Introduction

In the United States, approximately 1 in 4 persons prescribed pharmaceutical medications also consume a dietary supplement.^{1, 2} Dietary supplements that include herbs, vitamin and/or mineral preparations, and other dietary supplements such as glucosamine and fish oils, may augment or antagonise the actions of prescription and non-prescription drugs. This is because supplements have demonstrated pharmacologic actions that may then go on to produce therapeutic outcomes.³ Moreover, supplements that do not have a documented pharmacologic action can also significantly affect the absorption, metabolism, and disposition of other pharmaceutical products. Health professionals usually question the nutritional adequacy and safety of a patient’s diet, however the nutritional impact of medications is often overlooked. Pharmaceuticals have both beneficial and adverse effects, although there is a strong focus on the benefits. Furthermore, drug–drug interactions are generally integral to decision-making yet the impact of drug–food and drug–nutrient interactions are rarely acknowledged or, mostly, deemed clinically insignificant.

Some vitamin–mineral–herbal supplements require separation from medications by about 2–4 hours to avoid potential problems with absorption or interactions. See the medications in Table 37.1 for more specific advice in relation to this rule.

Table 37.1 Common herbs and nutrients and their interactions with medications

Drugs	Interactions
Central nervous system and sedating medication
Herb	Effect
St John’s wort	SSRIs and any other medication with serotoninergic effect (e.g. tramadol) Warn patients not to initiate St John’s wort when receiving SSRI medication — may cause serotonin syndrome Patients should discuss use of St John’s wort with their GP and their pharmacist

  Avoid with alcohol, benzodiazepines, barbiturates, psychoactive medication, narcotic opioids such as codeine, pethidine and oxycodone, and anti-anxiolytics as may potentiate sedating effect Anticoagulant medications^(a) Nutrient or herb Effects on anticoagulant St John’s wort Reduced serum levels of warfarin and reduces INR. Monitor INR carefully Gingko biloba Does not interact with warfarin and/or aspirin directly. Has anti-platelet activity. Does not significantly affect clotting status of warfarin. In combination with NSAIDS such as aspirin can cause severe bleeding (e.g. intra-cranial haemorrhage) Ginger May affect clotting status and potentiate effect of warfarin Garlic Asian ginseng (Panax ginseng) No effect on warfarin American ginseng (Panax quinquefolius) Decreases serum warfarin levels Siberian ginseng (Eleutherococcus senticosus) Has not been studied, however contains constituents that inhibit platelet aggregation Devil’s claw (Harpagophytum procumbens) Potentiates anticoagulant effects Glucosamine Potentiates warfarin effect and increases INR Fish oils 3–6g daily does not affect coagulation status in patients on warfarin. Caution is still needed due to their anti-platelet effect, especially at higher doses and stop use 2 weeks before surgery Vitamin E Enhances anti-platelet effect of aspirin. No clear increased risk of bleeding in patients on warfarin Cranberry juice, Seville oranges, pomegranate juice Papaya May increase INR Red clover (Trifolium pratense) Due to its coumarin content, red clover may increase the risk of bleeding. Avoid use with warfarin and 2 weeks prior to surgery Saw palmetto (Serenoa repens) May increase risk of bleeding. Avoid use with warfarin and 2 weeks prior to surgery Cardiovascular medications^(b) Herb Effect St John’s wort^(c) Decreases serum levels of verapamil, statins and digoxin Ginseng^(c) Increases digoxin levels Licorice Increases urinary excretion of potassium and reduces serum potassium. Can increase blood pressure. Avoid with antihypertensive medication, potassium depleting medication such as thiazide diuretics, corticosteroids such as prednisolone, corticosteroid inhalants and cortisol, digoxin Hawthorn May interact adversely with Digoxin. May potentiate blood pressure lowering effects, thereby requiring modified drug doses Fibre and gastrointestinal tract (GIT) supplements Supplement Effect Psyllium (dietary fibre)^(d) Slippery elm bark May reduce absorption of any medication as it coats the lining of the GIT Diabetes medications Nutrient and/or herb Effect on diabetes medication Hawthorn No interaction found Chromium, psyllium, ginseng, fenugreek, gymnema, bitter melon All have hypoglycaemic effects in patients with diabetes, which may be unpredictable. No specific changes in hypoglycaemic doses are needed unless blood sugar level changes occur HIV medications Nutrient and/or herb Effect on HIV medication Garlic and vitamin C Reduce serum antiretroviral medications Milk thistle, echinacea species and goldenseal No clinically relevant effect St John’s wort Risk of dangerous interaction. Discourage use of herb Ginkgo Possible drug failure Hormonal medications Nutrient and/or herb Effect on hormonal medication Ginseng Saw palmetto (Serenoa repens) Soy Red clover (Trifolium pratense) Vitex agnus castus May potentiate progesterone effect High dose iodine/kelp/seaweed

(a) All patients on warfarin should be monitored closely with the introduction of any complementary medicine such as garlic, fish oils, ginseng and ginkgo.

(b) Given the serious consequences associated with small changes in the coagulation status, patients on warfarin should be carefully monitored when: 1) initiating or stopping any nutritional or herbal supplement 2) commencing new bottles of the same product in case of product variation.

(c) Monitor serum digoxin levels in patients taking St John’s wort and ginseng.

(d) Separate psyllium by several hours to allow the absorption of drugs to occur more effectively.

Key points regarding herb-nutrient-drug interactions

Examine food habits or metabolic changes carefully in any patient who unexpectedly gains or loses weight while taking drugs.

Grapefruit juice, Seville orange juice and pomegranate juice inhibit cytochrome p450 (CYP450) and 3A4/5 in the liver and gut for up to 72 hours and can therefore increase serum concentration of some drugs (e.g statins, antidepressants, beta blockers, calcium channel blockers, hormone replacement therapy [HRT], warfarin, anticonvulsants, antipsychotics) into toxic ranges.

As a general rule separate vitamin–mineral–herbal supplements from medications by about 2–4 hours as they may increase or decrease each others absorption in the gut and/or affect metabolism, thus increasing risks of toxicity or insufficiency.

Types of herb–drug interactions

There are 2 types of interactions that occur between natural products and pharmaceuticals.

The evidence documenting dietary supplement–drug interactions varies extensively. There is at present no process for the systematic evaluation of dietary/nutritional supplement products for possible interactions with prescription medications. As a result of this deficit, there is an incomplete knowledge of the interactions that may occur. The information is largely researched from many different sources including animal studies, human case reports, case series, historical contraindications, and the extrapolation from basic pharmacology data, or from clinical trials. Many of the recommendations associated with herb–drug interactions are based on speculation rather than research.⁴ According to a recent study, overall the risk of actual harm from a herb–drug interaction is low.⁵ According to the authors the 5 most common natural products with a potential to affect medications include garlic, St John’s wort, ginkgo, valerian and kava. These herbal medicines accounted for 68% of the potential clinically signifi cant interactions in the survey. The 4 most common prescription medicines affected by supplements are antithrombotics, such as warfarin, antidepressants, sedatives and anti-diabetic agents.

Types of nutrient–drug interactions

Pharmaceuticals can affect and be affected by nutrition.

Drugs can also affect many nutritional factors such as appetite, taste acuity and gastrointestinal function. Food habits or metabolic changes should be examined carefully in any patient who unexpectedly gains or loses weight or has altered bowel motions while taking drugs.

As a general rule, it is advisable to separate vitamin and/or mineral supplements from medications by about 2–4 hours to reduce any potential interactions. However, where the drug affects metabolism or excretion of a nutrient such a simple rule may not apply.

Even though a patient’s diet may be supplying a moderate amount of vitamins and/or minerals, they may be tipped into nutritional insufficiency or deficiency due to their medications. If these deficiencies are not corrected through diet (and supplements if indicated) they may further complicate the management of the condition or create new health problems.

Nutrient supplementation may not necessarily be needed in combination with a nutrient-depleting pharmaceutical. Clinical symptoms of nutrient deficiency and/or insufficiency combined with laboratory data are needed to verify changes in nutritional status. A nutrient dense diet, however, makes an important contribution to the health of medicated patients and reduces the risk of nutritional disorders or altered drug efficacy. Health professionals need to be knowledgeable and vigilant of nutrition-related clinical symptoms that may be caused by pharmaceuticals.

Figure 37.1 lists the top 12 nutrient-depleting drugs (see also Appendix 2).^{6, 7}

Patient populations and specific pharmaceuticals

Cardiovascular medication

Loop and thiazide diuretics increase the excretion of K, Mg, Zn, vitamins B1, B12, B6, folate and impair appetite. High K foods and/or supplements are frequently prescribed; however, long-term use (more than 6 months) might lead to Mg deficiency which in turn can increase loss of K and B1. It is probably prudent to check red blood cell magnesium along with serum potassium and prescribe a magnesium supplement if low (e.g. magnesium orotate/chelate/ citrate are better absorbed). B1 deficiency can aggravate congestive heart failure, oedema, muscle pain, poor appetite, mental confusion and risk of falls. Thiazide diuretics can increase blood levels of calcium by decreasing excretion and, indirectly, by affecting vitamin D metabolism, therefore calcium and vitamin D supplements should be used with caution.

Ace inhibitors and angiotensin II antagonists attach to zinc and can cause zinc deficiency, which in turn may account for some of the drug side-effects (impaired appetite, altered taste, skin numbness and/or tingling). Garlic, hawthorn, olive leaf and fish oil supplements may increase the antihypertensive effects of the drugs requiring adjustment of medication dose. K supplements and high K foods are contraindicated due to increased risk of hyperkalaemia. These drugs contain magnesium so high-dose Mg supplements (>300mg/day) should be used with caution to avoid excessive intake. (See Appendix 2 for references.)

Of all the supplements used by patients who have cardiac disease, St John’s wort (used to treat mood disorders) is associated with the most interactions. It can decrease serum concentrations of drugs including most calcium channel blockers and statins.^{53, 54, 55} Blood pressure and lipid levels, respectively, should be monitored closely if a patient is taking 1 of these drugs concomitantly with St John’s wort.

The mechanisms of St John’s wort on the pharmacokinetics of other drugs is due to induction of cytochrome P450 (CYP450) isoenzymes CYP3A4, CYP2C9, and CYP1A2, and of the transport protein P-glycoprotein, leading to decreased concentration of medications.⁵⁶ In 1 study, St John’s wort was reported to have decreased digoxin blood levels by 25%. The most likely mechanism was by inducing P-glycoprotein and the clearance of digoxin.^{57, 58}

Ginseng which is a commonly used herb⁵ has been reported to cause an increase in digoxin serum levels in a case report of 1 patient.⁵⁹ At present digoxin levels should be monitored in patients taking Siberian ginseng or St John’s wort (or any supplement for that matter, since digoxin has a narrow therapeutic window).

Laxative medication

Laxatives can cause steatorrhoea with chronic use which is associated with reduced absorption of fat soluble vitamins (A, D, E, K) and increased excretion of K and Mg. Milk/Ca/Mg medication are not recommended within 2 hours of the laxative. It may be prudent to recommend a multivitamin with chronic use of laxatives

Psyllium commonly used as a dietary fibre is not absorbed by the small intestine. The purely mechanical action of psyllium mucilage absorbs excess water while stimulating normal bowel elimination. Although its main use has been as a laxative, it is more appropriately termed a true dietary fibre. With other related bulk-forming laxatives, these dietary supplements are often not considered to be medications by many patients. However, they can slow or diminish absorption of many pharmaceutical drugs.⁶⁰

Psyllium has been reported to reduce the concentration of carbamazepine absorption and its serum levels.⁶¹ In addition, a case report has demonstrated that psyllium decreased the absorption of lithium.⁶²

Hence, this data tends to indicate that bulk laxatives such as psyllium may need to be separated by several hours to allow absorption of drugs to occur more effectively.

Diabetes medication

Metformin/pioglitazone/sulfonylureas can decrease absorption of vitamin B12 and folate. Magnesium supplements can increase absorption of pioglitazone and sulfonylureas these drugs can also reduce appetite and alter taste. K/Mg citrate supplements may reduce their therapeutic effect. Short-term studies have not found glucosamine supplements to have an adverse effect on blood glucose levels in diabetics. Sulfonylureas can affect thyroid function (and cause weight gain) by reducing the uptake of iodine by the thyroid. (See Appendix 2 for references.)

Currently nutrient-herb–drug interactions are not well documented in patients being treated for type 2 diabetes mellitus (T2DM). However, a number of supplements have been reported to have intrinsic effects on serum glucose. In a recent randomised controlled trial (RCT) to demonstrate a hypotensive effect of hawthorn in patients with diabetes taking medication, it was reported that no herb–drug interaction was found.⁶³

Chromium and psyllium also have been reported to have hypoglycaemic effects.^{64, 65, 66} Also ginseng, fenugreek and Gymnema sylvestre have demonstrated in vivo hypoglycaemic activity and in patients with diabetes this effect might be additive when combined with oral hypoglycaemics or insulin.^{67, 68, 69}

Recently it has been reported that bitter melon (Momordica charantia) has a similar affect to rosiglitazone.⁷⁰ The cumulative evidence demonstrates that bitter melon and fenugreek may be useful for the treatment of T2DM.⁷¹

Patients taking supplements containing vitamin E, Mg, Cr, CoQ₁₀, lipoic acid, inositol or foods/supplements with Aloe vera juice, bitter melon, cinnamon, fenugreek, garlic, ginger, gymnema, ginseng, bilberry, guggul, gingko, milk thistle, guar, green tea, olive leaf extract, psyllium and turmeric may need closer monitoring of their blood glucose levels. These supplements may, therefore be useful in the pre-diabetic patient.

The effect of these supplements may be unpredictable in T2DM, and hypoglycaemic medication may need to be altered if blood glucose changes occur.²

HIV medication

Herbal medicines are widely used by HIV patients. Several herbal medicines have been shown to interact with antiretroviral drugs, which might lead to drug failure.⁶⁸ Echinacea purpurea (echinacea), garlic, ginkgo, milk thistle, and St John’s wort have the potential to cause significant interactions with antiretroviral medication.

Most antiretrovirals are metabolised via the CYP3A4 and P-glycoprotein systems. Dietary supplements that induce these systems may decrease serum levels of the antiretroviral drugs.

St John’s wort is the herbal supplement with the most evidence of an effect on these enzyme systems.⁷² Some degree of clinical research has demonstrated reductions in antiretroviral serum concentrations in patients who have taken garlic and vitamin C.^{73, 74} Other herbal products such as milk thistle, echinacea species, and goldenseal inhibit CYP450 enzymes in vitro, but do not appear to give rise to a clinically relevant effect.^72–76

The effectiveness of HIV therapy should be monitored in patients taking these supplements, particularly St John’s wort. Because of the risk of dangerous interactions, patients prescribed antiretrovirals should be discouraged from using St John’s wort.²

Anticonvulsant medications

An extensive early review has reported that there are numerous plant products that demonstrate anticonvulsant activity.⁷⁷ Even though there may not be an unequivocal and overwhelming scientific literature for herbal medicines interacting with anticonvulsant medications, there is strong biological plausibility for significant interactions between some herbal medicines (e.g. kava, valerian) and anticonvulsant medications. The Epilepsy Society of Southern New York in the US has cautioned that certain herbs, supplements and alternative medicines can cause or worsen seizures and may interact with pharmaceutical medications (see the table on the website).⁷⁸ Moreover, many herbal medicines from Traditional Chinese medicine (TCM) cultures, for example, have been documented to treat seizures and may have sedative effects, and can interact with other herbal medicines and supplements, as well as prescription medications.^{79, 80, 81}

Sedatives

The 5 most common natural products with a potential for interaction with pharmaceuticals included garlic, valerian, kava, ginkgo, and St John’s wort, and that these herbal medicines accounted for 68% of the potential clinically significant interactions in the survey.⁸² The study concluded that the 4 most common classes of prescription medications with a potential for interaction with herbal medicines included sedatives, antithrombotic medications, antidepressant agents, and anti-diabetic agents.

A study on the action of Kava in neurotransmission concluded that kava pyrones exhibited a profile of cellular actions that show a large overlap with several mood stabilisers, especially lamotrigine.⁸³

Immunosuppressant medication

A systematic review has concluded that St John’s wort interacts with cyclosporine, causing a decrease of cyclosporine blood levels and leading in several cases to transplant rejection.⁸⁴ An animal study has demonstrated that the immunosuppressive methotrexate has significant interactions with the eastern Asia herb of the root extract of kudzu (Pueraria lobata).⁸⁵ The co-administration of the herb with methotrexate significantly decreased the elimination of the drug and resulted in markedly increased exposure of methotrexate to the rats. Other herbs and/or nutrients that have the potential to stimulate the immune system and possibly counter the effects of immunosuppressants and corticosteroids include alfalfa, astragalus, andrographis, baical skullcap, echinacea, ginseng, goldenseal, withania, licorice root, and/or the mineral zinc.

Summary

A recent US report shows that approximately 66% of patients do not tell their medical practitioners about their nutritional/dietary supplement use.⁸⁶ Patients may not consider nutritional supplements to be legitimate drugs or to carry adverse risks.⁸⁷ Therefore, all patients should be asked about their use of dietary supplements irrespective of the type of supplement consumed. Clinicians should question their patients openly about their vitamins, herbs, other supplements, teas, tinctures, or natural products that they are consuming. All of these supplements should be treated as other drugs and recorded in the patient record.