) [16] 111115
Giles (2005) [17] 010−111
Keifer (2007) [48] 110−112
Nelsen (2002) [18] 11−1−111
Sweeney (2005) [19] −1−1−1−11−4
Tiffany (2002) [20] 110−101
Ulbricht (2003) [21] 110−112
Ulbricht (2004) [22] −1−1−1−11−4
Ulbricht (2005) [23] 010−100
Ulbricht (2005) [24] 010−111
Ulbricht (2005) [25] 111−113
Ulbricht (2006) [49] −1−1−1−11−4
Ulbricht (2007) [27] 110−112
Ulbricht (2007) [28] 110−101
Ulbricht (2007) [50] 110−112
Ulbricht (2008) [39] −1−1−1−10−4
Ulbricht (2009) [29] 010−100
Ulbricht (2009) [35] −1−1−1−10−4
Ulbricht (2009) [26] −1−1−1−10−4
Ulbricht (2009) [51] −1−1−1−10−4
Ulbricht (2010) [52] −1−1−1−10−4
Ulbricht (2010) [30] 010−100
Ulbricht (2010) [37] −1−1−1−10−4
Ulbricht (2010) [34] −1−1−1−10−4
Ulbricht (2010) [32] −1−1−1−10−4
Ulbricht (2011) [33] −1−1−1−10−4
Ulbricht (2011) [36] −1−1−1−10−4
Ulbricht (2011) [38] −1−1−1−10−4
Ulbricht (2011) [53] −1−1−1−10−4
Vora (2012) [54] −1−1−1−10−4
Whitten (2006) [31] 111115

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).

Table 4. The most clinically important herb–drug interactions
HMP Synthetic drug Clinical outcome
Ginkgo Anticoagulants, anti-inflammatory agents, antihypertensives, anaestheticsHaemorrhage, apraxia, haematoma, hyphaema, permanent neurological deficit, death
Ginseng Antidepressants, antidiabetics, anticoagulants, calcium channel blockers, cholesterol lowering agents, diuretics, hormonal agentsInhibition 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, sedativesComa, sedation, lethargy, drowsiness
St John's wort Antineoplastics, antimicrobials, antiretrovirals, hormonal agents, immunnosupressantsTransplant rejection, unwanted pregnancy, delayed emergence from anaesthesia, CVD collapse

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.

Appendix

Appendix 1 Search strategy for MEDLINE

 1(herb$ adj3 (caplet$ or capsule$ or compound$ or cream$ or decoction$ or drug$ or essence$ or extract$ or formul$ or heal$ or Infus$ or juice$ or medic$ or mixture$ or powder$ or prepar$ or prescri$ or product or products or remed$ or supplement$ or tablet$ or tea or teas or therap$ or tincture$ or tisane$ or treatment$)).ti,ab.
 2Herbal$.ti,ab.
 3(plant$ adj3 (caplet$ or capsule$ or compound$ or cream$ or decoction$ or drug$ or essence$ or extract$ or formul$ or heal$ or herb$ or Infus$ or juice$ or medic$ or mixture$ or powder$ or prepar$ or prescri$ or product or products or remed$ or supplement$ or tablet$ or tea or teas or therap$ or tincture$ or tisane$ or treatment$)).ti,ab.
 4(phytodrug$ or phytomed$ or phytopharmac$ or phytother$ or phytochemical$).ti,ab.
 5((natural$ or naturo$) adj3 (caplet$ or capsule$ or compound$ or cream$ or decoction$ or drug$ or essence$ or extract$ or formul$ or herb$ or Infus$ or juice$ or medic$ or mixture$ or powder$ or prepar$ or prescri$ or product or products or remed$ or supplement$ or tablet$ or tea or teas or therap$ or tincture$ or tisane$ or treatment$)).ti,ab.
 6(botanical$ adj3 (caplet$ or capsule$ or compound$ or cream$ or decoction$ or drug$ or essence$ or extract$ or formul$ or heal$ or herb$ or Infus$ or juice$ or medic$ or mixture$ or powder$ or prepar$ or prescri$ or product or products or remed$ or supplement$ or tablet$ or tea or teas or therap$ or tincture$ or tisane$ or treatment$)).ti,ab.
 7(traditional adj3 (caplet$ or capsule$ or compound$ or cream$ or decoction$ or drug$ or essence$ or extract$ or formul$ or herb$ or Infus$ or juice$ or medic$ or mixture$ or powder$ or prepar$ or prescri$ or product or products or remed$ or supplement$ or tablet$ or tea or teas or tincture$ or tisane$)).ti,ab.
 8(Chinese adj3 (caplet$ or capsule$ or compound$ or cream$ or decoction$ or drug$ or essence$ or extract$ or formul$ or herb$ or Infus$ or juice$ or medic$ or mixture$ or powder$ or prepar$ or prescri$ or product or products or remed$ or supplement$ or tablet$ or tea or teas or tincture$ or tisane$)).ti,ab.
 9(Ethnobotan$ or pharmacogno$ or Ethnopharmaco$ or ethnomedic$).ti,ab.
10(Ayur ved$ or Ayurved$ or kampo or siddha or unani).ti,ab.
11(folk adj3 (caplet$ or capsule$ or compound$ or cream$ or decoction$ or drug$ or essence$ or extract$ or formul$ or herb$ or Infus$ or juice$ or medic$ or mixture$ or powder$ or prepar$ or prescri$ or product or products or remed$ or supplement$ or tablet$ or tea or teas or tincture$ or tisane$)).ti,ab.
12exp Ethnobotany/
13exp Phytotherapy/
14exp Plants, Medicinal/
15exp Herb−Drug Interactions/
16exp Plant Exudates/
17exp Materia Medica/
18exp Herbal Medicine/
191 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18
20complicat$.ti,ab.
21(safe or safety or risk$).ti,ab.
22Side effect$.ti,ab.
23(tolerate or tolerability or tolerance or hypersensativ$ or aggravat$).ti,ab.
24(Adverse adj3 (effect$ or event$ or Interaction$ or outcome$ or Reaction$ or response$)).ti,ab.
25(Uninten$ adj3 (effect$ or event$ or Interaction$ or outcome$ or Reaction$ or response$)).ti,ab.
26(Unwanted adj3 (effect$ or event$ or Interaction$ or outcome$ or Reaction$ or response$)).ti,ab.
27(Unexpected adj3 (effect$ or event$ or Interaction$ or outcome$ or Reaction$ or response$)).ti,ab.
28(Undesir$ adj3 (effect$ or event$ or Interaction$ or outcome$ or Reaction$ or response$)).ti,ab.
29(harm$ adj3 (effect$ or event$ or Interaction$ or outcome$ or Reaction$ or response$)).ti,ab.
30(Toxic$ or Adulterat$ or Contaminat$ or Poison$ or hepatotoxic$).ti,ab.
31(Aftereffect or after effect).ti,ab.
32exp Drug Toxicity/
33exp Drug Contamination/
3420 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33
35Review$.ti.
3619 and 34 and 35

Ancillary