Botanical Contraindications and Drug Interactions

Botanical Contraindications and Drug Interactions

By Ian Lloyd, BSc (Pharm), Chartered Herbalist

Generally there are three types of information sources which document botanical/ drug interactions/contraindications; theoretical or empirical, case reports, and those seen in clinical trials.¹¹ The theoretical or empirical occurrences derive their evidence from in-vitro laboratory action, animal studies or historical usage. In many cases theoretical evidence is suggestive and provides evidence to advise caution. Case reports use data collected from individual patients with their reactions to individual botanical products. It is beneficial if these reports provide specific details ­ dose taken and duration, specific botanical product with Latin name, was the product analysed for contamination, etc. Ideally case reports should provide support for theoretical warnings. Clinical trial results provide the best evidence to support botanical warnings. Regrettably, at this time there is little data on botanical contraindications or interactions derived from clinical trials.

In this continuing education course, we will explore the contraindications and drug interactions associated with the most commonly-used botanical products.

BLACK COHOSH

Possibly the most commonly recommended botanical preparation used to help with menopause is black cohosh (Cimicifuga racemosa). Most of the clinical studies have used a product standardized to 1 mg of 27-deoxyacetein per dose or tablet. There has been some debate as to how this botanical helps with the symptoms associated with menopause. It is believed that black cohosh inhibits the secretion of luteinizing hormone (LH),^5,35 even though some studies have observed no changes in LH levels.³⁵ It had been proposed that this decrease in LH was due to an estrogen-like effect. Further studies have failed to find an estrogenic effect,⁵ and decreases in LH are now believed to be due to its interference with neurotransmitters.³⁵ There is still much work to be done to determine a definite mechanism of action.

There are no known drug interactions noted with black cohosh.⁷ It is considered to be contraindicated during pregnancy and lactation.^5,7 This is due to empirical evidence of its emmenagogue (an agent that stimulates menstrual flow) effect and possible toxicity when taken in high doses.¹¹ In in vitro animal studies, extracts of black cohosh have demonstrated affinity for estrogen receptors.³⁸ The human significance of this finding is not known.

There has been some concern over the use of black cohosh and the possible risk of proliferation of estrogen-receptor-positive cancerous cells. However, black cohosh has been shown to inhibit the growth of breast carcinoma cells.³⁵ Black cohosh was also found to antagonize the effects of estradiol on DNA synthesis.³⁵ There have even been study results that showed black cohosh augmented the anti-proliferative effects of Tamoxifen.³⁵ Due to the above findings, the use of black cohosh is not contraindicated in patients with a history of breast cancer.³⁵

ECHINACEA

There are three species of echinacea (E. angustifolia, E. purpurea, and E. pallida) that are used medicinally. Extracts of echinacea exert several actions on the body’s immune system: increasing phagocytosis, increasing production of interferon and interleukins, increased production of white blood cells and other non-specific immunostimulatory actions.^3,6,7Echinacea extracts do have some direct antibacterial properties. However, this is not considered to be significant.^3,7

There have been no documented cases of drug interactions with echinacea products.⁷ Due to its stimulation of the immune system, this botanical directly opposes the effects of immunosuppressants.⁷

People with allergies to daisies or sunflowers may experience mild allergic symptoms while taking echinacea products.³¹ It is generally considered to be contraindicated in systemic and autoimmune diseases, such as rheumatoid arthritis, tuberculosis, and multiple sclerosis,^5,11 although, there is no clinical evidence or case reports to support this.⁷ It is considered to be contraindicated for AIDS and HIV patients because it can enhance secretion of tumor necrosis factor and alpha-interferon. This may lead to depressed CD4 cell levels and increased HIV replication.¹¹Echinacea products are thought to be contraindicated in tuberculosis because they contain arabinagalactan constituents that may be similar to arabinagalactans found in Mycobacteria cell walls.¹¹ These arabinagalactans are associated with the suppression of the lymphocyte response observed in tuberculosis.¹¹ Again this evidence is considered empirical.

EVENING PRIMROSE OIL

This is the fifth most-popular herb in Canadian pharmacies.² The seeds of evening primrose (Oenothera biennis), are one of the richest sources of gamma-linolenic acid(GLA).²⁷ This essential fatty acid is used to help treat atopic eczema,^5,7,27 diabetic neuropathy,⁷ and premenstrual syndrome.^3-5,7,15

Evening primrose oil appears to be safe for most people.²⁷ There is the possibility of an increased risk of epileptic episodes for schizophrenics taking phenothiazines.²⁸ However some authors question this possibility.⁷ Evening primrose oil can increase production of prostaglandin E1 (PGE₁) and may act synergistically with NSAIDs.²⁷ Evening primrose oil should be used with caution in patients concurrently taking anticoagulants.⁷

FEVERFEW

This product is known mainly for its ability, when taken regularly, to help reduce the frequency and severity of migraine headaches.^3,7 The mechanism of action is not fully understood, but it may involve the inhibition of prostaglandin synthesis.⁷ There have been no reported drug interactions with feverfew (Tanacetum parthenium). It has been suggested that nonsteroidal antiinflammatory drugs (NSAIDs) or corticosteroids may reduce the efficacy of feverfew.⁷ It is considered to be contraindicated in pregnancy due to empirical evidence of its emmenagogue effect.¹¹ Individuals with a hypersensitivity to other members of the daisy family should not use feverfew.⁷

Patients taking anticoagulants should be cautioned and monitored for bleeding. There is theoretical evidence that feverfew may decrease platelet aggregation and interact with anticoagulant therapy.⁷ Feverfew is contraindicated in nursing mothers and in infants under two years of age.³⁷

GARLIC

This product is the second best-selling product in Canadian pharmacies, to a total of $10.1 million dollars in 1998.² The most prominent indication for garlic preparations is to help treat hyperlipidemia and hypercholesterolemia. It is also used to a lesser extent to treat hypertension and as an antimicrobial.^3-7 This botanical is generally considered safe when used for dietary purposes,^4,11 but when taken in higher doses the potential for adverse effects becomes possible. Garlic (Allium sativum) is considered to be contraindicated during pregnancy and lactation.^7,11 In vitro and animal studies, it has shown uterine-stimulating effects.¹¹ The odour of garlic has been noticed in the milk of lactating mothers and has been associated with colic in their children.⁷ One paper also suggests that this botanical be avoided after tissue transplants, due to its reported ability to enhance natural killer cell function, a major mechanism responsible for tissue rejection.⁷ There have been reports of allergic reactions to garlic preparations.^3-7 Since garlic contains active thiol groups, it should be avoided by individuals who suffer from attacks of pemphigus, a rare auto-immune disease.⁷

The most noted drug interaction with garlic involves its ability to enhance the effectiveness of anticoagulants. There are case reports detailing excessive post-operative bleeding in patients who revealed a large, chronic garlic intake.^11,13,14 It is also possible that garlic may potentiate the anticoagulant effects of warfarin and ASA.⁷ One reference believes that garlic may interfere with existing diabetic management.¹⁵ This may be due to its hypoglycemic effect, which has been documented in animal studies.¹¹

Regular dietary consumption of garlic appears to be relatively safe.¹¹ Those patients currently taking anticoagulant medicines should be cautioned about taking larger amounts of garlic preparations.

GINGER

Ginger is a soothing remedy for the stomach and an aid for indigestion. Larger doses have considerable therapeutic effects. Larger than dietary doses of ginger root (Zingiber officinale) are used to help fight nausea, inflammation and indigestion.⁴ The exact mechanism of action of ginger is not known. Chemical constituents of ginger have demonstrated the ability to inhibit platelet aggregation,^3,7 inhibit prostaglandin synthesis,³ and antagonize 5-HT₃ receptors.⁷

There have been no specific drug interactions noted with ginger. Empirical evidence suggests that it should be used with caution when patients are currently on anticoagulant therapy.^11,15 Yet, no case reports of bleeding complications could be found. Ginger is also considered to be contraindicated for patients with gallstones. This is due to empirical and animal evidence suggesting that ginger is a cholagogue, or a stimulator of bile flow.¹¹

Paradoxically, this botanical has an argument for contraindication¹¹ and efficacy when used in pregnancy.²⁹ Empirical evidence has stated that ginger, when taken in larger amounts, can have emmenogogue and abortifacient effects.¹¹ In contrast, there have been clinical trials showing safety and efficacy in nausea associated with pregnancy.²⁹ The dose used was 250 mg powdered ginger, four times a day.²⁹ This appears to be the maximum dose to ensure safety in pregnancy.³⁰ Many authors feel that ginger can be another treatment option for nausea during pregnancy.^3,29,30

GINKGO

The fourth most popular botanical product in Canadian pharmacies² happens to be one of the oldest plant species known to man.⁵ Today it is used to help improve memory,²⁰ intermittent claudication,²¹ Alzheimer’s and dementia.²³ The exact mechanism of action is not known but it appears extracts of Ginkgo biloba can inhibit platelet activating factor (PAF).^5,7 It is this inhibition of PAF that is responsible for most of this herb’s contraindications. The only absolute contraindication is hypersensitivity to Ginkgo biloba preparations.⁵ This may be due to the presence of ginkgolic acids, which are similar compounds to the allergens found in poison ivy.²² Its safety in pregnancy and lactation has not been established.⁷

Many authors caution that extracts of Ginkgo biloba may potentiate the effects of anticoagulants.^4,7,11 There have been case reports of ginkgo products causing bleeding complications when taken alone,²⁵ and when taken with ASA.²⁴ One animal study investigated the effects on platelet aggregation with the combination of ginkgo and ticlopidine. The results showed that there was decreased platelet aggregation seen compared to ticlopidine alone.²⁶ For this reason, patients should be warned about the possible impact that extracts of Ginkgo biloba may have on their anticoagulant therapy.

GINSENG

Ginseng is the third most popular herbal product in Canadian pharmacies, with sales of $7.1 million in 1998.² There are three types of ginseng commonly seen in pharmacies: Asian ginseng (Panax ginseng), Canadian or American ginseng (Panax quinquefolium), and Siberian ginseng (Eleutherococcus senticosus).³ Siberian ginseng is not in the same genus as the Panax ginseng but it has a similar action on the body.^4,5,10

Ginseng is used to help combat stress and fatigue, and increase athletic performance.^3,6,10 Many argue that there are few human clinical studies to support ginseng use,³ but its historical use in Asia should not be overlooked.^7,8 It is believed that ginseng’s ability to alleviate fatigue involves the modulation of the hypothalamic-pituitary-adrenal axis (HPA).⁶ This can induce the secretion of adrenocorticotropic hormone (ACTH), which assists in the production and secretion of certain adrenal hormones.^3,6,7 Ginseng also has the ability to stimulate the CNS.^3,6,7,9,10

There have been a few case reports of drug interactions with Panax ginseng and Siberian ginseng. One case report revealed that taking Panax ginseng with the monoamine oxidase (MAO) inhibitor phenelzine led to manic-like symptoms.¹¹ In one clinical study, Panax ginseng had a hypoglycemic effect in diabetic patients.¹² There is one case report of unexplained elevated digoxin levels while a patient was taking Siberian ginseng.^4,7,10 It is believed that this was due to contamination of the Siberian ginseng product.^7,10 Animal studies have shown both an increase and decrease in the effectiveness of barbiturate-induced sleeping time.⁷ In one clinical study, Siberian ginseng enhanced the efficacy of monomycin and kanamycin in children under treatment for Shigella dysentery.¹¹

It is recommended that all ginseng be used with caution in hypertension, premenopausal women with unstable hormonal cycles, concomitant use of stimulants and all people with diabetes.^3-7,10-12 Its safety in pregnancy, lactation and children has not been established.^3-7,10-12 There have been case reports concerning neonatal/ maternal androgenization with Panax ginseng use. This effect was believed to be due to contamination.¹⁰ Extract of ginseng has been shown to inhibit the aggregation of human platelets and should be used with caution in people using anticoagulants.³⁹

KAVA

The roots of the kava shrub (Piper methysticum) are used for their muscle relaxant and anxiolytic properties.^3,15,17 It is believed that the kavalactones, the pharmacologically active compounds of kava, act by modulating the limbic system¹⁷ and do not bind to GABA or benzodiazepine receptors.^11,17 This botanical also has no known affinity for opioid receptors.¹¹ While kava is relatively safe at recommended dosages, there are a few contraindications.

It is generally thought to be contraindicated in pregnancy, due to the loss of uterine tone seen with in vitro experiments.¹¹ Due to its sedative activity it is not recommended for use during endogenous depression.¹¹ Empirical evidence suggests that caution should be exercised when operating a motor vehicle or heavy machinery due to kava’s possible sedating effects.^5,11 Finally, prolonged or excessive use may lead to dependency and a pellagra-like skin change.⁵

Most of the drug interactions involve kava’s ability to enhance the action of known CNS depressants and barbiturates. There is one case report of concurrent use of alprazolam and kava resulting in a semicomatose state.¹⁸ Kava was thought to indirectly increase the affinity of phenobarbital for GABA-receptors in mice.¹¹ Animal studies have also shown an increase in the hypnotic effect of alcohol when given with kava.^11,17 Interestingly, there is one case report where kava reduced the effects of levodopa in a Parkinson’s disease patient. This reduction in efficacy was thought to be due to dopamine antagonism by kava.¹⁹

Kava is considered to be contraindicated with concurrent benzodiazepine, barbiturate or alcohol use, levodopa therapy, pregnancy and lactation.

ST. JOHN’S WORT

Popular media has made this one of the more asked-about botanical products. Extracts of St. John’s wort (Hypericum perforatum) are used primarily to treat mild to moderate depression.³² The mechanism of action is not quite clear. However, studies have suggested that this botanical may inhibit reuptake of neurotransmitters (serotonin and norepinephrine), inhibit monoamine oxidase and catechol-O-methyltransferase.^5,7,11

Excessive exposure to UV-light is considered to be contraindicated while taking St. John’s wort.^5,32 A constituent of St. John’s wort, hypericin, can cause a photosensitization reaction in fair-skinned people.³² St. John’s wort is considered contraindicated during pregnancy due to empirical evidence that it can act as an emmenogogue and abortifacient.¹¹ In vitro and animal studies have demonstrated uterine stimulatory action.¹¹ There is little published literature about human exposure to St. John’s wort during pregnancy or lactation. There have been two case studies reported.³³ In one of the cases, there was late onset thrombocytopenia and jaundice in the infant at the fifth day, but little information was provided about the second case.³³ Until more is known, it would be advisable to avoid the use of this product during pregnancy.

There have been few reported drug interactions with St. John’s wort. This herb has demonstrated the ability to antagonize the effects of reserpine, prolong narcotic- induced sleeping time, and reduce barbiturate-induced sleeping times.^11,32 It was once considered that those taking St. John’s wort should avoid food high in tyramine to avoid a possible MAO hypertensive crisis.^3,4,7,11 However, reports of in vivo MAO inhibition are lacking.³² This fact combined with the extensive use of St. John’s wort in Europe cause authors to question this tyramine warning.³² Due to the inhibition of serotonin reuptake, it is advisable to avoid St. John’s wort use while taking other selective serotonin reuptake inhibitors (SSRIs).^5,7,11

VALERIAN

This herbal is best known for its ability to help with sleeping difficulties. There is a small amount of clinical data regarding its efficacy, drug interactions and contraindications. It is thought that valerian (Valeriana officinalis) promotes sleep and relaxation via increased GABA secretion and inhibition of its reuptake.⁵ Most of the information on its safety is extrapolated from in vitro and animal findings.

Animal studies have shown increased sleeping times when valerian was given with pentobarbital and thipoental.¹¹ It is also believed that this botanical may enhance the effects of other CNS depressants and alcohol^.7 Due to possible teratogenic effects, seen in animal studies, it is considered to be contraindicated in pregnancy until more is known.⁷ The German Commission E monograph for valerian lists no contraindication or drug interactions.

CONCLUSION

Pharmacists are considered to be reliable sources of information about self-medication and over-the-counter (OTC) medications. One could argue that botanicals, vitamins and supplements should be considered OTC medications. As the most accessible and trusted healthcare professional, pharmacists are in the unique position of being able to extend the current definition of pharmaceutical care to include the appropriate and safe use of botanicals and other supplements.

As research has shown, many patients do not tell their physicians about their supplement use.¹ It is important that pharmacists relay appropriate information about botanical safety. By utilizing the information from this course and the other references listed, pharmacists should be able to answer most questions related to the safe use of botanicals.

Dr. V.E. Tyler argues that true herbal medicines have a greater safety profile than allopathic drugs.³⁶ In many cases this is true, but in cases where botanicals are used with prescription drugs it may not hold true. One could argue that there is little clinical evidence documenting contraindications or drug interactions with botanicals. It would be prudent to err on the side of caution based on the evidence available. As with pharmaceuticals, post-marketing adverse reaction reporting provides valuable safety information. As a profession, pharmacists should display pharmaco-vigilance by warning patients about possible risks and documenting adverse reactions to botanical products. If warranted, these adverse reactions should be reported to the Canadian ADR Centre (http://www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english/forms/adverse_e.pdf). These services will greatly further the knowledge regarding the appropriate usage and safety of botanical medicines.

REFERENCES

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6. Muller, Julie, and Clauson, Kevin. (1998). Top Herbal Products Encountered in Drug Information Requests. Drug Benefit Trends [online]10(5):43-50. Available: http://www.medscape.com/SCP/DBT/1998/v10.n05/d3287.mull/d3287.mull-01.html [1999, Sept 8]

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8. Hobbs, C. (1997,March/April). Ginseng Facts and Folklore. Herbs For Health,35-38.

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19. Schelosky L, Raffauf C, Jendroska K, Poewe W.(1995). Kava and dopamine antagonism. J. Neuro. Neurosurg. Psychiatry. 58(5),639-40.

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39. Park HJ, Rhee MH, Park KM, Nam KY, Park KH. Effect of non-saponin fraction from Panax ginseng on cGMP and thromboxane A2 in human platelet aggregation. J. Ethnopharmacol(1995), Dec 15;49(3):157-62.

CE FACULTY

This Month: Botanical Contraindications and Drug Interactions

Author:

Ian Lloyd BSc (Pharm), is a Pharmacist and Chartered Herbalist practising at Cadboro Bay Pharmacy in Victoria, B.C. He has written for various publications on the subject of herbal medicines, the most notable being his regular column in Pharmacy Post. He has written CE lessons and reviewed educational material from herbal products manufacturers and other CE courses. He routinely answers questions about herbal products for patients and physicians.

Reviewers:

All lessons are reviewed by three pharmacists for accuracy, completeness and relevance to current pharmacy practice.

Coordinators:

Jina Hahn, B.Sc.Phm.
Heather Howie

Questions