Cancer Therapy Vol 2, 475-500, 2004

1Consultant Psychiatrist and Honorary Senior Lecturer, Homerton University Hospital and Institute of Psychiatry, London UK

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*Correspondence: Dr Ursula Werneke, Consultant Psychiatrist, Homerton University Hospital, East Wing, Division of Psychiatry, Homerton Row, London E9 6SR, UK; e-mail: Ursula.Werneke@elcmht.nhs.uk

Key words: alternative medicine for cancer, single or combined anticarcinogenic CAMs, anti-carcinogenics and immuno-stimulants, antioxidants —vitamins and other remedies, remedies with endocrine properties, psychoactive remedies,

Abbreviations: bovine spongioform encephalopathy, (BSE); complementary alternative medicines, (CAM); cytochrome P, (CYP); g -linolenic acid, (GLA); diamino-N(10)-methylpteroic acid, (DAMPA); glomerular filtration rate, (GFR); methotrexate, (MTX); multi-drug resistance, (MDR); Natural Medicines Comprehensive Database, (NMCD); Physicians' Desk Reference, (PDR); prostaglandin-E1, (PGE1); prostate specific antigen, (PSA); randomised controlled trials, (RCTs); tumor necrosis factor, (TNF)

There is no conflict of interest. Ursula Werneke has received a grant form Pfizer Ltd and honoraria and speaker fees from Eli Lilly Ltd, all unrelated to this particular study and unrelated to the topic of CAMs in general.

The use of complementary alternative medicines (CAM) by patients suffering from chronic disorders, such as cancers and associated physical and psychological problems, is well documented (Eisenberg 1993; Ernst and Cassileth, 1999). CAMs are either used on their own (alternative) or in addition to conventional medicine (complementary) (Zimmerman and Thompson, 2002). Depending on the definition and inclusion criteria chosen, estimates of prevalence of CAM use in cancer patients range from 7% to 80% (Ernst and Cassileth, 1998; Risberg et al, 1998; Rees 2000, Richardson et al, 2000; Sparber et al, 2000; Bernstein and Grasso 2001; Ashikaga et al, 2002; Werneke et al, 2004a) (Table 1).

CAMs can be grouped into herbal remedies, food supplements including vitamin preparations, trace elements and other substances such as omega-3 fatty acids. Cancer patients may take CAMs for a variety of reasons: to combat the cancer, strengthen the immune system, counter side effects of conventional treatments and treat psychological problems including low mood and anxiety. Some patients may look for a more holistic approach to treatment, feeling that conventional cancer care tends to neglect their spiritual needs and leaves them out of control of their treatment (Sparber, 2000). Others hope that CAMs being "natural" have fewer or no side effects, while some cancer patients may feel disillusioned by the apparent ineffectiveness of conventional treatment.

However, use of CAM and especially of herbal remedies and supplements is not without problems. Some may not be effective, and others have potentially dangerous side effects and interactions with conventional treatments.

Particularly, the potential for interactions between CAMs and chemotherapeutic agents poses a challenge, since the number of novel antineoplastic agents exerting their effects by many different mechanisms is increasing. This reflects improved understanding of disease states and cellular makeup so that specific pathways can be targeted. Relatively new mechanisms of action include enzyme inhibition through protease inhibitors and protein-tyrosine kinase inhibitors and immuno-modulation, e.g. through monoclonal antibodies. Standard cytotoxic agents exert their effects in a number of ways, e.g. alkylation of cell DNA thereby impairing replication and causing cytotoxicity; enzyme inhibition preventing synthesis or action of cellular components such as pyrimidines and purines required for DNA and RNA synthesis; binding to DNA intercalating between base pairs and so upsetting the helical structure preventing cell replication; enzymic breakdown of products required for growth and replication; or production of intracellular free radicals resulting in cellular damage (Chabner and Longo, 2001).

The aim of this review is to identify and categorize CAMs commonly encountered in clinical oncology practice, to review the evidence base for their purported effectiveness and to discuss potential adverse effects and interactions relating to their use.

We searched the Medline and Cochrane databases for CAMs used in cancer treatment. We divided the substances into different categories: cancer treatments, anti-cancer remedies with immunostimulating effect, antioxidants, remedies with endocrine properties, psychotropic remedies and other substances frequently used by cancer patients. Search terms included the identified substances in each category, "effectiveness", "trial", "review", "side effects", "adverse drug reaction" and "interaction". All recovered papers were reviewed for further relevant references. All evidence was collated and ranked as available. We also accessed web-based resources such as Natural Medicines Comprehensive Database (NMCD) 2004 and CAM formularies such as the Physicians' Desk Reference for Herbal Medicines (PDR) 2001 for further information on the identified substances. Where available, we used reviews summarising the proposed mechanism of action and effectiveness, since presenting all the evidence in detail would have been beyond the scope of this paper and duplicating existing work. Whenever possible, we gave meta-analyses and double blind randomised controlled trials (RCTs) priority, but we also included other evidence including case reports, when the findings were relevant to our review. CAM names are usually given in English, and the scientific names are listed in Appendix 1.

CAMs can interact with chemotherapy in several ways, by either interfering with the pharmacokinetics or the mechanism of action, thereby altering the effectiveness of chemotherapy.

The pharmacokinetics of most anticancer drugs are highly variable between patients and may be genetically determined. For instance, oxidative metabolism depends on the variability of the expression of the different cytochrome P450 enzymes, not only in the liver but also in extra-hepatic tissue including tumor tissue (Kivisto et al, 1995). Of the cytochrome system, CYP 3A4 seem to play the most important role. Sixty percent of all clinically used drugs are metabolized through CYP 3A4 including warfarin, ciclosporin, oral contraceptives, anticonvulsants, (e.g carbamazepine) and digoxin (Lake et al, 1992; Michalets 1998; Lill et al, 2000). Anticancer agents metabolized through CYP 3A4 include tamoxifen (Hukkanen et al, 1998), camptothecins (Sparreboom 2004), cyclophosphamide (Quintieri et al, 2000), ifosfamide (Quintieri et al, 2000), paclitaxel (Nallani et al, 2004), epipodophyllotoxins e.g teniposide, etoposide (Relling et al, 1994) and vinblastine (Zhou-Pan et al, 1993). Numerous CAMs, such as St John's wort, goldenseal, quercitin, cat's claw, licorice, red clover, soy, valerian, kava kava (NMCD, 2004) interact with CYP 3A4 and can alter the metabolism of other complementary or conventional medicines (Table 1-7). Foodstuffs can also affect the CYP system; e.g. grapefruit is a potent CYP 3A4 inhibitor (Ho and Saville, 2001). Some CAMs such as echinacea (Figure 1) and gingko may either inhibit or induce CYP 3A4, and the effect may depend on the extract composition, the duration of treatment and the dose used (Sparreboom 2004). Some of these and other CAMs also affect other P450 enzymes, e.g. CYP 2C9 and 2C19, which metabolize tamoxifen (Hukkanen et al, 1998), ifosfamide (Chang et al, 1997) or cyclophosphamide and teniposide (Sparreboom et al, 2004) respectively. However, CYP interactions observed in vitro may not necessarily assume clinical significance (Zuber et al, 2002; Sparreboom et al, 2004) and often no recommendations can be made where studies in humans are not available.

CAMs can also influence the transmembraneous p-glycoprotein pump, which participates in the transport of drugs out of cells. Increased levels of p-glycoprotein are found in multi-drug resistance (MDR). In consequence, tumor cells become resistant to a variety of drugs after exposure to a single drug. Drugs which are substrates to the CYP 3A enzymes are particularly affected. Examples include anthracyclines, epipodophyllotoxins, taxol and vinca alkaloids (Kivisto et al, 2004). Two psychoactive plants, St John's wort (Figure 2) and ginkgo (Figure 3), may interfere with the p-glycoprotein pump. They may not only alter the effectiveness of chemotherapy but also change the results of MDR nuclear scans (Werneke and McCready, 2004). On the other hand some CAMs including selenium, quercitin and related flavonoids, sylmarin derived from milk thistle and curcumin contained in tumeric may inhibit the p-glycoprotein pump (Zhou et al, 2004, Bjorkhem-Bergman et al 2002). Catechins from green tea may exert differential effects (Zhou et al 2004).

Single anticarcinogenic CAMs are extracted from one source, e.g. one plant, only. They include goldenseal, grape seed, hydrazine, laertrile (apricot) and shark cartilage (Table 2A). For most of these remedies, the mechanism of action remains unclear and clinical studies are scarce. An exception is shark cartilage, which contains several macroproteins including U-995 and AE-941 (Neovastat), which have antiangiogenic and pro-apoptotic properties. AE-941 is currently being tested in clinical trials for renal, lung cancer and multiple myeloma (Bukowski 2003; Gringas et al, 2003). Previously, only parenteral formulations were effective, since oral formulations were not absorbed (Ernst and Cassileth, 1999)

Figure 1. Echinacea

Figure 2. St John's wort

Figure 3. Ginkgo biloba

Table 1. Prevalence of CAM use in Cancer patients

Table 2A. Cancer treatments: single agents

No clinical data has been offered for the efficacy of amygdalin, which is the major component of laetrile. Instead, amygdalin can be broken down to hydrogen cyanide which is toxic, and its use should be actively discouraged. It was claimed that cancer tissues were rich in an enzyme that causes amygdalin to release cyanide thereby destroying cancer cells. Non-cancerous tissues would be protected from this fate by another enzyme rendering cyanide harmless. Later, it was marketed as a vitamin (vitamin B17), possibly to evade its ban (Wilson, 2000).

Combined CAMs are agents derived form several sources. They are combinations of different herbs or plant extracts with other substances. These may have synergistic effects or buffer the toxic effects of the other components (Vickers, 2002, Williamson 2001), but they may also increase the potential for side effects. Carctol, essiac and flor-essence are used for cancer in general (Table 2B). PC-SPES, PC-Hope and 714X are applied specifically to prostate cancer (Table 2C). Carctol is an Ayurvedic preparation which is derived from eight different plants, some of which have antioxidant, anticarcinogenic and antiestrogenic properties. Clinical efficacy is unproven, and the potential for side effects and drug interactions may be much higher than claimed by its suppliers. Essiac is named after its inventor, Caisse, spelt backwards (Ernst and Cassileth, 1999). It is a combination of four herbs: burdoch, sheep sorrel, rhubarb and slippery elm. Sheep sorrel may act as an antioxidant since the leaves contain b -carotene. No mechanism of action has been postulated for the anticarcinogenic properties of the other three herbs involved. Flor-essence is a combination of essiac with four other herbs: water cress and kelp may act as antioxidants, blessed thistle has been attributed with some unspecified anti-carcinogenic activity and red clover is a phyto-estrogen.

The clinical efficacy is unproven, and high doses may be required. This theoretically increases the potential for side effects and possibly affects the nature of potential drug interactions. Watercress, sheep sorrel and rhurbarb can all compromise the kidney function, presumably since they contain oxalic acid.

Table 2B. Cancer treatments: combined agents used for all cancers

Table 2C. Cancer treatments: combined agents used for prostate cancer

Burdoch may interact with antidiabetic drugs, sheep sorrel with digitalis and diuretics and water cress with warfarin (NMCD, 2004).

PC-SPES, PC standing for prostate cancer and SPES meaning hope in Latin, is a combination of eight herbs with antioxidant, cytotoxic and estrogenic properties. PC-SPES has been shown to lead to a reduction in prostate specific antigen (PSA) in androgen independent prostate cancer (Pfeiffer et al, 2000; Small et al, 2000). Possibly, due to its phytoestrogen content, PC-SPES has been associated with thrombosis. It was withdrawn for the US market after contaminations with estrogens, warfarin and indomethacin were reported. The estrogen was presumably added to increase its efficacy, whereas warfarin and indomethacin may have been used to decrease the thrombosis risk. PC-SPES has reemerged as PC-HOPE, which extends the original combination with quercitin and sterolins. Whereas quercitin has anti-carcinogenic properties (Nair et al, 2004), sterolins are used as immune stimulants (Kidd, 2003). No clinical trials have been conducted. Quercitin is a CYP 3A4 inhibitor (Ho and Saville, 2001) and may affect corresponding substrates as outlined above.

714X is also used for prostate cancer, but is unlikely to be effective (NMCD, 2004). The name reflects the inventor's initials: 7^th and 14^th letter of the alphabet and his birth year 1924, X is the 24^th letter in the alphabet (Barrett, 1999) 714X is a combination of camphor with several minerals including nitrates dissolved in water. Camphor can lead to significant hepatotxicity and CNS depression. Nitrates are contraindicated in patient using phosphodiesterase 5 inhibitors (e.g. sildenafil) for the oral treatment for erectile dysfunction.

Some CAMs are thought to be both anti-carcinogenics and immunostimulants. The herbal remedies cat's claw, echinacea, mistletoe and pau d'arco (Table 3A) are examples. Despite the theoretical understanding of their mechanism of action the evidence for the clinical effectiveness of these agents is sparse. A systematic review of ten trials using mistletoe did not show any effectiveness (Ernst et al, 2003). However, improvement of quality of life has been noted (Ernst et al, 2003; Schuhmacher et al, 2003; Piao et al, 2004; Semiglasov et al, 2004). All these remedies may interfere with immuno-suppressant therapies and corticosteroids. Echinacea may specifically interact with monoclonal antibodies targeting malignant B cells (Stimpel et al, 1984; Luettig et al, 1989). Also, echinacea should only be taken intermittently and not long-term. It can have differential effects on the CYP 3A4 system leading either to inhibition or induction (Sparreboom, 2004). Three non-herbal remedies were identified with purported anticarcinogenic and immuno-stimulating action: b -glucans, kombucha tea and thymus extract (Table 3B).

Table 3A. Herbal anti-carcinogenics and immunostimulants

Table 3B. Other anticarcinogenics and immune-stimulants

b glucans are yeast components which are suggested to have 'possible efficacy' when used in conjunction with conventional therapy for different cancers (e.g. head and neck and cervical cancers) (NMCD, 2004).They are known to synergize with monoclonal antibodies and carmustine (Hong et al, 2002; Finkelstein et al, 2003). Initial RCTs have shown a significant increase of survival time for advanced cervical and gastric cancer (Fujimoto et al, 1984; Miyazaki et al, 1995). Kombucha tea is an infusion of bacteria, yeast, tea and sugar, and there is no evidence of effectiveness in the oncology setting. There are reports of contamination with aspergillus and anthrax (Gamundi and Valdivia 1995; Sadjadi 1998), and immuno-compromised patients may be particularly at risk. Equally, thymus therapy has not shown to be efficient in cancer, but carries a significant risk of contamination including a theoretical risk of bovine spongioform encephalopathy (BSE) transmission (NMCD, 2004).

Certain nutrients in fruits and vegetables appear to protect the body against oxygen induced damage to tissues which occurs as part of the normal metabolism. These so-called anti-oxidants reduce oxidative stress by handling free-radicals and hydrogen-peroxide. However, antioxidants may affect chemotherapies which rely on oxidative action. For instance, alkylating agents, podphyllum agents and anthracycline antitumor antibiotics, create reactive oxygen species which are required to modify DNA. Doxorubicin creates free radicals through oxidation of nicotinamide adenine dinucleotide phosphate (Labriola and Livington, 1999).

Clinically active anthracyclines such as doxorubicin have a number of mechanisms of cytotoxic action. They can bind to DNA and affect cell replication by inhibition of DNA topoisomerase II catalytic activity. They also create oxygen species (undergo electron reduction) to produce reactive compounds that can cause wide spread damage to intracellular components. This is also believed to play a role in the cardiotoxicity of the drug. One electron reduction is catalysed by flavin centred dehydrogenases or reductases e.g. CYP 450 reductase or nicotinamide adenine denucleotide reductase. These enzymes are distributed throughout human cells, allowing anthracyclines to produce activity in a number of organs. The reduction process produces the corresponding semiquinone free radical which donates its electron to oxygen creating the superoxide ion which produces hydrogen peroxide. Hydrogen peroxide is then cleaved by the semiquinone to produce the hydroxyl free radical which is responsible for cell destruction. In most cases, cells have defensive mechanisms to prevent cellular damage (Chabner and Longo, 2001).

Vitamins with antioxidative properties include vitamin A and its precursor b -carotene, vitamin C and E (Table 4A). They have been shown to decrease the risk of several cancers, either in combination with other vitamins or supplements (Table 4A). Data on the anti-carcinogenic effectiveness are sparse. Vitamin C supplements may have no benefits (Moertel, 1985), and high dose supplements should usually be avoided (UK Food Standard Agency, 2003). Particularly, combination of high dose vitamin C with methotrexate (MTX) should be avoided, since vitamin C acidifies urine leading precipitation of MTX and its less water soluable metabolites 7-OH-MTX and 2, 4-diamino-N(10)-methylpteroic acid (DAMPA), which cannot be excreted. This may lead to kidney damage and increased plasma levels of MTX (Sketris et al, 1984) resulting in reduced clearance and increased toxicity. b -carotene may also be harmful, and increase the risk of lung and prostate cancer in smokers (The a -Tocopherol, b Carotene Cancer Prevention Study Group, 1994; Heinonen et al, 1998; Patrick, 2000), but the mechanism of this adverse effect remains unclear.

Frequently used other antioxidants include co-enzyme Q10, green tea, selenium, tomato and tumeric (Table 4B). Apart from co-enzyme Q10, they are mostly used for cancer prevention. Selenium in particular has been associated with a decreased risk of lung, prostate and colorectal cancer (Clark, 1996). Selenium should only be taken in the recommended dosage, since the therapeutic/toxic index is low (NMCD, 2004). However, dose recommendations vary internationally. Also, all these other antioxidant remedies can interact with concomitant anticoagulants. Tumeric, additionally, interferes with anti-platelet drugs (NMCD, 2004)

Table 4A. Antioxidants (AOs): vitamins

Table 4B. Antioxidants: other substances

Remedies in this grouping are mostly concerned with effects on sex-steroids. Commonly used phyto-estrogens include dong quai, panax ginseng, licorice, red clover, soy and wild yam (Table 5A). Some of these may have anticarcinogenic activity, but most cancer patients may use them to decrease side effects of hormonal treatment such as long term treatment with tamoxifen and its postmenopausal symptoms. The evidence for reduction of such symptoms is inconclusive for most substances, although there is some preliminary evidence for the effectiveness of soy (Vincent and Fitzpatrick, 2000; Ernst and Huntley, 2004). All phytestrogens should be taken with caution in breast cancer, because they may stimulate the proliferation of estrogen receptor positive cancer cells (Abebe, 2002; Bodinet and Freudenstein, 2004). Naturally, they are likely to interact with all estrogenic drugs such as tamoxifen.

Theoretically, all phyto-estrogens increase the thrombosis risk. On the other hand, some phyto-estogens such as dong quai, red clover and soy have coumarinic properties which decrease the INR (Abebe, 2002). Licorice and red clover inhibit CYP 3A4. Soy additionally affects other microsomal enzymes and can interact with corresponding substrates (Anderson et al, 2003; NMCD, 2004; Sparreboom, 2004). Other remedies with endocrine effects include black cohosh, evening primrose oil and saw palmetto (Table 5B). Black cohosh exerts its estrogenic effect through an unknown mechanism and may have some effect on post-menopausal symptoms (Ernst and Huntley, 2003). Black cohosh may also inhibit proliferation of estrogen receptor positive and negative breast cancer cells (Einbond et al, 2004; Honstanska et al, 2004). There have been case reports of hepatotoxicity (Whiting et al, 2002).

Evening primrose oil and its main constituent g -linolenic acid has weak anti-estrogenic properties which may enhance the effect of tamoxifen (Ingram et al, 2002; Kenny et al, 2004). g -linolenic acid can also increase the toxicity of paclitaxel and vinorelbime in breast cancer (Menendez et al, 2002). The evidence of its effectiveness for mastalgia and post-menopausal symptom relief is inconclusive. It can decrease the effectiveness of antiepileptics including sodium valproate (Miller, 1989). g -linolenic acid is also found in other plants such as borage. Saw palmetto has androgenic and anti-estrogenic effects and is primarily used for the reduction of symptoms of benign prostate hypertrophy (PDR, 2002). It has a number of varied postulated drug interactions including anticoagulants, antiplatelet and estrogenic drugs. Saw-palmetto and evening primrose oil have coumarinic effects.

In a recent study of CAM use among cancer patients, 32% used psychoactive remedies (Werneke et al, 2004a). Popular substances include anxiolytics and sedatives such as Bach flower remedies, kava kava and valerian (Table 6A). Bach flower remedies is a combination of 38 herbs. There is also a "rescue remedy" version that contains five herbs. It has failed to show efficacy in a meta-analysis (Ernst et al, 2002b). As this is similar to homeopathic formulations, the potential for side effects and drug interactions is low.

Table 5A. Remedies with endocrine properties: estrogen agonists

Table 5B. Remedies with endocrine properties: other

Valerian is a hypnotic, but evidence on its effectiveness remains inconclusive although a mechanism of action had been postulated (Stevinson and Ernst, 1999). Valerian inhibits CYP 3A4 and can potentiate the effect of other sedatives. Kava kava is an effective anxiolytic, but has been withdrawn from the UK market due to concerns about hepatotoxicity. Panax ginseng and ginkgo are popular cognitive enhancers (Table 6B). Both remedies have effects on the cerebral blood flow (Maclennan et al, 2002; Ahlemeyer and Kriegelstein 2003). They also have cholinergic properties (Tang et al, 2002), which are known to improve cognition (Lewis et al, 1999; Tang et al, 2002). They both interact with anti-thrombotic drugs and have effects on the CYP450 system. Ginkgo additionally may interfere with the p-glycoprotein pump (Sparreboom, 2004). St John's wort is used as an antidepressant, however its efficacy may be limited to mild depressive episodes. Some recent larger studies including more severely depressed patients have not shown any effect (Werneke et al, 2004b). Patients taking St John's wort should be reminded not to take the extract with other serotonergic antidepressants. Also, St John's wort is an inducer of CYP 3A4 and the p-glycoprotein pump. This can make pro-drugs, e.g. cyclophosphamide and ifosfamide, which are converted into the active forms through CYP3A4, more effective. Other chemotherapies, such as paclitaxel and epipodophyllotoxins may become less effective.

Clearly, patients may take many other CAMs, and it would be impossible to discuss all. For instance, in our recent study, 164 patients took 133 combinations of remedies (Werneke et al, 2004a). Here we discuss four CAMs, which are commonly used: cod liver oil, ginger, kelp and milk thistle.

Cod liver oil is used for many indications including arthritis and depression. For arthritis, effectiveness has been demonstrated in several trials (Gruenewald et al, 2002; Curtiz et al, 2004) no added benefit, however, in conjunction with NSAIDs (Stammers et al, 1992).

Table 6A. Psychotropic substances: antidepressants and sedatives

Table 6B. Psychotropic substances: cognitive enhancers

Table 7. Other remedies used by cancer patients

For depression, the evidence currently remains inconclusive (Marangell et al, 2003; Su et al, 2003). Cod liver oil can increase INR and interact with non-steroidal anti-inflammatory drugs and warfarin. Also, occasionally individual products may be contaminated. Ginger is effective in chemotherapy induced nausea (Ernst and Pittler, 2000). Theoretically, it can interact with a variety of drugs including anticoagulants, and the PDR 2001 for herbal medicines suggests that ginger should be contraindicated in pregnancy, possibly due to an increased bleeding risk. Kelp comprises various species such as laminaria and bladderwreck. It is a common product of anticancer diets, particularly macrobiotic diets. There is insufficient evidence for effectiveness, but possibly kelp acts as an antioxidant. Kelp can change thyroid function because it contains iodine (Konno et al, 1994; Henzen et al, 1999). In the case of radiotherapy for differentiated thyroid cancer, radioiodine uptake can be altered by exogenous iodine (Werneke and McCready, 2004). Kelp can contain potassium and lead to hyperkalemia in predisposed patients. Finally, milk thistle is used as a liver tonic. It also has antioxidant and pro-apoptotic properties (Tyagi et al, 2004). Milk thistle is generally well tolerated but can inhibit CYP 2C9 and 3A4.

We have attempted to review CAMs which cancer patients may be likely to use. There are many more remedies we could have considered, but we decided to limit our review to those remedies frequently discussed in the literature or come across in our own clinical work or in discussions with colleagues. In this article, we give an overview summarizing available evidence. Each remedy would warrant a review on its own, and that is why the list of side effects and interactions is not exhaustive.

List of organic remedies and their scientific names

their use thereafter. In some cases, it may be better to continue the remedy. For instance, if chemotherapies are based on glomerular filtration rate (GFR) measurements, depending on the remedy, it may be advisable that the patients do not alter their pattern of intake after their GFR has been measured (Werneke and Mc Cready, 2004).

Consultations about CAMs can be complex and may demand more time than is available in routine clinics. Service models need to be designed and tested to meet this challenge, with consideration even being given to specialist clinics providing regular updated advice to clinicians, pharmacists and patients.

We would like to thank Don Albert who kindly provided the image of St John's wort.