Cancer Therapy Vol 2, 475-500, 2004

Complementary alternative medicine for cancer: a review of effectiveness and safety

Review Article

Ursula Werneke^1,*, David Ladenheim², Tim McCarthy³

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

² Senior Pharmacist, Barts and the London NHS Trust, London, UK

³Oncology Pharmacist, London, UK

__________________________________________________________________________________

*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.

Received: 8 November 2004; Accepted: 29 November 2004; electronically published: December 2004

Summary

The use of complementary alternative medicines (CAM) in cancer patients is well documented but their effectiveness is often not established. They may be less harmless than commonly assumed. We reviewed CAMs most commonly encountered in oncology practice, their effectiveness, potential adverse effects and interactions. These were divided into the following categories: i. Single or combined anti-carcinogenic remedies; ii. Anti-carcinogenics and immuno-stimulants; iii. Antioxidants; iv. Remedies with endocrine properties; v. Psychoactive remedies and vi. Other remedies used by cancer patients. In each category, potentially useful and potentially harmful substances were identified. Many of the potential side effects and interactions described are based on hypotheses about pharmacokinetic and pharmacodynamic properties, which frequently have only been demonstrated in vitro but could have significant clinical implications if found in vivo. Particularly, the potential significance of the cytochrome P (CYP) 450 system and the p-glycoprotein pump for drug interactions require further investigation. Currently, most advice available to patients taking CAMs depends on the plausibility of the hypothesized effects and side effects. Prospective systematic surveillance of CAMs is required to improve the evidence base. Meanwhile, the use of CAMs with potential for serious interactions reducing efficacy of conventional treatments should not be encouraged.

I. Introduction

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.

II. Method

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.

III. Results

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.

A. Pharmacokinetics

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).

B. Single or combined anticarcinogenic CAMs

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

Study	Country	Sample size	Cancer type	CAM use
Werneke et al, 2004	UK	318	All	52%
Ashikaga et al, 2002	USA	148	Breast	72%
Berstein and Grasso, 2001	USA	100	All	80%
Rees, 2000	UK	1023	Breast	32%
Richardson et al, 2000	USA	453	all	63%
Sparber et al, 2000	USA	100	all	75%
Ernst and Cassileth, 1998	13 countries		all	7% to 64%
Risberg et al, 1998	Norway	252	all	45%

Table 2A. Cancer treatments: single agents

Remedy	Postulated mechanism of action for oncology related indications	Effectiveness for oncology related indications	Potentially serious side effects	Potential drug interactions
Goldenseal: berberine	Inhibition of tumor promoters (Nishino et al, 1986)	In vitro only (Nishino et al, 1986)	¯ blood pressure and death from respiratory failure (NMCD 2004); QTc interval (Xu, 1989); contraindicated in pregnancy (PDR, 2001)	CYP 3A4 inhibition (Foster et al, 2003); QTc prolonging drugs including quinine and antipsychotics; caution with antihypertensives due to risk of hypotensive effects (Covington, 1996)
Grape seed: proantho-cyanidins	Antiproliferative, antiangiogenic, proapoptotic, antioxidant activity (Singh et al, 2004); synergistic with doxorubicin (Sharma et al, 2004); suppression of estrogen biosynthesis (Eng et al, 2004)	No clinical evidence available	None identified	Anticoagulants: con-comitant use with warfarin might increase warfarin's effects and the risk of bleeding (NMCD, 2004)
Hydrazine	Unclear, also used for cancer induced cachexia	Tested in RCTs: not effective (Kosty et al, 1994; Loprinzi et al, 1994a, b)	Central and peripheral neurological effects; hypo-or hyperglycemia (NMCD, 2004)	Antidiabetics, CNS depressants; monoamineoxidase inhibitors (NMCD, 2004)
Laetrile (apricot): amygdalin	Unclear	Not effective (Moertel 1982; Foster et al, 1993; Newall et al, 1996)	Safety concern because of cyanide contents (NMCD, 2004)	None identified
Shark cartilage	Antiangiogenic activity and inhibition of tumor neovascularisation: inhibition of matrix proteinase and collagenase activity, induction of endothelial cell apoptosis (Gringas et al, 2003); two macro-proteins, U-995 and AE-941 (Neovastat) implicated (Gonzales et al, 2001)	U-995 inhibits tumor growth in animal model when given intra-peritoneally (Sheu et al, 1998); AE-941: clinical trials for renal, lung cancer and multiple myeloma ongoing (Bukowski, 2003; Gringas et al, 2003); effectiveness depends on bioavailability of remedy	Anaphylaxis possible when given parenterally (Ernst and Cassileth, 1999); one case report of hepatitis (Ashar and Vargo, 1996)	None identified

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

Remedy	Postulated mechanism of action	Effectiveness	Potentially serious side effects	Potential drug interactions
Carctol: Indian sarsaparilla, blistering ammania, puncture vine (diosgenin) cubebs, Chinese sarsaparilla, garden cress thyme leaved gratiola, Himalayan rhubarb	Indian sarsaparilla: inhibits carcinogenesis of nitroso-amins (Iddamaldeniya, 2003); antioxidant (Mary et al, 2003); puncture vine: augmentation of estrogenic effect ( c.f. table 5); Chinese sarsaparilla, cubebs and Himalayan rhubarb: antioxidants (Karthikeyan and Rani, 2003, Krenn et al, 2003)Tripathi et al, 2003) garden cress: related to watercress (c.f. flor-essence); Blistering ammania, thyme leaved gratiola: unclear	No clinical evidence available	Indian sarsaparilla: INR since contains coumarin (globalherb-supplies); cubebs: gastric acid (NCMD, 2004); puncture vine: hypoglycemia in animal experiment (Li et al, 2002), one case report of pneumothorax through ingestion of spikes (Dudley, 1983); blistering ammania: skin irritant, topically can produce blisters (BoDD, 2004); Himalayan rhubarb: hypoglycaemia in vitro (Suresh et al, 2004)	Indian sarsaparilla: ¯ of aminoglycoside induced nephrotoxicity (Kotnis et al, 2004); anti-coagulants; cubebs: ¯ effectiveness of antiulcer drugs (NCMD, 2004); puncture vine: effect of antihyperglycemics, effect of estrogen containing drugs (c.f. table 5); garden cress: related to water-cress: cf. flor-essence; Himalayan rhubarb: effect of antihyper-glycemics
Essiac: burdock, sheep sorrel, rhubarb, slippery elm	Burdoch: unclear; sheep sorrel: antioxidant, leaves contain b-carotene (NMCD, 2004); rhubarb: unclear; slippery elm: unclear	In vitro: antiproliferative effects in high concentrations (Tai et al, 2004); no clinical data available (Kaegi 1998; Tamayo et al, 2000)	Burdoch: hypoglycemia, allergies; sheep sorrel and rhubarb: contain oxalate, caution in patients with kidney stones, hypokalaemia; rhubarb: arrhythmias, allergies (PDR, 2000; NMCD, 2004)	Burdoch: antidiabetic drugs; sheep sorrel and rhubarb: digitalis, diuretics corticosteroids due to potassium loss; slippery elm and rhubarb: possibly ¯ absorption of other drugs (PDR, 2000; NMCD, 2004)
Flor-essence: as essiac + watercress, blessed thistle, red clover and kelp	Watercress: contains b-carotene (NMCD, 2004); inhibits carcinogenesis of nitrosoamins (Hecht et al, 1995); induction of apoptosis (Chiao, 2004); blessed thistle: antitumour activity (NMCD, 2004);	No clinical data available (Kaegi, 1998; Tamayo et al, 2000)	Watercress: kidney damage with large doses (NMCD, 2004); blessed thistle: (NMCD, 2004); cf. tables 4-7 for the other ingredients	Watercress: anticoagulants (NMCD, 2004); blessed thistle: antiacids, H2 blockers, protone pump inhibitors (NMCD, 2004); cf. tables 4-7 for the other ingredients

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

Remedy	Postulated mechanism of action	Effectiveness	Potentially serious side effects	Potential drug interactions
PC-SPES: dyer’s woad, licorice, chrysanthemum, panax pseudo-ginseng, rabdosia, reishi, saw palmetto, Balkai scullcap	Dyers woad unclear; crysanthemum: unclear; licorice: phytoestrogen, cytotoxic in higher doses (c.f. table 6a); reishi: immune stimulating, antitumour; rabdosia, Balkai skullcap, saw palmetto: all cytotoxic; panax pseudoginseng: antioxidant, phytoestrogen (cf. Table 6a)	Significant PSA decline in androgen-independent prostate cancer (Small et al, 2000; Pfeiffer et al, 2002)	Thrombosis, allergies (Small et al, 2000); contamination with diethyl-stilbestrol, indomethacin, and warfarin (Sovak et al, 2002)	Warfarin and hormonal treatments; cf. all other tables for individual agents
PC-HOPE: as PC-SPES + quercitine and sterolin	Quercitin: up-regulation of tumor suppressor genes and reciprocal down-regulation of oncogenes and cell cycle genes (Nair et al, 2004); sterolins: balance T-helper 1 and T-helper 2 activity (Kidd, 2003)	No clinical data available	Unclear	Quercitin: CYP3A4 and CYP 2C9 inhibition; CYP 3A4 induction also reported (Sparreboom et al, 2004)
714X: various combinations of substances, e.g. (1) camphor, ammonium chloride and nitrate, sodium chloride, ethanol, and water; or (2) camphor, sodium chloride, calcium, copper, zinc and other elements	Unclear	No clinical data available	Oral camphor: significant toxicity including CNS depression and coma; hepatotoxic (NMCD, 2004)	Contains nitrates: nitrates are contraindicated with phosphodiesterase 5 inhibitors

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.

C. Anti-carcinogenics and immuno-stimulants

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

Remedy	Postulated mechanism of action	Effectiveness	Potentially serious side effects	Potential drug interactions
Cat’s claw	Stimulation of interleukin-1 and -6 production by alveolar macrophages (Lemaire, 1999); apoptosis (Sheng, 1998); antimutagenic activity; apoptosis and inhibition of malignant leukocyte proliferation (NMCD, 2004)	In vitro evidence only	¯ blood pressure (NMCD, 2004)	CYP 3A4 inhibition (Budzinki et al, 2000); immunosuppressants (NMCD, 2004); effect of antihyper-tensives (NMCD, 2004)
Echinacea	production of complement properdin as a marker of immune system stimulation (Kim et al, 2002); stimulation of B lymphocytes which monoclonal antibodies are targeting (Stimpel et al, 1984; Luettig et al, 1989); stimulation of phagocytosis; activity and mobility of leukocytes; induction of macro-phages to produce cytokines (TNFa, IL-1, interferonb-2) (Stimpel et al, 1984; Luettig et al, 1989)	Inconclusive for prevention and treatment for common cold /upper respiratory tract infections (Melchart et al, 2000; Ernst, 2002a; Goel et al, 2004); possibly effective in reducing chemotherapy-induced leucopenia (Melchart et al, 2000)	Long term use discouraged (PDR, 2000); allergic reactions including maculopapular rashes, asthma and anaphylaxis (Mullins and Heddle 2002; Taylor et al, 2003); risk of allergic reaction in patients with atopy (Mullins and Heddle 2002); hepatotoxicity (Miller, 1998)	CYP 3A4 inhibition (Strandell et al, 2004); possibly differential effect on CYP 3A4: induction or inhibition depending on route of administration of substrate and composition of extract (Sparreboom, 2004); immunosuppressants and corticosteroids (Budzinski et al, 2000; NMCD, 2004); monoclonal antibodies targeting B lymphocytes (Stimpel et al, 1984; Luettig et al, 1989); risk of hepato-toxicity with anabolic steroids, amiodarone, methotrexate, and ketoconazole (Miller, 1998)
Mistletoe: lectins including viscumin	Stimulation of cytokins (Riberau-Gayon et al, 1997; Mansky et al, 2003); modulation of neutrophile response (Pelletier et al, 2001)	Not effective on systematic review of ten RCTs (Ernst et al, 2003); improvement of quality of life (Ernst et al, 2003; Schuhmacher et al, 2003; Piao et al, 2004; Semiglasov et al, 2004)	Angioedema (Piao et al, 2004); intracerebral pressure and allergic reactions (Ernst et al, 2003); hypotension (NMCD, 2004)	Immunosuppressants (NMCD, 2004)
Pau d’arco: b-lapachone	Induction of apoptosis (Dubin et al, 2001; Choi et al, 2003)	Insufficient evidence	Severe gastro-intestinal symptoms, dizziness, anemia; bleeding risk as vitamin K antagonist (NMCD, 2004)	Anticoagulants, antiplatelets (NMCD, 2004)

Table 3B. Other anticarcinogenics and immune-stimulants

Remedy	Postulated mechanism of action	Effectiveness	Potentially serious side effects	Potential drug interactions
b-glucans: lentinan, schizophyllan (sizofiran)	Synergizes with monoclonal antibody therapy through activation of compliment factor CR3, (Hong et al, 2003) and carmustine through inhibition of glyoxalase I (Finkelstein et al, 2002): glyoxylase I inhibits anti-apoptosis signals in tumour cells (Fullerton et al, 2003; Tsuroro 2003)	Adjuvant use with conventional cancer treatment Lentinan: survival time for several cancers reported (Kidd, 2000); Schizophyllan: survival time for cervical cancer (Okamura et al, 1989) and head and neck cancer (Kimura et al, 1994)	Hypo / hypertension related to parenteral use (NMCD, 2004)	Immunosuppressant drugs (NMCD, 2004)
Kombucha Tea (fungal infusion, of a mixture of bacteria, yeasts, tea and sugar)	Unclear (Hauser 1990)	No evidence as treatment for cancer or immunostimulant (Ernst, 2003)	Since the culture must grow at room temperature for seven to ten days, contamination and growth of other organisms including aspergillus and anthrax (Gamundi and Valdivia 1995; Sadjadi 1998); hepatotoxic (Whiting et al, 2002); one death reported (CDC, 1995)	None reported
Thymus therapy	Activation of natural killer cells; cytotoxic activity; mitogen-induced interferon levels in human lymphocytes, inhibition of tumor growth (Ernst and Cassileth, 1999)	Insufficient evidence (Ernst, 1997)	Risk of infection in immunocompromised patients including a theoretical risk of BSE transmission (NMCD, 2004); risk of severe allergic reactions when injected (Ernst and Cassileth, 1999)	Immunosuppressants

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).

D. Antioxidants –vitamins and other remedies

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

Remedy	Postulated mechanism of action	Effectiveness	Potentially serious side effects	Potential drug interactions
Vitamin A	AO	Dietary: ¯ risk of pre-menopausal breast cancer in women with a positive family history (Russel, 2000)	Acute toxicity leads to neuro-psychiatric symptoms including delirium and coma; hepatotoxicity ranges from changes in liver function cirrhosis and death (Russel, 2000); hyper-vitaminosis A leads to skin, bone and nail abnormalities and blood dyscrasisas (Food standards agency, 2003); benign intracranial hypertension (Dhiravibulya, 1991; Visani, 1996); INR (Watanabe et al, 1997b)	Benign intracranial hypertension in combination with tetracyclines (Walters and Gubbay, 1981; Dhiravibulya 1991); anticoagulants (Watanabe, 1997); retinoids toxicity risk (NMCD, 2004); caution with drugs known for their potential hepatotoxicity
b-Carotene	AO	Dietary: ¯ risk of pre-menopausal breast cancer (Zhang et al, 1999), prostate cancer (Cook et al, 1999), colon cancer (Nkondjock and Ghadirian, 2004), ovarian cancer (Cramer et al, 2001) Supplement: ¯ risk of gastric cancer in combination with other antioxidants in malnourished populations (Blot et al, 1999)	risk of lung and prostate cancer in smokers (The a-Tocopherol, b Carotene Cancer Prevention Study Group 1994; Heinonen et al, 1998; Patrick 2000); potential recurrence of colorectal adenomas in people who smoke or drink alcohol. (Druginfozone, 2003)	Potential ¯ effect of simvastatin / niacin combination when used with a selenium / b-carotene / vitamins C and E supplement (Brown et al, 2001); statins: potential ¯ effect when used with b-carotene (NMCD, 2004)
Vitamin C (Ascorbic acid)	AO	Dietary (200 mg daily): ¯ risk of oral, oesophageal, stomach, colon and lung cancer (Levine 1999; Zhang et al, 1999) Supplement: no benefits (Moertel et al, 1985)	Gastro-intestinal problems with high doses (Food Standards Agency, 2003): 1000 mg or more daily can cause renal problems including hematuria due to oxalate accumulation; mega-doses associated with deep vein thrombosis	¯ effect / plasma level of heparin, statins, aluminium protease inhibitors and warfarin; effect/ plasma level of acetaminophen, salicylates, dubutamin (NMCD, 2004); high dose: acute renal failure in combination with methotrexate.; also methootrexate plasma levels (Sketris, 1984)
Vitamin E	AO	¯ risk of prostate cancer and prostate cancer mortality; alone or in combination with b-carotene (Heinonen et al, 1998); ¯ bladder cancer mortality with long term use (Jacobs et al, 2002); ¯ risk of gastro-oesophageal cancer in combination with selenium and b-carotene (Wang et al, 1994); ¯ risk of colorectal cancer in combination with multivitamins (White et al, 1997)	High doses risk of bleeding due to antagonism of vitamin K dependent clotting factors	¯ of cisplatin induced neurotoxicity (Pace et al, 2003); topical treatment of anthracycline or mitomycin extravasation in combination with dimethylsulfoxide (Ludwig et al, 1987); anticoagulants, statins (Brown et al, 2001); ¯ nitrate tolerance (Watanabe et al, 1997a)

Table 4B. Antioxidants: other substances

Remedy	Postulated mechanism of action	Effectiveness	Potentially serious side effects	Potential drug interactions
Co-enzyme Q10 (Ubiquinone)	AO	Supplement:? advanced breast cancer in combination with surgery and other oxidants and omega 3 and omega 6 fatty acids (Lockwood et al, 1995)	None identified	¯ warfarin efficacy, antidiabetics and antihypertensives (NMCD 2004)
Green tea: catechins	AO: may activate multiple pathways (Hsu et al, 2003), including modification of mitogenic signals (Gouni-Berthold and Sachinidis, 2004)	Possibly effective in prevention of various cancers including prostate (Klein and Thompson, 2004), bladder colorectal and pancreatic cancer (Ji et al, 1997); no clear evidence for prevention of breast (Suzuki et al, 2004) and stomach cancer (Borrelli et al, 2004); may protect against bladder cancer (Wakai et al, 2004), but one case-control study found risk of bladder cancer (Lu et al, 1999)	CNS Stimulation in high doses (PDR, 2000)	Contains caffeine and interacts with other stimulating drugs; ¯ warfarin efficacy (large amounts); anti-platelet activity (NMCD, 2004); theophylline levels (Sato et al, 1993); possible lithium levels with abrupt caffeine withdrawal (Jefferson 1988); modulation of effects of doxorubicin Stammler and Volm 1997)
Selenium	AO	¯ risk of lung, colorectal and prostate cancer (Clark et al, 1996, 1998); ¯ all cancer mortality (Clark et al, 1996)	Acute toxicity: nausea causes vomiting, nail changes irritability and weight loss; chronic toxicity: resembles arsenic toxicity (NCMD, 2004).	Cf. b-carotene
Tomato: lycopene	AO: lycopene or combination of several constituents (Hwang and Bowen, 2002)	Potential ¯ risk of prostate cancer, effect dose dependent (Etminan et al, 2004); weak evidence for ¯ risk of ovarian cancer (Cramer et al, 2001) and lung cancer (Arab et al, 2002)	Theoretically, cholinergic poisoning through high dietary intake possible (Krasowski et al, 1997)
Tumeric: curcumin	AO: curcumin and related substances; inhibition of angiogenesis (Gao et al, 2003); inhibition of transcription (Aggarval et al, 2003)	Preliminary evidence for cancer prevention and treatment (Aggarval et al, 2003); preliminary evidence for stabilization of colorectal cancer refractory to other treatments (Sharma et al, 2001)	Gall bladder contraction: do not use in patients with obstructed biliary drugs and gallstones (PDR, 2000)	risk of bleeding when used with other anticoagulant / antiplatelet drugs (NMCD, 2004)

E. Remedies with endocrine properties

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.

G. Psychoactive remedies

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

Remedy	Postulated mechanism of ction	Effectiveness	Potentially serious side effects	Potential drug interactions
Dong Quai (Chinese Angelica)	Unclear, estrogenic properties suggested but not demonstrated (Oerter et al, 2003)	Not effective for reduction of hot flushes (Kronenberg and Fugh-Bergman, 2002)	May stimulate growth of breast cancer cells (Amato et al, 2002); bleeding risk: anti-platelet (Abebe, 2002) and coumarinic activity (Heck et al, 2000)	NSAIDs, anticoagulants
Panax Ginseng: ginsenosides	Estrogen receptor agonist (Lee et al, 2003)	Not effective (North American Menopause Society, 2004); estrogenic activity may depend on formulation (Polan et al, 2004)	May stimulate growth of breast cancer cells (Amato et al, 2002; Lee et al, 2003); c.f. Table 7	C.f. table 7
Licorice	Estrogen receptor agonist, but cytotoxic at higher doses (Maggiolini et al, 2002); ¯ testosterone levels in men, induction of apoptosis (Rafi et al, 2002)	In vitro evidence only	Hyper-aldosteronism: hypokalemia and hypertension	CYP3A4 inhibition; hypokalemia: diuretics, digitalis and insulin; potentiation of corticosteroids, and negate the effect of antihypertensives (NMCD, 2004);
Red Clover	Estrogen receptor agonist (Ernst and Huntley, 2003)	Inconclusive evidence for reduction of postmenopausal symptoms (Ernst and Huntley, 2003); preliminary evidence for effectiveness in the treatment of mastalgia, osteoporosis and benign prostatic hyperplasia (NMCD, 2004)	May induce cell proliferation in estrogen receptor positive breast cancer (Bodinet and Freudenstein, 2004); INR (Abebe, 2002)	CYP3A4 inhibition, anticoagulants, NSAIDs, contraceptives, tamoxifen (Abebe, 2002; NMCD, 2004)
Soy (soya): genistein	Estrogen agonist by itself, antagonist in the presence of estrogen (Ratna, 2002); antioxidant and antiangiogenic properties, may induce apoptosis (Sarkar and Li, 2003)	Preliminary evidence for reduction of postmenopausal symptoms (Vincent and Fitzpatrick, 2000; Ernst and Huntley, 2004); possibly protective against breast cancer, however effect may be limited to women of Asian origin (Yamamoto et al, 2003); possibly reduction of prostate cancer risk (Messina, 2003)	May induce cell proliferation in estrogen receptor positive breast cancer (Allred et al, 2004, Bodinet and Freudenstein, 2004); risk of bladder cancer with high dietary intake (Sun et al, 2002); risk of kidney stones in oxalate containing soy products (Massey et al, 2001); ¯ INR (Cambria-Kiely, 2002)	NSAIDs, anticoagulants, estrogens (NMCD, 2004); ¯ effect of tamoxifen (Jones et al, 2002); inhibition of CYP 1A, 2E1, 2A6, 2C9, 2D6, 3A4, 3A7 and UGT1A1, 2B15 (Sparreboom et al, 2004)
Wild Yam: diosgenin	Augmentation of estrogenic effect (Aradhana, 1992)	No clinical evidence available	Picrotoxin like activity: seizures in overdose? (PDR, 2001)	¯ effect of indomethacin (PDR, 2001); effect of estrogen containing drugs (Aradhana, 1992)

Table 5B. Remedies with endocrine properties: other

Remedy	Postulated mechanism of action	Effectiveness	Potentially serious side effects	Potential drug interactions
Black Cohosh	LH depression through binding to estrogen receptors and through an independent mechanism (LH) (Duker et al, 1991; Seidlova-Wuttke et al, 2003)	Possibly inhibits proliferation of estrogen receptor positive and negative breast cancer cells (Einbond et al, 2004; Honstanska et al, 2004); weak evidence for ¯ postmenopausal symptoms (Ernst and Huntley, 2003); one RCT on hot flushes in breast cancer patients showed no effect (Jacobson et al, 2001)	Hepatotoxic (Whiting et al, 2002)	effect of antihypertensives; toxicity of other hepatotoxic drugs such as acetaminophen (PDR, 2000; NMCD, 2004)
Evening primrose oil: g-linolenic acid	Cancer: potentiation of cyto-toxicity of paclitaxel and vinorelbime in breast cancer (Menendez et al, 2002); weak anti-estrogenic properties may enhance the response to tamoxifen (Ingram et al, 2002; Kenny et al, 2004) Mastalgia: g-linolenic acid (GLA) is metabolized to dihomo-g-linolenic acid (DGLA): a precursor of the prostaglandin-E1 (PGE1), which is inflammatory (Darlington and Stone, 2001) Menopause: as above	Cancer: only in vitro evidence available (Menendez et al, 2002) Mastalgia: evidence inconclusive (Gateley et al, 1992; Blommers et al, 2002; Ingram et al, 2002) Menopause: inconclusive, reduction of episodes of night time flushing (Chenoy et al, 1994)	¯ seizure threshold; (Miller, 1989); INR (NMCD, 2004); associated with obstetric complications (Dove and Johnson, 1999)	¯ effectiveness of antiepileptic medication, e.g. sodium valproate (Miller, 1989); anticoagulants; in vitro inhibition of CYP1A2, 2C9, 2C19, 2D6 and 3A4 (Sparreboom et al, 2004)
Saw palmetto	Inhibition of testosterone conversion to DHT (Prager et al, 2002); inhibition of DHT binding to the cytosolic DHT androgenic receptor and the a1-adrenoreceptor in the prostate thereby inhibiting hyperplasia (Goepel, 1999), not confirmed in vivo (Goepel et al, 2001); inhibition of cell growth in prostate cancer (Goldmann et al, 2001); antiestrogenic effect (PDR, 2000)	Effective for symptom relief in benign prostate hypotrophy but may not reduce enlargement (PDR, 2002)	One case report of cholestatic hepatitis (NMCD, 2004)	¯ effectiveness of estrogens and oral contraceptives; risk of bleeding when used with other anticoagulant antiplatelet drugs (NMCD, 2004)

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.

H. Other remedies used by cancer patients

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

Remedy	Postulated mechanism of action	Effectiveness	Potentially serious side effects	Potential drug interactions
Bach Flower Remedies	38 herbs with postulated differential effects, rescue remedies for acute stress contain five different herbs	Not effective (Ernst, 2002b)	Unclear	Unclear
Kava Kava: kava lactones / kava pyrones	Sedative / anxiolytic GABAergic effects (Jussofie, 1994; Dinh et al, 2001), D2 antagonist (Shelosky et al, 1995)	Meta-analysis of nine studies showed significant reduction of Hamilton anxiety score (Pittler and Ernst, 2003)	At least 68 cases of liver toxicity (NMCD, 2004); one case report of movement disorder (Meseguer et al, 2002)	CYP1A2, 2C9, 2C19, 2D6 and 3A4 inhibition (Mathews et al, 2002), CNS depressants and hepatotoxic drugs (Russmann et al, 2001)
St John’s wort: hyperforin	MAOI inhibition and GABAergic activity (Cott, 1997), monoamine re-uptake (Perovic and Muller, 1995; Neary and Bu, 1999), up-regulation of 5HT1A and 5HT2A receptors (Teufer-Mayer and Gleitz, 1997); modulation of cytokine production (Thiele et al, 1994)	Four meta-analyses with trend toward reduced effect size, possibly effective in mild depression (Werneke et al, 2004b)	Similar to serotonergic antidepressants; photosensitivity (Whiskey et al, 2001)	Serotonergic antidepressants; CYP 1A2, 2C9, 2C19, 2D6 3A4 and induction of p-glycoprotein pump (Peebles et al, 2001; Mannel 2004)
Valerian	GABAergic effects (Houghton, 1999)	Inconclusive evidence (Stevinson and Ernst, 1999)	Cognitive impairment and drowsiness; case reports of hepatotoxicity (Klepser and Klepser, 1999)	In vitro inhibition of CYP 2C19, 2D6 and 3A4 (Srandell et al, 2004), however clinical significance unclear (Donovamn et al, 2004); effect of sedatives (NMCD, 2004):

Table 6B. Psychotropic substances: cognitive enhancers

Remedy	Postulated mechanism of action	Effectiveness	Potentially serious side effects	Potential drug interactions
Ginkgo Biloba	Cognitive enhancer antioxidant (Oken et al, 1998, Tabet et al, 2000); cerebral blood flow through platelet activation factor inhibition and nitric oxide pathways; (Maclennan et al, 2002) (Ahlemeyer and Kriegelstein, 2003); cholinergic effects (Tang et al, 2002)	No consistent positive effect on cognitive performance in healthy individuals shown (Canter and Ernst, 2002); possible improvement of cognitive function in patients with organic cognitive decline (Birks et al, 2002)	bleeding time, case reports of intracerebral haemorrhage (Matthews, 1998; Benjamin 2001); possibly adverse effects on male and female fertility (Ondrizek, 1999); one case report of Stevens- Johnsons syndrome possibly attributed to Ginkgo (NMCD, 2004)	Antithrombolytic agents including warfarin (PDR, 2000); evidence for effects on CYP1A2, 2C9, 2D6 and 3A4 inconsistent: CYP2C19: inhibition (Sparreboom, 2004); CYP2D6: potentially of no clinical significance (Markowitz et al, 2003); CYP3A4: either inhibition (Ohnishi et al, 2003; He and Edeki, 2004) or induction (Sugiyama et al, 2004); or of no clinical significance (Markowitz et al, 2003); potential interference with the p-glycoprotein pump (Sparreboom et al, 2004)
Panax Ginseng: ginsenosides	Interference with platelet aggregation and coagulation (PDR, 2000); neuroprotection through nicotinic activity (Lewis et al, 1999); antioxidant effects (Chan and Tomlinson, 2000); possibly immuno-stimulating and antcarcinogenic activity (Xiaoguang et al, 1999; Shin et al, 2000); weak phyto-estrogenic effects (Lee, 1998)	Improvement of mental arithmetic and abstraction; age-delaying properties unproven (Vogeler et al, 1999)	Insomnia, mania, hyper-and hypotension, vaginal bleeding (PDR, 2000); Stevens-Johnsons syndrome (NMCD, 2004)	Insulin and oral hyperglycemics, antithrombolytic agents including warfarin, MAOIs (phenelzine), loop diuretics, immuno-suppressants (NMCD, 2004) (PDR, 2000); inhibition of CYP 3A4 may be extract specific (Sparreboom et al, 2004); in vitro CYP 3A4 induction without clinical correlate reported (Anderson et al, 2003); in vitro but no clinical evidence for inhibition of CYP 2C9, 2C19 and 2D6 (Henderson et al, 1999)

Table 7. Other remedies used by cancer patients

Substance	Postulated mechanism of action	Effectiveness	Potentially serious side effects	Potential drug interactions
Cod liver oil	Cardiac: ¯ triglycerides and, ¯ VLDLs and HDL (Jensen et al, 1989) Arthritis: suppression of cytokines? (Darlington and Stone, 2001) Depression: influences catecholaminergic serotonergic and cholinergic neurotrans-mission, modulation of signal transmission mechanisms in neuronal membranes, modulation of prostaglandins and ion channels (Haag, 2003)	¯ triglycerides and hypertension demonstrated in RCTs (Vessby and Boberg, 1990; Toft et al, 1995; Dyerberg et al 2004) Arthritis: effectiveness demonstrated in several trials (Curtis et al, 2004, Gruenewald et al, 2002); no benefit in conjunction with NSAIDs (Stammers et al, 1992) Depression: results of small trials with short endpoints inconclusive (Marangell et al, 2003; Su et al, 2003); possibly effective when added to lithium in bipolar affective disorder (Bowden 2001)	INR with high or changing doses (Fugh-Bergman, 2000); contamination possible,e.g. with dioxin (Alvarez, 1991); of blood sugar levels and insulin resistance possible (Vessby and Boberg, 1990)	effect of warfarin, aspirin and non-steroidal anti-inflammatory drugs (Fugh-Bergman, 2000)
Ginger: gingerols, gingeridone	Antiemetic, mechanism of action unclear, possibly centrally acting on serotonin receptors (Ernst and Pittler, 2000)	Nausea and vomiting including chemotherapy induced nausea (Ernst and Pittler, 2000)	Contraindicated in pregnancy (PDR, 2000); well tolerated in therapeutic doses; cardiac arrhythmias associated with large doses (NMCD, 2004)	Theoretically with anti-ulcer drugs (including H2-antagonists, protone pump inhibitors and antacids), anticoagulants, antihypertensives, antidiabetics and barbiturates (NMCD, 2004)
Kelp	Constituent of anti-cancer diets, mechanism of action unclear, possibly antioxidant (Maruyama et al, 1991)	Insufficient evidence	Hypo-and hyperthyroidism (Konno et al, 1994; Henzen et al, 1999)	risk of hyperkalemia with potassium, supplements, potassium sparing diuretics, and ACE inhibitors; digoxin toxicity may be potentiated due to hyperkalaemia; thyroid hormones (NMCD, 2004)
Milk thistle: silymarin	Liver tonic, antioxidant, inhibitor of tumor necrosis factor (TNF) (NMCD, 2004); cell cycle arrest and apoptosis in human bladder transitional cell carcinoma (Tyagi et al, 2004); inhibition of telomerase activity and secretion of prostate specific antigen in prostate cancer cells (Thelen et al, 2004)	In vitro evidence only	Usually well tolerated, mild laxative (NMCD, 2004)	CYP 2C9, 2D6, 2E1 and 3A4 inhibition, but clinical relevance unclear (Zuber et al, 2002); may affect the elimination of drugs which undergo glucuronidation as part of their metabolism (Kivisto et al, 1995; NMCD, 2004)

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.

IV. Discussion

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.

Our review highlights that many side effects and interactions are based on hypotheses about pharmacokinetic and pharmacodynamic properties, frequently only demonstrated in vitro. Also, effects may vary between different extracts of the same remedy, since products are usually not standardized, and there is no universal quality control. It is possible that in vitro effects will never assume clinical relevance and remain speculative. Conversely, adverse effects may emerge over time in remedies which have previously judged harmless. Thus, currently, much advice to patients taking CAM depends on the plausibility of hypothesized effects and side effects. Prospective systematic surveillance of CAMs is required to improve the evidence base. Such studies may be complicated by the fact that many patients take combinations of remedies rather than one single substance, so that it will not always be possible to attribute an adverse reaction unambiguously to one agent (Werneke et al, 2004c). Meanwhile, the use of CAMs with potentially serious interactions or a significant reduction in efficacy of the conventional treatment, should not be encouraged.In summary, clinicians and pharmacists need to be aware of CAM-induced side effects or interactions and should be able to identify hazards, advising patients accordingly and avoiding uncritical encouragement of potentially harmful use. Ignorance in this area, given the independent usage of CAMs, may lead to criticism and possibly litigation (Cohen and Eisenberg, 2002). Equally, patients should be encouraged to disclose information about CAMs to health care professionals. Such discussions need to be conducted sensitively in order to avoid alienating patients who may feel that they have not been taken seriously or have been criticised for using CAM. Also, even if remedies interact with conventional therapies, CAMs do not always have to be stopped. Often, it may suffice to monitor patients more frequently or adjust the doses of conventional drugs. It may be possible to discontinue remedies during chemotherapy cycles or diagnostic procedures, but resume

APPENDIX 1

List of organic remedies and their scientific names

Common name	Scientific name
Baikal scullcap	Scutellaria baicalensis
Black cohosh (black snakeroot)	Actaea racemosa (Cimicifuga racemosa)
Blessed thistle	Cnicus benedictus
Burdock	Arcticum lappa
Blistering ammania Chinese sarsaparilla (Chobchini)	Ammani vesicatoria (Ammani bacciferra L.) Smilex china L.
Cat’s claw Cubebs	Uncaria tomentosa (Uncaria guianensi) Piper cubeba
Crysantmum	Dendranthema morifolium
Dong quai	Angelica siniensis
Dyer’s woad	Isatis indigotica
Echinacea Garden cress	Echinacea angustifolia / Echinacea purpurea Lepidium sativum
Ginger	Zingiber officinale
Ginkgo	Ginkgo biloba
Goldenseal	Hydrastis canadensis
Grape seed	Vitis vinifera (Vitis coignetiae)
Green tea	Camelia siniensis
Himalayan rhubarb	Rheumemodi Wall
Indian sarsaparilla Kava Kava	Hemidesmus indicus Piper methysticum.
Kelp	Laminaria digitata / Laminaria japonica
Laetrile (Apricot)	Prunus armeniaca
Licorice	Glycyrrhiza uralensis (Glycyrrhiza glabra)
Milk thistle	Silybum marianum
Mistletoe	Viscum album
Panax ginseng	Panax ginseng
Panax pseudoginseng (San-Qui ginseng)	Panax pseudoginseng (Panax notoginseng)
Pau d’arco Puncture vine	Tabebuia impetiginosa Tribulus terrestris
Rabdosia	Rabdosia rubescens
Red clover	Trifolium pratense
Reishi	Ganoderma lucidum
Rhubarb	Rheum officinale
Saw palmetto	Serenoa repens
Shark cartilage	Squalus acanthias
Sheep sorrel (Yellow dock)	Rumex crispus
Slippery elm	Ulmus rubra (Ulmus fulva)
Soy (Soya)	Glycine max (Glycine soja)
St John’s wort Thyme leaved gratiola	Hypericum perforatum Blepharis edulis
Tomato	Lycopersicon esculentum
Tumeric	Curcuma longa (Curcuma domestica)
Watercress	Naturstium officinale
Wild yam	Dioscorea villosa (Dioscorea composite)

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.

Acknowledgements

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

References

Abebe W (2002) Herbal medication: potential for adverse interactions with analgesic drugs. J Clin Pharm Ther 27, 391-401.

Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 23, 363-398.

Ahlemeyer B, Krieglstein J (2003) Neuroprotective effects of Ginkgo biloba extract. Cell Mol Life Sci 60, 1779-92.

Allred CD, Allred KF, Ju YH, Goeppinger TS, Doerge DR, Helferich WG (2004) Soy processing influences growth of estrogen-dependent breast cancer tumors in mice. Carcinogenesis 25, 1649-1657.

Alvarez R (1991) Standard Reference Materials for dioxins and other environmental pollutants. Sci Total Environ 104, 1-7.

Amato P, Christophe S, Mellon PL (2002) Estrogenic activity of herbs commonly used as remedies for menopausal symptoms. Menopause 9, 145-150.

Anderson GD, Rosito G, Mohustsy MA, Elmer GW (2003) Drug interaction potential of soy extract and Panax ginseng. J Clin Pharmacol 43, 643-648.

Arab L, Steck-Scott S, Fleishauer AT (2002) Lycopene and the lung. Exp Biol Med (Maywood) 227, 894-899.

Aradhana, Rao AR, Kale RK (1992) Diosgenin--a growth stimulator of mammary gland of ovariectomized mouse. Indian J Exp Biol 30, 367-370.

Ashar B, Vargo E (1996) Shark cartilage-induced hepatitis. Ann Intern Med 125, 780-1.

Ashikaga T, Bosompra K, O’Brian P, Nelson L (2002) Use of complementary and alternative medicine by breast cancer patients: prevalence, patterns and communication with physicians. Support Care Care 10, 542-548.

Barrett S (1999) Fanciful claims for 714X. http://www.quackwatch.org.

Benjamin J, Muir T, Briggs K, Pentland B (2001) A case of cerebral haemorrhage-can Ginkgo biloba be implicated? Postgrad Med J 77, 112-113.

Bernstein BJ, Grasso T (2001) Prevalence of complementary and alternative medicine use in cancer patients. Oncology (Huntingt) 15, 1267-1272.

Birks J, Grimley Evans J, Van Dongen M. (2003) Ginkgo Biloba for Cognitive Impairment and Dementia (Cochrane Review). In: The Cochrane Library, Issue 4, Chichester, UK: John Wiley and Sons, Ltd.

Bjorkhem-Bergman L, Jonsson K, Eriksson LC, Olsson JM, Lehmann S, Paul C, Bjornstedt M (2004) Drug-resistant human lung cancer cells are more sensitive to selenium cytotoxicity. Effects on thioredoxin reductase and glutathione reductase. J Pharm Pharmacol 56, 1001-1005.

Blommers J, de Lange-De Klerk ES, Kuik DJ, Bezemer PD, Meijer S (2002) Evening primrose oil and fish oil for severe chronic astalgia: a randomized, double-blind, controlled trial. Am J Obstet Gynecol 187, 1389-1394.

Blot WJ, Li JY, Taylor PR (1993) Nutritional intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 85, 1483-1492.

Bodinet C, Freudenstein J (2004) Influence of marketed herbal menopause preparations on MCF-7 cell proliferation. Menopause. 11, 281-289.

Borrelli F, Capasso R, Russo A, Ernst E (2004) Systematic review: green tea and gastrointestinal cancer risk. Aliment Pharmacol Ther 19, 497-510.

Botanical Dermatology Database (BoDD) (2004) http:// www.bodd.cf.ac.uk.

Bowden CL (2001) Novel treatments for bipolar disorder. Expert Opin Investig Drugs 10, 661-671.

Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ (2001) Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 29, 1583-1592.

Budzinski JW, Foster BC, Vandenhoek S, Arnason JT (2000) An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Phytomedicine 7, 273-282.

Bukowski RM (2003) AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Expert Opin Investig Drugs 12, 1403-1411.

Cambria-Kiely JA (2002) Effect of soy milk on warfarin efficacy. Ann Pharmacother 36, 1893-1896.

Canter PH, Ernst E (2002) A systematic review of controlled trials of the cognitive effects of ginkgo biloba extracts in healthy people. Psychopharmacology Bulletin 36, 108-123.

CDC (1995) Unexplained severe illness possibly associated with consumption of Kombucha tea-Iowa, 1995. MMWR 44, 892-893, 899-900.

Chabner BA and Longo DLI eds (2001) Cancer chemotherapy and Biotherapy. 3^rd edition. Lippincott Williams and Wilkins, http://www.lww.com.

Chan P, Tomlinson B (2000) Antioxidant effects of Chinese traditional medicine: focus on trilinolein isolated from the Chinese herb sanchi (Panax pseudoginseng). J Clin Pharmacol 40, 457-461.

Chang TK, Yu L, Maurel P, Waxman DJ (1997) Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines Cancer Res 57, 1946-1954.

Chenoy R, Hussain S, Tayob Y, O'Brien PM, Moss MY, Morse PF (1994) Effect of oral gamolenic acid from evening primrose oil on menopausal flushing. BMJ 308, 501-503.

Cheung NK, Modak S (2002) Oral (1-->3),(1-->4)-b-D-glucan synergizes with antiganglioside GD2 monoclonal antibody 3F8 in the therapy of neuroblastoma. Clin Cancer Res 8, 1217-1223.

Chiao JW, Wu H, Ramaswamy G, Conaway CC, Chung FL, Wang L, Liu D (2004) Ingestion of an isothiocyanate metabolite from cruciferous vegetables inhibits growth of human prostate cancer cell xenografts by apoptosis and cell cycle arrest. Carcinogenesis 25, 1403-1408.

Choi BT, Cheong J, Choi YH (2003) b-Lapachone-induced apoptosis is associated with activation of caspase-3 and inactivation of NF-kappaB in human colon cancer HCT-116 cells. Anticancer Drugs 14, 845-850.

Clark LC, Combs GF Jr, Turnbull BW, Slate EH, Chalker DK, Chow J, Davis LS, Glover RA, Graham GF, Gross EG, Krongrad A, Lesher JL Jr, Park HK, Sanders BB Jr, Smith CL, Taylor JR (1996) Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. JAMA 276, 1957-1963.

Clark LC, Dalkin B, Krongrad A, Combs GF Jr, Turnbull BW, Slate EH, Witherington R, Herlong JH, Janosko E, Carpenter D, Borosso C, Falk S, Rounder J (1998) Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br J Urol 81, 730-734.

Cohen MH and Eisenberg DM (2002) Potential physician malpractice liability associated with complementary and integrative medicinal therapies. Ann Intern Med 136, 596-603.

Cook NR, Stampfer MJ, Ma J, Manson JE, Sacks FM, Buring JE, Hennekens CH (1999) b-carotene supplementation for patients with low baseline levels and decreased risks of total and prostate carcinoma. Cancer 86, 1783-1792.

Cott, JM (1997) In vitro receptor binding and enzyme inhibition by hypericum perforatum extract. Pharmacopsychiatry 30, 108-112.

Covington TR (ed) (1996) Handbook of Nonprescription Drugs. 11th ed. Washington, DC: Am Pharmaceutical Association.

Cramer DW, Kuper H, Harlow BL, Titus-Ernstoff L (2001) Carotenoids, antioxidants and ovarian cancer risk in pre- and postmenopausal women. Int J Cancer 94, 128-314.

Curtis CL, Harwood JL, Dent CM, Caterson B (2004) Biological basis for the benefit of nutraceutical supplementation in arthritis. Drug Discov Today 9, 165-172.

Darlington LG, Stone TW (2001) Antioxidants and fatty acids in the amelioration of rheumatoid arthritis and related disorders. Br J Nutr 85, 251-269.

Dhiravibulya K, Ouvrier R, Johnston I, Procopis P, Antony J (1991) Benign intracranial hypertension in childhood: a review of 23 patients J Paediatr Child Health 27, 304-307.

Dinh LD, Simmen U, Bueter KB, Bueter B, Lundstrom K, Schaffner W (2001) Interaction of various Piper methysticum cultivars with CNS receptors in vitro. Planta Med 67, 306-311.

Donovan JL, DeVane CL, Chavin KD, Wang JS, Gibson BB, Gefroh HA, Markowitz JS (2004) Multiple Nighttime Doses of Valerian (Valeriana officinalis) had Minimal Effects on CYP 3A4 activity and No Effect on CYP 2D6 Activity in Healthy Volunteers. Drug Metab Dispos [Epub ahead of print].

Dove D, Johnson P (1999) Oral evening primrose oil: its effect on length of pregnancy and selected intrapartum outcomes in low-risk nulliparous women. J Nurse Midwifery 44, 320-324.

Druginfozone (2003) Wednesday 21^st May 2003. http://druginfozone.nhs.uk.

Dubin M, Fernandez Villamil SH, Stoppani AO (2001) Cytotoxicity of b-lapachone, an naphthoquinone with possible therapeutic use. Medicina (B Aires) 61, 343-350.

Dudley JP (1983) Bilateral pneumothorax resulting from the bronchoscopic removal of a puncture vine fruit. Ann Otol Rhinol Laryngol 92, 396-397.

Duker EM, Kopanski L, Jarry H, Wuttke W (1991) Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Med 57, 420-424.

Dyerberg J, Eskesen DC, Andersen PW, Astrup A, Buemann B, Christensen JH, Clausen P, Rasmussen BF, Schmidt EB, Tholstrup T, Toft E, Toubro S, Stender S (2004) Effects of trans- and n-3 unsaturated fatty acids on cardiovascular risk markers in healthy males. An 8 weeks dietary intervention study. Eur J Clin Nutr 58, 1062-1070.

Einbond LS, Shimizu M, Xiao D, Nuntanakorn P, Lim JT, Suzui M, Seter C, Pertel T, Kennelly EJ, Kronenberg F, Weinstein IB (2004) Growth inhibitory activity of extracts and purified components of black cohosh on human breast cancer cells. Breast Cancer Res Treat 83, 221-231.

Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL (1993) Unconventional medicine in the United States. Prevalence, costs and pattern of use. N Engl J Med 328, 246-252.

Eng ET, Ye J, Williams D, Phung S, Moore RE, Young MK, Gruntmanis U, Braunstein G, Chen S (2003) Suppression of estrogen biosynthesis by procyanidin dimers in red wine and grape seeds. Cancer Res 63, 8516-8522.

Ernst E (1997) Thymus therapy for cancer? A criteria-based, systematic review. Eur J Cancer 33, 531-535.

Ernst E (2002a) The risk-benefit profile of commonly used herbal therapies: Ginkgo, St. John's Wort, Ginseng, Echinacea, Saw Palmetto, and Kava. Ann Intern Med 136, 42-53.

Ernst E (2002b) "Flower remedies": a systematic review of the clinical evidence. Wien Klin Wochenschr 30, 963-966.

Ernst E (2003) Kombucha: a systematic review of the clinical evidence. Forsch Komplementarmed Klass Naturheilkd 10, 85-87.

Ernst E, Cassileth BR (1998) The prevalence of complementary/alternative medicine in cancer: a systematic review. Cancer 83, 777-782.

Ernst E, Cassileth BR (1999) How useful are unconventional cancer treatments? Eur J Cancer 35, 1608-1613.

Ernst E, Pittler MH (2000) Efficacy of ginger for nausea and vomiting: a systematic review of randomized clinical trials. Br J Anaesth 84, 367-371.

Ernst E, Schmidt K, Steuer-Vogt MK (2003) Mistletoe for cancer? A systematic review of randomised clinical trials. Int J Cancer 107, 262-267.

Etminan M, Takkouche B, Caamano-Isorna F (2004) The role of tomato products and lycopene in the prevention of prostate cancer: a meta-analysis of observational studies. Cancer Epidemiol Biomarkers Prev 13, 340-345.

Finkelstein MP, Aynehchi S, Samadi AA, Drinis S, Choudhury MS, Tazaki H, Konno S (2002) Chemosensitization of carmustine with maitake b-glucan on androgen-independent prostatic cancer cells: involvement of glyoxalase I. J Altern Complement Med 8, 573-580.

Food Standards Agency: Expert Group on Vitamins and Minerals: Safe upper levels for vitamins and Minerals. May 2003. http://www.foodstandards.gov.uk.

Foster BC, Vandenhoek S, Hana J, Krantis A, Akhtar MH, Bryan M, Budzinski JW, Ramputh A, Arnason JT (2003) An in vitro inhibition of human cytochrome P450 mediated metabolism of marker substrates by natural products. Phytomedicine 10, 334-342.

Foster S, Tyler VE (1993) Tyler's Honest Herbal: A Sensible Guide to the Use of Herbs and Related Remedies. 3rd ed., Binghamton, NY: Haworth Herbal Press.

Fugh-Berman (2000) Herb-drug interactions. Lancet 355, 134-138.

Fullerton SA, Samadi AA, Tortorelis DG, Choudhury MS, Mallouh C, Tazaki H, Konno S (2000) Induction of apoptosis in human prostatic cancer cells with b-glucan (Maitake mushroom polysaccharide). Mol Urol 4, 7-13.

Gamundi R, Valdivia M (1995) The Kombucha mushroom: two different opinions Sidahora Oct-Nov, 34-35.

Gao C, Ding Z, Liang B, Chen N, Cheng D (2003) Study on the effects of curcumin on angiogenesis Zhong Yao Cai 26, 499-502.

Gateley CA, Miers M, Mansel RE, Hughes LE (1992) Drug treatments for mastalgia: 17 years experience in the Cardiff Mastalgia Clinic. J R Soc Med 85, 12-15.

Ghadirian P, Lacroix A, Maisonneuve P, Perret C, Potvin C, Gravel D, Bernard D, Boyle P (1997) Nutritional factors and colon carcinoma: a case-control study involving French Canadians in Montreal, Quebec, Canada. Cancer 80, 858-864.

Gingras D, Boivin D, Deckers C, Gendron S, Barthomeuf C, Beliveau R (2003) Neovastat--a novel antiangiogenic drug for cancer therapy. Anticancer Drugs 14, 91-96.

Globalherbsupplies (2004) http://www.globalherbalsupplies.com /herb_information/hemidesmus_indicus.htm.

Goel V, Lovlin R, Barton R, Lyon MR, Bauer R, Lee TD, Basu TK (2004) Efficacy of a standardized echinacea preparation (Echinilin) for the treatment of the common cold: a randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther 29, 75-83.

Goepel M, Dinh L, Mitchell A, Schafers RF, Rubben H, Michel MC (2001) Do saw palmetto extracts block human a1-adrenoceptor subtypes in vivo? Prostate 46, 226-232.

Goepel M, Hecker U, Krege S, Rubben H, Michel MC (1999) Saw palmetto extracts potently and noncompetitively inhibit human a1-adrenoceptors in vitro. Prostate 38, 208-215.

Goldmann WH, Sharma AL, Currier SJ, Johnston PD, Rana A, Sharma CP (2001) Saw palmetto berry extract inhibits cell growth and Cox-2 expression in prostatic cancer cells. Cell Biol Int 25, 1117-1124.

Gonzalez RP, Leyva A, Moraes MO (2001) Shark cartilage as source of antiangiogenic compounds: from basic to clinical research. Biol Pharm Bull 24, 1097-1101.

Gouni-Berthold I, Sachinidis A. (2004) Molecular mechanisms explaining the preventive effects of catechins on the development of proliferative diseases. Curr Pharm Des 10, 1261-1271.

Gruenwald J, Graubaum HJ, Harde A (2002) Effect of cod liver oil on symptoms of rheumatoid arthritis. Adv Ther 19, 101-107.

Haag, M (2003) Essential fatty acids and the brain. Can J Psychiatry 48,195-203.

Hauser SP (1990) Dr. Sklenar's Kombucha mushroom infusion--a biological cancer therapy. Documentation No. 18 Schweiz Rundsch Med Prax 79, 243-246.

He N, Edeki T (2004) The inhibitory effects of herbal components on CYP2C9 and CYP3A4 catalytic activities in human liver microsomes. Am J Ther 11, 206-212.

Hecht SS, Chung FL, Richie JP Jr, Akerkar SA, Borukhova A, Skowronski L, Carmella SG (1995) Effects of watercress consumption on metabolism of a tobacco-specific lung carcinogen in smokers. Cancer Epidemiol Biomarkers Prev 4, 877-884.

Heck AM, DeWitt BA, Lukes AL (2000) Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm 57, 1221-1227

Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman AM, Haapakoski J, Malila N, Rautalahti M, Ripatti S, Maenpaa H, Teerenhovi L, Koss L, Virolainen M, Edwards BK (1998) Prostate cancer and supplementation with a-tocopherol and b-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst 90, 440-446.

Henderson GL, Harkey MR, Gershwin ME, Hackman RM, Stern JS, Stresser DM (1999). Effects of ginseng components on c-DNA-expressed cytochrome P450 enzyme catalytic activity. Life Sci 65, PL209-PL214.

Henzen C, Buess M, Brander L (1999) Iodine-induced hyperthyroidism (iodine-induced Basedow's disease): a current disease picture. Schweiz Med Wochenschr 129, 658-664.

Ho PC, Saville DJ (2001) Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds. J Pharm Pharmaceut Sci 4, 217-227.

Hong F, Hansen RD, Yan J, Allendorf DJ, Baran JT, Ostroff GR, Ross GD (2003) b-glucan functions as an adjuvant for monoclonal antibody immunotherapy by recruiting tumoricidal granulocytes as killer cells. Cancer Res 63, 9023-9031.

Hostanska K, Nisslein T, Freudenstein J, Reichling J, Saller R (2004) Cimicifuga racemosa extract inhibits proliferation of estrogen receptor-positive and negative human breast carcinoma cell lines by induction of apoptosis. Breast Cancer Res Treat 84, 151-160.

Houghton PJ (1999) The scientific basis for the reputed activity of Valerian. J Pharm Pharmacol 51, 505-512.

Hsu S, Yu FX, Huang Q, Lewis J, Singh B, Dickinson D, Borke J, Sharawy M, Wataha J, Yamamoto T, Osaki T, Schuster G (2003) A mechanism-based in vitro anticancer drug screening approach for phenolic phytochemicals. Assay Drug Dev Technol 1, 611-618.

Hukkanen J, Mantyla M, Kangas L, Wirta P, Hakkola J, Paakki P, Evisalmi S, Pelkonen O, Raunio H (1998) Expression of cytochrome P450 genes encoding enzymes active in the metabolism of tamoxifen in human uterine endometrium. Pharmacol Toxicol 82, 93-97.

Huntley AL, Ernst E (2003) A systematic review of herbal medicinal products for the treatment of menopausal symptoms. Menopause 10, 465-476.

Huntley AL, Ernst E (2004) Soy for the treatment of perimenopausal symptoms-a systematic review. Maturitas 47, 1-9.

Hwang ES, Bowen PE (2002) Can the consumption of tomatoes or lycopene reduce cancer risk? Integr Cancer Ther 1, 121-32; discussion 132.

Iddamaldeniya SS, Wickramasinghe N, Thabrew I, Ratnatunge N, Thammitiyagodage MG (2003) Protection against diethylnitrosoamine-induced hepatocarcinogenesis by an indigenous medicine comprised of nigella sativa, hemidesmus indicus and smilax glabra: a preliminary study. J Carcinog. 2, 6.

Induction and recovery of hepatic drug metabolizing enzymes in rats treated with Ginkgo biloba extract. Food Chem Toxicol. 42, 953-957.

Ingram DM, Hickling C, West L, Mahe LJ, Dunbar PM (2002) A double-blind randomized controlled trial of isoflavones in the treatment of cyclical mastalgia. Breast 11, 170-174.

Jacobs EJ, Henion AK, Briggs PJ, Connell CJ, McCullough ML, Jonas CR, Rodriguez C, Calle EE, Thun MJ (2002) Vitamin C and vitamin E supplement use and bladder cancer mortality in a large cohort of US men and women. Am J Epidemiol 156, 1002-1010.

Jacobson JS, Troxel AB, Evans J, Klaus L, Vahdat L, Kinne D, Lo KM, Moore A, Rosenman PJ, Kaufman EL, Neugut AI, Grann VR (2001) Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol 19, 2739-45.

Jefferson JW (1988) Lithium tremor and caffeine intake: two cases of drinking less and shaking more. J Clin Psychiatry 49, 72-73.

Jensen T, Stender S, Goldstein K, Holmer G, Deckert T (1989) Partial normalization by dietary cod-liver oil of increased microvascular albumin leakage in patients with insulin-dependent diabetes and albuminuria. N Engl J Med 321, 572-577.

Ji BT, Chow WH, Hsing AW, McLaughlin JK, Dai Q, Gao YT, Blot WJ, Fraumeni JF Jr (1997) Green tea consumption and the risk of pancreatic and colorectal cancers. Int J Cancer 70, 255-258.

Jones JL, Daley BJ, Enderson BL, Zhou JR, Karlstad MD (2002) Genistein inhibits tamoxifen effects on cell proliferation and cell cycle arrest in T47D breast cancer cells. Am Surg 68, 575-577.

Jussofie A, Schmiz A, Hiemke C (1994) Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology (Berl) 116, 469-474.

Kaegi E (1998) Unconventional therapies for cancer: 1 Essaic. CMAJ 158, 897-902.

Karthikeyan J, Rani P (2003) Enzymatic and non-enzymatic antioxidants in selected Piper species. Indian J Exp Biol 41, 135-140.

Kenny FS, Pinder SE, Ellis IO, Gee JM, Nicholson RI, Bryce RP, Robertson JF (2000) g linolenic acid with tamoxifen as primary therapy in breast cancer. Int J Cancer 85, 643-648.

Kidd P (2003) Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev 8, 223-246.

Kidd PM (2000) The use of mushroom glucans and proteoglycans in cancer treatment. Altern Med Rev 5, 4-27.

Kim LS, Waters RF, Burkholder PM (2002) Immunological activity of larch arabinogalactan and Echinacea: a preliminary, randomized, double-blind, placebo-controlled trial. Altern Med Rev 7, 138-149.

Kimura Y, Tojima H, Fukase S, Takeda K (1994) Clinical evaluation of sizofilan as assistant immunotherapy in treatment of head and neck cancer. Acta Otolaryngol Suppl 511, 192-195.

Kivisto KT, Kroemer HK, Eichelbaum M (1995) The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions. Br J Clin Pharmacol 40, 523-530.

Klein EA, Thompson IM (2003) Update on chemoprevention of prostate cancer. Curr Opin Urol 14, 143-149.

Klepser TB, Klepser ME (1999) Unsafe and potentially safe herbal therapies. Am J Health Syst Pharm 56, 125-138.

Konno N, Makita H, Yuri K, Iizuka N, Kawasaki K (1994) Association between dietary iodine intake and prevalence of subclinical hypothyroidism in the coastal regions of Japan. J Clin Endocrinol Metab 78, 393-397.

Kosty MP, Fleishman SB, Herndon JE 2nd, Coughlin K, Kornblith AB, Scalzo A, Morris JC, Mortimer J, Green MR (1994) Cisplatin, vinblastine, and hydrazine sulfate in advanced, non-small-cell lung cancer: a randomized placebo-controlled, double-blind phase III study of the Cancer and Leukemia Group B. J Clin Oncol 12, 1113–1120.

Kotnis MS, Patel P, Menon SN, Sane RT (2004) Renoprotective effect of Hemidesmus indicus, a herbal drug used in gentamicin-induced renal toxicity. Nephrology (Carlton) 9, 142-152.

Krasowski MD, McGehee DS, Moss J (1997) Natural inhibitors of cholinesterases: implications for adverse drug reactions. Can J Anaestesiol 44, 525-534.

Krenn L, Presser A, Pradhan R, Bahr B, Paper DH, Mayer KK, Kopp B (2003) Sulfemodin 8-O-b-D-glucoside, a new sulfated anthraquinone glycoside, and antioxidant phenolic compounds from Rheum emodi. J Nat Prod 66, 1107-1109.

Kronenberg F, Fugh-Berman A (2002) Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials. Ann Intern Med 137, 805-813.

Labriola D, Livingston R (1999) Possible interactions between dietary antioxidants and chemotherapy. Oncology (Huntingt) 13, 1003-1008.

Lake KD, Nolen JG, Slaker RA, Reutzel TJ, Milfred SK, Solbrack DF, Hoffman FM (1992) Over-the-counter medication in cardiac transplant recipients: guidelines for use. Ann Pharmacotherapy 26, 1566-1575.

Lee BM, Lee SK, Kim HS (1998) Inhibition of oxidative DNA damage, 8-OHdG, and carbonyl contents in smokers treated with antioxidants (vitamin E, vitamin C, b-carotene and red ginseng). Cancer Lett 132, 219-227.

Lee YJ, Jin YR, Lim WC, Park WK, Cho JY, Jang S, Lee SK (2003) Ginsenoside-Rb1 acts as a weak phytoestrogen in MCF-7 human breast cancer cells. Arch Pharm Res 26, 58-63.

Lemaire I, Assinewe V, Cano P, Awang DV, Arnason JT (1999) Stimulation of interleukin-1 and -6 production in alveolar macrophages by the neotropical liana, Uncaria tomentosa (una de gato) J Ethnopharmacol 64, 109-115.

Levine M, Rumsey SC, Daruwala R, Park JB, Wang Y (1999) Criteria and recommendations for vitamin C intake. JAMA 281, 1415-1423.

Lewis R, Wake G, Court G, Court JA, Pickering AT, Kim YC, Perry EK (1999) Non-ginsenoside nicotinic activity in ginseng species. Phytother Res 13, 59-64.

Li M, Qu W, Wang Y, Wan H, Tian C (2002) Hypoglycemic effect of saponin from Tribulus terrestris Zhong Yao Cai 25, 420-422.

Lill J, Bauer LA, Horn JR and Hansten PD (2000) Cyclosporine-drug interactions and the influence of patient age. AM J Health-Syst Pharm 57, 1579-1584.

Lockwood K, Moesgaard S, Yamamoto T, Folkers K (1995) Progress on therapy of breast cancer with vitamin Q10 and the regression of metastases. Biochem Biophys Res Commun 212, 172-177.

Loprinzi CL, Goldberg RM, Su JQ, Mailliard JA, Kuross SA, Maksymiuk AW, Kugler JW, Jett JR, Ghosh C, Pfeifle DM (1994a) Placebo-controlled trial of hydrazine sulfate in patients with newly diagnosed non-small-cell lung cancer. J Clin Oncol 12, 1126–1129.

Loprinzi CL, Kuross SA, O'Fallon JR, Gesme DH Jr, Gerstner JB, Rospond RM, Cobau CD, Goldberg RM (1994b) Randomized placebo-controlled evaluation of hydrazine sulfate in patients with advanced colorectal cancer. J Clin Oncol 12, 1121–1125.

Ludwig CU, Stoll HR, Obrist R, Obrecht JP (1987) Prevention of cytotoxic drug induced skin ulcers with dimethyl sulfoxide (DMSO) and a-tocopherole. Eur J Cancer Clin Oncol 23, 327-329.

Luettig B, Steinmuller C, Gifford GE, Wagner H, Lohmann-Matthes ML (1989) Macrophage activation by the polysaccharide arabinogalactan isolated from plant cell cultures of Echinacea purpurea. J Natl Cancer Inst 81, 669-675.

Maclennan KM, Darlington CL, Smith PF (2002) The CNS effects of Ginkgo biloba extracts and ginkgolide B. Prog Neurobiol 67, 235-257.

Maggiolini M, Statti G, Vivacqua A, Gabriele S, Rago V, Loizzo M, Menichini F, Amdo S (2002) Estrogenic and antiproliferative activities of isoliquiritigenin in MCF7 breast cancer cells. J Steroid Biochem Mol Biol 82, 315-322.

Mannel M (2004) Drug Interactions with St John's Wort: Mechanisms and Clinical Implications. Drug Saf 27, 773-797.

Mansky PJ, Grem J, Wallerstedt DB, Monahan BP, Blackman MR (2003) Mistletoe and gemcitabine in patients with advanced cancer: a model for the phase I study of botanicals and botanical-drug interactions in cancer therapy. Integr Cancer Ther 2, 345-352.

Marangell LB, Martinez JM, Zboyan HA, Kertz B, Kim HF, Puryear LJ (2003) A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry 160, 996-998.

Markowitz JS, Donovan JL, Lindsay DeVane C, Sipkes L, Chavin KD(2003) Multiple-dose administration of Ginkgo biloba did not affect cytochrome P-450 2D6 or 3A4 activity in normal volunteers. J Clin Psychopharmacol 23, 576-581.

Maruyama H, Watanabe K, Yamamoto I (1991) Effect of dietary kelp on lipid peroxidation and glutathione peroxidase activity in livers of rats given breast carcinogen DMBA. Nutr Cancer 15, 221-228.

Mary NK, Achuthan CR, Babu BH, Padikkala J (2003) In vitro antioxidant and antithrombotic activity of Hemidesmus indicus (L) R.Br. J Ethnopharmacol 87, 187-191.

Massey LK, Palmer RG, Horner HT (2001) Oxalate content of soybean seeds (Glycine max: Leguminosae), soyfoods, and other edible legumes. J Agric Food Chem 49, 4262-4266.

Mathews JM, Etheridge AS, Black SR (2002) Inhibition of human cytochrome P450 activities by kava extract and kavalactones. Drug Metab Dispos 30, 1153-1157.

Matsuoka H, Seo Y, Wakasugi H, Saito T, Tomoda H (1997) Lentinan potentiates immunity and prolongs the survival time of some patients. Anticancer Res 17, 2751-2755.

Matthews MK Jr. (1998) Association of Ginkgo biloba with intracerebral hemorrhage Neurology 50, 1933-1944.

Melchart D, Clemm C, Weber B, Draczynski T, Worku F, Linde K, Weidenhammer W, Wagner H, Saller R (2002) Polysaccharides isolated from Echinacea purpurea herba cell cultures to counteract undesired effects of chemotherapy--a pilot study. Phytother Res 16, 138-142.

Melchart D, Linde K, Fischer P, Kaesmayr J (2000) Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev (2):CD000530.

Menendez JA, Ropero S, del Barbacid MM, Montero S, Solanas M, Escrich E, Cortes-Funes H, Colomer R (2002) Synergistic interaction between vinorelbine and g-linolenic acid in breast cancer cells. Breast Cancer Res Treat 72, 203-219.

Meseguer E, Taboada R, Sanchez V, Mena MA, Campos V, Garcia De Yebenes J (2002) Life-threatening parkinsonism induced by kava-kava. Mov Disord 17, 195-196.

Messina MJ (2003) Emerging evidence on the role of soy in reducing prostate cancer risk. Nutr Rev 61, 117-131.

Michalets EL (1998) Review of Therapeutics, Update: Clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 18, 84-112.

Miller LG (1998) Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 158, 2200-2211.

Moertel CG, Fleming TR, Creagan ET, Rubin J, O'Connell MJ, Ames MM (1985) High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison. N Engl J Med 312, 137-141.

Moertel CG, Fleming TR, Rubin J, Kvols LK, Sarna G, Koch R, Currie VE, Young CW, Jones SE, Davignon JP (1982) A clinical trial of amygdalin (Laetrile) in the treatment of human cancer. N Engl J Med 306, 201-206.

Mullins RJ, Heddle R (2002) Adverse reactions associated with echinacea: the Australian experience. Ann Allergy Asthma Immunol 88, 42-51.

Nair HK, Rao KV, Aalinkeel R, Mahajan S, Chawda R, Schwartz SA (2004) Inhibition of prostate cancer cell colony formation by the flavonoid quercetin correlates with modulation of specific regulatory genes. Clin Diagn Lab Immunol 11, 63-69.

Nallani SC, Goodwin B, Buckley AR, Buckley DJ, Desai PB (2004) Differences in the induction of cytochrome P450 3A4 by taxane anticancer drugs, docetaxel and paclitaxel, assessed employing primary human hepatocytes. Cancer Chemother Pharmacol 54, 219-229.

Natural Medicines Comprehensive Database (2004); http://naturaldatabase.com.

Neary JT, Bu Y (1999) Hyperforin inhibits uptake of serotonin and norepinephrine in astrocytes. Brain Research 816, 358-363.

Newall CA, Anderson LA, Philpson JD (1996) Herbal Medicine: A Guide for Healthcare Professionals. London, UK: The Pharmaceutical Press, 1996

Nishino H, Kitagawa K, Fujiki H, Iwashima A (1986) Berberine sulfate inhibits tumor-promoting activity of teleocidin in two-stage carcinogenesis on mouse skin. Oncology 43, 131-134.

Nkondjock A, Ghadirian P (2004) Dietary carotenoids and risk of colon cancer: case-control study. Int J Cancer 110, 110-116.

North American Menopause Society (2004) Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society. Menopause 11, 11-33.

Oerter Klein K, Janfaza M, Wong JA, Chang RJ (2003) Estrogen bioactivity in fo-ti and other herbs used for their estrogen-like effects as determined by a recombinant cell bioassay. J Clin Endocrinol Metab 88, 4077-4079.

Ohnishi N, Kusuhara M, Yoshioka M, Kuroda K, Soga A, Nishikawa F, Koishi T, Nakagawa M, Hori S, Matsumoto T, Yamashita M, Ohta S, Takara K, Yokoyama T (2003) Studies on interactions between functional foods or dietary supplements and medicines. I. Effects of Ginkgo biloba leaf extract on the pharmacokinetics of diltiazem in rats. Biol Pharm Bull 26, 1315-1320.

Okamura K, Suzuki M, Chihara T, Fujiwara A, Fukuda T, Goto S, Ichinohe K, Jimi S, Kasamatsu T, Kawai N (1989) Clinical evaluation of sizofiran combined with irradiation in patients with cervical cancer. A randomized controlled study; a five-year survival rate. Biotherapy 1, 103-107.

Oken BS, Storzbach DM, Kaye JA (1998) The efficacy of ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol 55, 1409-1415.

Ondrizek RR, Chan PJ, Patton WC, King A (1999) Inhibition of human sperm motility by specific herbs used in alternative medicine. J Assist Reprod Genet 16, 87-91.

Pace A, Savarese A, Picardo M, Maresca V, Pacetti U, Del Monte G, Biroccio A, Leonetti C, Jandolo B, Cognetti F, Bove L (2003) Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. J Clin Oncol 21, 927-931.

Patrick L (2000) b-carotene: the controversy continues. Alt Med Rev 5, 530-545

Peebles KA, Baker RK, Kurz EU, Schneider BJ, Kroll DJ (2001) Catalytic inhibition of human DNA topoisomerase IIa by hypericin, a naphthodianthrone from St. John's wort (Hypericum perforatum). Biochem Pharmacol 62, 1059-1070.

Pelletier M, Lavastre V, Savoie A, Ratthe C, Saller R, Hostanska K, Girard D (2001) Modulation of interleukin-15-induced human neutrophil responses by the plant lectrin Viscum album agglutinin-I. Clin Immunol 101, 229-236.

Perovic S, Müller WE (1995) Pharmacological profile of hypericin extract. Effect on serotonin uptake by postsynaptic receptors. Arzneimittelforschung 45, 1145-1148.

Pfeifer BL, Pirani JF, Hamann SR, Klippel KF (2000) PC-SPES, a dietary supplement for the treatment of hormone-refractory prostate cancer. BJU Int 85, 481-485.

Physicians' Deck Reference (PDR) for Herbal Medicines 2^nd edition (2000), Medical Economics Company, Montevale New Jersey.

Physicians' Deck Reference (PDR) for Herbal Medicines 2^nd edition (2001), Medical Economics Company, Montevale New Jersey.

Piao BK, Wang YX, Xie GR, Mansmann U, Matthes H, Beuth J, Lin HS (2004) Impact of complementary mistletoe extract treatment on quality of life in breast, ovarian and non-small cell lung cancer patients. A prospective randomized controlled clinical trial. Anticancer Res 24, 303-309.

Pittler MH, Ernst E (2003) Kava extract for treating anxiety (Cochrane Review). In: The Cochrane Library, Issue 4, Chichester, UK: John Wiley and Sons, Ltd.

Polan ML, Hochberg RB, Trant AS, Wuh HC (2004) Estrogen bioassay of ginseng extract and ArginMax, a nutritional supplement for the enhancement of female sexual function. J Womens Health (Larchmt) 13, 427-430.

Prager N, Bickett K, French N, Marcovici G (2002) A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-a-reductase in the treatment of androgenetic alopecia. J Altern Complement Med 8, 143-152.

Quintieri L, Rosato A, Napoli E, Sola F, Geroni C, Floreani M, Zanovello P (2000) In vivo antitumor activity and host toxicity of methoxymorpholinyl doxorubicin: role of cytochrome P450 3A. Cancer Res 60, 3232-3238.

Rafi MM, Vastano BC, Zhu N, Ho CT, Ghai G, Rosen RT, Gallo MA, DiPaola RS (2002) Novel polyphenol molecule isolated from licorice root (Glycrrhiza glabra) induces apoptosis, G2/M cell cycle arrest, and Bcl-2 phosphorylation in tumor cell lines. J Agric Food Chem 50, 677-684.

Ratna WN (2002) Inhibition of estrogenic stimulation of gene expression by genistein. Life Sci 71, 865-877.

Relling MV, Nemec J, Schuetz EG, Schuetz JD, Gonzalez FJ, Korzekwa KR (1994) O-demethylation of epipodophyllotoxins is catalyzed by human cytochrome P450 3A4. Mol Pharmacol 45, 352-358.

Ribereau-Gayon G, Jung ML, Frantz M, Anton R (1997) Modulation of cytotoxicity and enhancement of cytokine release induced by Viscum album L. extracts or mistletoe lectins. Anticancer Drugs 8, S3-S8.

Richardson MA, Sanders T, Palmer JL, Greising A, Singletary SE (2000) Complementary/alternative medicine use in a comprehensive cancer centre and the implications for oncology. J Clin Oncol 18, 2505-2014.

Risberg T, Lund E, Wist E, Kaasa S, Wilsgards T (1998) Cancer patients use nonproven therapy: 5-year follow-up study. J Clin Oncol 16, 1-2.

Ross GD, Vetvicka V, Yan J, Xia Y, Vetvickova J (1999) Therapeutic intervention with complement and b-glucan in cancer. Immunopharmacology 42, 61-74.

Russell RM (2000) The vitamin A spectrum: from deficiency to toxicity. Am J Clin Nutr 71, 878-884.

Russmann S, Lauterberg BH, Hebling A (2001) Kava hepatotoxicity. Ann Intern Med 135, 68.

Sadjadi J (1998) Cutaneous anthrax associated with the Kombucha "mushroom" in Iran. JAMA 280, 1567-1568.

Sarkar FH, Li Y (2003) Soy isoflavones and cancer prevention. Cancer Invest 21, 744-757.

Sato J, Nakata H, Owada E, Kikuta T, Umetsu M, Ito K (1993) Influence of usual intake of dietary caffeine on single-dose kinetics of theophylline in healthy human subjects. Eur J Clin Pharmacol 44, 295-298.

Schelosky L, Raffauf C, Jendroska K, Poewe W (1995) Kava and dopamine antagonism. Neurol Neurosurg Psychiatry 58, 639-640.

Schumacher K, Schneider B, Reich G, Stiefel T, Stoll G, Bock PR, Hanisch J, Beuth J (2003) Influence of postoperative complementary treatment with lectin-standardized mistletoe extract on breast cancer patients. A controlled epidemiological multicentric retrolective cohort study. Anticancer Res 23, 5081-5087.

Seidlova-Wuttke D, Hesse O, Jarry H, Christoffel V, Spengler B, Becker T, Wuttke W (2003) Evidence for selective estrogen receptor modulator activity in a black cohosh (Cimicifuga racemosa) extract: comparison with estradiol-17b. Eur J Endocrinol 149, 351-362.

Semiglasov VF, Stepula VV, Dudov A, Lehmacher W, Mengs U (2004) The standardised mistletoe extract PS76A2 improves QoL in patients with breast cancer receiving adjuvant CMF chemotherapy: a randomised, placebo-controlled, double-blind, multicentre clinical trial. Anticancer Res 24, 1293-1302.

Sharma G, Tyagi AK, Singh RP, Chan DC, Agarwal R (2004) Synergistic anti-cancer effects of grape seed extract and conventional cytotoxic agent doxorubicin against human breast carcinoma cells. Breast Cancer Res Treat 85, 1-12.

Sharma RA, McLelland HR, Hill KA, Ireson CR, Euden SA, Manson MM, Pirmohamed M, Marnett LJ, Gescher AJ, Steward WP (2001) Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res 7, 1894-1900.

Sheng Y, Pero RW, Amiri A, Bryngelsson C (1998) Induction of apoptosis and inhibition of proliferation in human tumor cells treated with extracts of Uncaria tomentosa. Anticancer Res 18, 3363-3368.

Shin HR, Kim JY, Yun TK, Morgan G, Vainio H (2000). The cancer-preventive potential of Panax ginseng: a review of human and experimental evidence. Cancer Causes Control 11, 565-576.

Singh RP, Tyagi AK, Dhanalakshmi S, Agarwal R, Agarwal C (2004) Grape seed extract inhibits advanced human prostate tumor growth and angiogenesis and upregulates insulin-like growth factor binding protein-3. Int J Cancer 108, 733-740.

Small EJ, Frohlich MW, Bok R, Shinohara K, Grossfeld G, Rozenblat Z, Kelly WK, Corry M, Reese DM (2000) Prospective trial of the herbal supplement PC-SPES in patients with progressive prostate cancer. J Clin Oncol 18, 3595-3603.

Sovak M, Seligson AL, Konas M, Hajduch M, Dolezal M, Machala M, Nagourney R (2002) Herbal composition PC-SPES for management of prostate cancer: identification of active principles. J Natl Cancer Inst 94, 1275-1281.

Sparber A, Bauer L, Curt G, Eisenberg D, Levin T, Parks S, Steinberg SM, Wootton J (2000) Use of complementary medicine by adult patients participating in cancer clinical trials. Onc Nurs Forum 27, 623-630.

Sparreboom A, Cox MC, Archarya MA, Figg WD (2004) Herbal remedies in the United States: potential adverse interactions with anticancer agents. J Clin Oncol 22, 2489-2503.

Stammers T, Sibbald B, Freeling P (1992) Efficacy of cod liver oil as an adjunct to non-steroidal anti-inflammatory drug treatment in the management of osteoarthritis in general practice. Ann Rheum Dis 51, 128-129.

Stammler G, Volm M (1997) Green tea catechins (EGCG and EGC) have modulating effects on the activity of doxorubicin in drug-resistant cell lines. Anticancer Drugs 8, 265-268.

Stevinson C, Ernst E (1999) Valerian for insomnia: a systematic review of randomized clinical trials. Sleep Medicine 1, 91-99.

Stimpel M, Proksch A, Wagner H, Lohmann-Matthes ML (1984) Macrophage activation and induction of macrophage cytotoxicity by purified polysaccharide fractions from the plant Echinacea purpurea. Infect Immune 46, 845-849

Strandell J, Neil A, Carlin G (2004) An approach to the in vitro evaluation of potential for cytochrome P450 enzyme inhibition from herbals and other natural remedies Phytomedicine 11, 198-104.

Strandell J, Neil A, Carlin G (2004) An approach to the in vitro evaluation of potential for cytochrome P450 enzyme inhibition from herbals and other natural remedies. Phytomedicine 11, 98-104.

Su KP, Huang SY, Chiu CC, Shen WW (2003) Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol 13, 267-71.

Sugiyama T, Kubota Y, Shinozuka K, Yamada S, Yamada K, Umegaki K (2004) Induction and recovery of hepatic drug metabolizing enzymes in rats treated with Ginkgo biloba extract. Food Chem Toxicol 42, 953-7.

Sun CL, Yuan JM, Arakawa K, Low SH, Lee HP, Yu MC (2002) Dietary soy and increased risk of bladder cancer: the Singapore Chinese Health Study. Cancer Epidemiol Biomarkers Prev 11, 1674-1677.

Suzuki Y, Tsubono Y, Nakaya N, Suzuki Y, Koizumi Y, Tsuji I (2004) Green tea and the risk of breast cancer: pooled analysis of two prospective studies in Japan. Br J Cancer 90, 1361-1363.

Tabet N, Birks J, Grimley Evans J (2004) Vitamin E for Alzheimer's disease. In: The Cochrane Library, Issue 1, Chichester, UK: John Wiley and Sons, Ltd.

Tai J, Cheung S, Wong S, Lowe C (2004) In vitro comparison of Essiac and Flor-Essence on human tumor cell lines. Oncol Rep 11, 471-476.

Tamayo C, Richardson MA, Diamond S, Skoda I (2000) The chemistry and biological activity of herbs used in flor essence herbal tonic and essiac. Phytother 14, 1-14.

Tang F, Nag S, Shiu SY, Pang SF (2002) The effects of melatonin and Ginkgo biloba extract on memory loss and choline acetyltransferase activities in the brain of rats infused intracerebroventricularly with b-amyloid. Life Sci 71, 2625-2631.

Taylor JA, Weber W, Standish L, Quinn H, Goesling J, McGann M, Calabrese C (2003) Efficacy and safety of echinacea in treating upper respiratory tract infections in children: a randomized controlled trial. JAMA 290, 2824-2830.

Teufel-Mayer R, Gleitz J (1997) Effects of long-term administration of hypericum extracts on the affinity and density of the central serotonergic 5-HT1 A and 5-HT2 A receptors. Pharmacopsychiatry 30 Suppl 2, 113-116.

The a-Tocopherol, b Carotene Cancer Prevention Study Group (1994) The effect of vitamin E and b carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330, 1029-35.

Thelen P, Wuttke W, Jarry H, Grzmil M, Ringert RH (2004) Inhibition of telomerase activity and secretion of prostate specific antigen by silibinin in prostate cancer cells. J Urol 171, 1934-1938.

Thiele B, Brink I, Ploch M (1994) Modulation of cytokine expression by hypericin extract. J Geriatric Psych Neurol 7, S60-S62.

Toft I, Bonaa KH, Ingebretsen OC, Nordoy A, Jenssen T (1995) Effects of n-3 polyunsaturated fatty acids on glucose homeostasis and blood pressure in essential hypertension. A randomized, controlled trial. Ann Intern Med 123, 911-918.

Tripathi YB, Upadhyay AK, Chaturvedi P (2001) Antioxidant property of Smilex china Linn.Indian J Exp Biol 39, 1176-9.

Tsuruo T (2003) Molecular cancer therapeutics: recent progress and targets in drug resistance. Intern Med 42, 237-243.

Tyagi A, Agarwal C, Harrison G, Glode LM, Agarwal R (2004) Silibinin causes cell cycle arrest and apoptosis in human bladder transitional cell carcinoma cells by regulating CDKI-CDK-cyclin cascade, and caspase 3 and PARP cleavages. Carcinogenesis [Epub ahead of print]

van Schaik RH (2004) Implications of cytochrome P450 genetic polymorphisms on the toxicity of antitumor agents. Ther Drug Monit 26, 236-240.

Vessby B, Boberg M (1990) Dietary supplementation with n-3 fatty acids may impair glucose homeostasis in patients with non-insulin-dependent diabetes mellitus. J Intern Med 228, 165-171.

Vickers A (2002) Botanical medicines for the treatment of cancer: rationale, overview of current data, and methodological considerations for phase I and II trials. Cancer Invest 20, 1069-1079.

Vincent A, Fitzpatrick LA (2000) Soy isoflavones: are they useful in menopause? Mayo Clin Proc 75, 1174-1184.

Visani G, Manfroi S, Tosi P, Martinelli G (1996) All-trans-retinoic acid and pseudotumor cerebri. Leuk Lymphoma 23, 437-442.

Vogeler BK, Pittler MH, Ernst E (1999) The efficacy of ginseng. A systematic review of randomized controlled trials. Eur J Clin Pharmacol 55, 567-575.

Wakai K, Hirose K, Takezaki T, Hamajima N, Ogura Y, Nakamura S, Hayashi N, Tajima K (2004) Foods and beverages in relation to urothelial cancer: case-control study in Japan. Int J Urol 11, 11-19.

Walters BN, Gubbay SS (1981)Tetracycline and benign intracranial hypertension: report of five cases. Br Med J (Clin Res Ed) 282, 19-20.

Wang GQ, Dawsey SM, Li JY, Taylor PR, Li B, Blot WJ, Weinstein WM, Liu FS, Lewin KJ, Wang H (1994) Effects of vitamin/mineral supplementation on the prevalence of histological dysplasia and early cancer of the esophagus and stomach: results from the General Population Trial in Linxian, China. Cancer Epidemiol Biomarkers Prev 3, 161-166.

Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y (1997a) Randomized, double-blind, placebo-controlled study of supplemental vitamin E on attenuation of the development of nitrate tolerance. Circulation 96, 2545-2550.

Watanabe R, Murata M, Takayama N, Tokuhira M, Kizaki M, Okamoto S, Kawai Y, Watanabe K, Murakami H, Kikuchi M, Nakamura S, Ikeda Y (1997b) Long-term follow-up of hemostatic molecular markers during remission induction therapy with all-trans retinoic acid for acute promyelocytic leukemia. Keio Hematology-Oncology Cooperative Study Group (KHOCS). Thromb Haemost 77, 641-645.

Werneke U, Earl J, Seydel C, Horn O, Crichton P, Fannon D (2004a) Potential health risks of complementary alternative medicines in cancer patients. Br J Cancer 90, 408-413.

Werneke U, Horn O, Taylor D (2004b) How effective is St John’s wort? – The evidence revisited. J Clin Psych 65, 611-617.

Werneke U, Earl J, Seydel C, Horn O, Crichton P, Fannon D (2004c) Reply: Assessing health risks of complementary alternative medicines in cancer patients. Br J Cancer 91, 996-997.

Werneke U, McCready VR (2004) Complementary alternative medicine and nuclear medicine. Eur J Nucl Med Mol Imaging 31, 599-603.

Whiskey E, Werneke U, Taylor D (2001) A systematic review of hypericum perforatum in depression. Int Clin Psychopharmacol 16, 239-252.

White E, Shannon JS, Patterson RE (1997) Relationship between vitamin and calcium supplement use and colon cancer. Cancer Epidemiol Biomarkers Prev 6, 769-774.

Whiting PW, Clouston A, Kerlin P (2002) Black cohosh and other herbal remedies associated with acute hepatitis. Med J Aust 177, 440-443.

Williamson EM (2001) Synergy and other interactions in phytomedicines. Phytomedicine 8, 401-409.

Wilson B (2000) The rise and fall of Laetrile. http://www.quackwatch.org

Xiaoguang C, Hongyan L, Xiaohong L, Zhaodi F, Yan L, Lihua T, Rui H (1998) Cancer chemopreventive and therapeutic activities of red ginseng. J Ethnopharmacol 60, 71-78.

Xu Z, Cao HY, Li Q (1989) Protective effects of berberine on spontaneous ventricular fibrillation in dogs after myocardial infarction. Zhongguo Yao Li Xue Bao 10, 320-324.

Yamamoto S, Sobue T, Kobayashi M, Sasaki S, Tsugane S (2003) Japan Public Health Center-Based Prospective Study on Cancer Cardiovascular Diseases Group. Soy, isoflavones, and breast cancer risk in Japan. J Natl Cancer Inst 95, 906-913.

Zhang S, Hunter DJ, Forman MR, Rosner BA, Speizer FE, Colditz GA, Manson JE, Hankinson SE, Willett WC (1999) Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. J Natl Cancer Inst 91, 547-56.

Zhou S, Lim LY, Chowbay B (2004) Herbal modulation of P-glycoprotein. Drug Metab Rev 36, 57-104.

Zhou-Pan XR, Seree E, Zhou XJ, Placidi M, Maurel P, Barra Y, Rahmani R (1993) Involvement of human liver cytochrome P450 3A in vinblastine metabolism: drug interactions. Cancer Res 53, 5121-5126.

Zimmerman RA, Thompson IM Jr (2002) Prevalence of complementary medicine in urologic practice. A review of recent studies with emphasis on use among prostate cancer patients. Urol Clin North Am 29, 1-9.

Zuber R, Modriansky M, Dvorak Z (2002) Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Phytother Res 16, 632-638.

Ursula Werneke, M.D.