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Drug-Nutrient Interactions


- by Dr. James Meschino, DC, MS, ROHP

Introduction

As vitamin and herbal supplements are used by increasing numbers of people, health practitioners must be knowledgeable about their safety. Adverse side effects of certain supplement products are described in the literature, as well as various drug-nutrient interactions. In clinical practice recognizing adverse effects of vitamin and herbal supplementation is not routine and unfortunately their reporting is even less frequent. Pharmacists, physicians, nurses, and other health practitoners are encouraged to report adverse effects and product quality issues through the FDA Special Nutritionals Adverse Event Monitoring system or the MedWatch system, or to the USP Practitioner's Reporting Network. Postmarketing surveillance can identify adverse effects and products of poor quality. This in turn improves information and recommendations to consumers. Of the limited number of dietary supplement adverse event reports to the FDA in 1998, 7% involved St. John's wort, 8% ginkgo biloba, and at least 17% ephedra-containing products.

All medicinal agents have potentially unexpected effects including toxicity, and herbal products are no different. As with other drugs, the risk of unexpected effects may be influenced by a user's age, gender, genetics, nutrition status, and concurrent disease states and treatments.

Four Biggest Concerns with Drug-Nutrient Interactions 

  1. Bleeding disorders 
  2. Brain chemistry imbalances 
  3. Heart muscle (myocardial) dysfunction 
  4. Internal organ damage and/or toxicity

1. Bleeding disorders

A number of herbal and vitamin supplements, when ingested at or above specific dosages, are known to have anti-coagulant effects. In certain instances, these products taken alone, or in combination with other anti-coagulant drugs have resulted in bleeding disorders. As such, the following supplements should not be recommended to patients taking anti-coagulant drugs unless prothrombin time can be carefully monitored (INR), in order to guard against bleeding disorders. Further, the use of these supplements, even the absence of concurrent anti-coagulant drug use, may still increase the risk of a bleeding disorder and thus, practitioners should carefully monitor patients using these products under any circumstances:

A. Ginkgo Biloba Extract

Ginkgo biloba extract contains active ingredients which are known to decrease platelet aggregation.


One week's use of Ginkgo biloba extract was associated with spontaneous bleeding from the iris into the anterior chamber of the eye. Another report described bilateral subdural hematomas attributed to taking Ginkgo biloba for at least 1.5 years. Taking it for more than 6 months was associated with a subarachnoid hemorrhage in a 61-year-old man.


Case 1: ASA plus Gingko (40 mg twice per day resulted in bleeding into the iris after one week) 

Case 2: Warfarin plus Ginkgo (no dosage reported)

Case 3: Ginkgo alone (Bilateral subdural hematoma) – 60 mg twice daily

Case 4: Ginkgo alone – (subdural hematoma) – 50 mg, three times daily


These bleeding episodes stopped in all cases reported above after ginkgo was discontinued.

B. Garlic

Only one case report of an elderly man ingesting 2,000 mg of garlic (4 cloves) daily for an undetermined period of time, developed a spontaneous epidural hematoma (the patient denied use of any anti-clotting medication or anti-inflammatory). A patient taking garlic prior to cosmetic surgery experienced bleeding complications and had a clotting time of 12.5 minutes. After cessation of garlic consumption, her clotting time dropped to 6 minutes and there were no complications during a second procedure. As such, S. Mills and K Bone suggest that garlic intake and garlic supplementation should be discontinued 10 days prior to surgery. Garlic contains disulfide compounds (e.g. ajoene) that:

  • Decrease platelet aggregation 
  • Increase fibrinolytic activity

N.B. Equivalent of one clove of garlic reduces platelet aggregation to the same degree as one aspirin (Ajoene content appears to be most responsible for anti-coagulant properties of garlic.

In a double-blind, placebo-controlled study on 60 volunteers with elevated cerebrovascular risk factors and increased spontaneous platelet aggregation, it was demonstrated that 800 mg of garlic powder per day over 4 weeks led to a significant reduction in platelet aggregation and circulating platelet aggregates. These findings were confirmed by a follow up study performed by C. Legani et al in 1993. Consumption of a fresh clove of garlic daily for a period of 16 weeks was shown to reduce serum thromboxane by about 80%. Thromboxane is a powerful procoagulant eicosanoid produced within platelets. A 1991 controlled study by JV Gadkari et al, published in Postgraduate Medicine demonstrated that raw garlic significantly increased clotting time and fibrinolytic activity after months of daily consumption in normal volunteers.

C. Ginseng

One case report of ginseng altering prothrombin time or the INR (time needed for blood to clot). Ginseng antagonizes the effects of warfarin, increasing prothrombin time, which returns to normal with discontinued use of ginseng.

D. Angelica Species (Dong Quai, e.g.,)

  • A 46-year-old woman taking warfarin experienced increased strength of the anticoagulant properties of the drug after starting to use dong quai for menopause. The daily amount of dong quai was 1,130–2,260 mg per day. Her bleeding tendency returned to normal after discontinuing the dong quai. 
  • Dong quai contains at least six coumarin derivatives, which decrease platelet clotting function and increase risk of photosensitivity-induced dermatitis 
  • Rabbit studies demonstrate that Angelica Species potentiates the effect of warfarin on prothrombin time.

E. Coenzyme Q10 Supplementation

  • There are 4 case reports where CQ10 supplementation has interfered (countered) with the ant-coagulant effects of warfarin on prothrombin time (increases clotting) 
  • Coenzyme Q10 molecule resembles vitamin K and thus, may have procoagulant tendencies as a result

F. Cranberry

There have been at least five case reports suggesting that cranberry juice increases the activity of warfarin, possibly by inhibiting the breakdown of warfarin in the body. Because of this potential interaction, people taking warfarin should avoid, or limit the intake of, cranberry juice.

G. Dan shen (Salvia miltiorrhiza)

A Chinese herb, was associated with increased warfarin activity in several cases. Dan shen should only be used under close medical supervision by people taking warfarin.

H. Other Natural Health Products – that can potentially affect prothrombin time (no human cases yet reported)

  1. Other Coumarin-containing herbs
          a.Licorice – may also increase blood pressure due to presence of glycchertinic acid
          b.Red Clover – may also increase photosensitivity-induced dermatitis and bleeding disorders. 
  2. Ginger – gingerols exhibit anti-platelet clotting properties

    Herbs containing coumarin derivatives
    Although there are no specific studies demonstrating interactions with anticoagulants, the following herbs contain coumarin-like substances that may interact with warfarin and may cause bleeding. These herbs include angelica root, arnica flower, anise, asafoetida, celery, chamomile, corn silk, fenugreek, horse chestnut, licorice root, lovage root, parsley, passion flower, herb, quassia, red clover, rue, sweet clover, and sweet woodruff.

  3. Feverfew – parthenolide exhibits anti-platelet clotting properties
  4. White Willow Bark Extract – contains salicylic acid at low concentration (15% std grade). Studies do not demonstrate an anti-platelet clotting tendency with white willow bark, when taken at recommended levels of intake (see module 5) 
  5. Turmeric – curcumin affects prostaglandin synthesis and may, in turn, decrease platelet clotting 
  6. Essential oils (Borage, Flaxseed, Fish oil) – Omega-3 fats decrease platelet clotting behavior via their effects on prostaglandin series-3 synthesis 
  7. Vitamin E Decreases platelet clotting tendency Safe up to 400 I.U. per day in conjunction with warfarin or aspirin Testing at 800 I.U. and 1,200 I.U. per day yield equivocal results on safety with respect to altering the INR 
  8. Bromelain enzymes – may decrease platelet clotting tendency and increases fibrinolysis 
  9. Devil’s Claw – was associated with purpura (bleeding under the skin) in a patient treated with warfarin.However, key details in this case—including other medications taken and the amounts and duration of warfarin and devil’s claw taken—were not reported, making it impossible to evaluate this reported interaction. Until more is known, people taking warfarin should avoid taking devil’s claw. The harpogoside content may potentiate the effect of warfarin.
  10. Papain enzymes – these proteolytic enzymes may also potentiate the effect of warfarin 
  11. St John’s Wort (Hypericum perforatum) - according to a preliminary report, volunteers taking 900 mg per day of St. John’s wort were given a single dose of an anticoagulant similar in action to warfarin. There was a significant drop in the amount of the drug measured in the blood. Seven case studies reported to the Medical Products Agency in Sweden also found a decrease in the anticoagulant activity of warfarin when St. John’s wort was taken at the same time. This may have occurred because certain chemicals found in St. John’s wort activate liver enzymes that are involved in the elimination of some drugs.

2. Effects on Brain Chemistry

A. Mania Symptoms and Other Potential Side Effects of Ginseng

Ginseng has produced mania symptoms (headache, euphoria, CNS stimulation and tremors) when added to antidepressant medications (MAO-inhibitor). Note that other side effects of ginseng use may include transient nervousness, excitation, insomnia, inability to concentrate, headache, hypertension, epistaxis, and allergic reactions. Ginseng may produce an estrogen-like effect manifesting as mastalgia and vaginal bleeding, as reported in elderly, postmenopausal women taking a modest oral dosage or with topical application. It also may induce CYP enzymes (phase 1 detoxification enzymes), and reportedly interacted with warfarin in a patient with a mechanical heart valve and decreased the international normalized ratio (INR) below therapeutic range within 2 weeks. Thus concurrent anticoagulant therapy and ginseng is best avoided. Taken with phenelzine (a MAO inhibitor-antidepressant) it may cause insomnia, tremor, headache, and mania. Siberian ginseng may increase serum digoxin levels, possibly due to assay interference or in vivo conversion of a component; the increase recurred with rechallenge.

Individuals with hypertension, diabetes, psychologic disorders, or insomnia should avoid or cautiously use ginseng.

B. Excessive Sedations

Valerian root and kava can produce excessive sedation when added to barbiturates and antihistamines. Valerian root (Valeriana officinalis) is considered a sedative and anxiolytic. Valerian is reported to cause headache, excitability, ataxia, and gastrointestinal complaints. An intentional oral overdose resulted in rapid onset of fatigue, chest tightness, abdominal cramps, lightheadedness, and tremors of the hands and feet. A suggested mechanism of action involves the gamma- aminobutyric acid receptor. A case of valerian withdrawal syndrome involving cardiac abnormalities and delirium in a hospitalized patient responded to treatment with benzodiazepines. Valerian should be avoided by patients taking benzodiazepines, barbiturates, opiates, and alcohol as their effects may be prolonged. Patients should be provided with same precautions regarding alertness as for other sedatives, if valerian is recommended or the patient is using it as a self-selected therapy.

The anxiolytic effect of kava (Piper methysticum) is well described. Documented side effects are headache, dizziness, and gastrointestinal discomfort. Localized numbness may occur after oral ingestion. With long-term use or high dosages (300 g/wk) kava may cause dry, scaly skin and discoloration (yellow) of the skin and nails, photosensitivity, and eye redness. Photophobia and diplopia also can occur with excessive consumption. The active pyrones act as muscle relaxants and anticonvulsants. Taking kava with other central nervous system (CNS) depressants, including ethanol, is to be avoided due to significant interactions, such as a comatose state. The potential for abuse must be closely evaluated. Most recently reports of liver damage have been associated with regular


use of kava. (see additional details regarding Valerian and Kava in the following sections of this module)

C. Mild Serotonin Syndrome

St. John’s Wort, and 5-hydroxytryptophan can increase brain levels of serotonin and thereby potentiate the effects of:

  • Serotonin reuptake inhibitors (SRRI) (e.g. Prozac) 
  • Monoamine oxidase inhibitors (MA0) 
  • Tricyclic Antidepressants (TAD)

In this instance there is an increased risk of serotonin syndrome, which involves the following signs and symptoms:

Muscle rigidity

Hyperthermia

Autonomic instability

Mental confusion

Myoclonus

Delerium

Coma

D. Coma

Kava plus alprazolam has induced coma. It is imperative not to recommend Kava or Valerian supplements in combination with any drugs that induce a sedative or anti-anxiolytic effect.

E. Lower Seizure Threshold

Evening primrose oil, borage oil can lower seizure threshold in patients on anti-seizure medications (e.g., phenothiazines) Vitamin B6 supplementation may interfere with anticonvulsant medication

F. Seizures

Ma Huang (ephedra) can induce seizures in otherwise normal individuals. It should not be used by epileptics.

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Drug-Nutrient Interactions

Dr. James Meschino, 

DC, MS, ROHP

3. Heart Muscle Dysfunction

A. Digitalis/Digoxin Toxicity

  • Hawthorn and ginseng are known to potentiate the action of other cardioglycoside medications, such as digitalis/digoxin (elevates serum digoxin levels) 
  • Ginseng slows drug detoxification in liver 
  • Hawthorn increases cyclic AMP in a similar manner as does digitalis and digoxin

B. Hypertension

  • Licorice root alone or in combination with tricyclic antidepressants can elevate blood pressure.

A major drawback to the use of Licorice is that doses of more than 3 gms of Licorice root daily (or doses as low as 100 mg of glycyrrhin) have caused hypertension, sodium and water retention, hypokalemia, and suppression of the rennin – aldosterone- angiotensin system. Low serum potassium (hypokalemia), resulting from the use of Licorice, has resulted in cardiac arrhythmias and ECG abnormalities. These changes are thought to occur as a result of general depression of the rennin - aldosterone – angiotensin system, and together constitute pseudo (hyper) aldosteronism. As such, patients with high blood pressure or an existing cardiovascular disorder, renal failure, or liver disease should be extremely cautious with Licorice use.

Licorice has also been shown to reduce testosterone levels in some men by inhibiting enzymes involved in testosterone synthesis, and therefore should be avoided by men combating impotence, infertility, or decreased libido.

As a result of these common side effects, long-term use of Licorice extract or whole Licorice supplementation should only be undertaken if prescribed by a qualified health professional, who is able to monitor side effects, including certain parameters of the blood chemistry profile. Licorice may also interfere with hormone replacement therapy and hypoglycemic therapy. It inhibits or enhances the activity of prednisone, and should not be used in conjunction with a vast number of medications, as outlined below.

The following side effects are common at doses of 400 mg or more of glycyrrhizin per day:

  • Hypertension
  • Sodium and water retention 
  • Excessive potassium excretion (hypokalemia)
  • Cardiac Arrhythmias 
  • Amenorrhea 
  • Hyperprolactemia (with possible infertility) 
  • Several deaths have resulted from the ingestion of Licorice products. 

The Dutch Nutrition Information Bureau suggest that no more than 200 mg of glycyrrhizin should be consumed daily.

According to the German Commission E Monographs, Licorice is contraindicated in the following conditions: cholestatic liver disorders, liver cirrhosis, hypertension, hypokalemia, severe kidney insufficiency and pregnancy, as well as in cases of edema or congestive heart failure.

Drug-Nutrient Interactions

Licorice supplementation has been shown to cause electrolyte imbalances in some individuals and thus, its use is contraindicated in patients on the following medications:

  1. Digoxin and Digitalis
  2. Laxatives
  3. Lithium
    Licorice has also been reported to alter the effectiveness of the following drugs and thus, its use is contraindicated in patients on the following medications:
  4. Antihypertensive drugs
  5. Diuretics
  6. Corticosteroid drugs (e.g., predisone): Licorice can either potentiate or inhibit the effects of predisone and other coricosteroid drugs.
  7. Nitrofurantoin: Licorice increases the absorption and blood levels of this drug.
  8. Anticoagulants: Licorice has been shown to increase risk of a bleeding disorder if taken concurrently with warfarin or coumadin.
  9. Tricyclic antidepressants: licorice has been shown to elevate blood pressure in patients taking these drugs

Side Note

Most of the Licorice candy available in North America is flavored with anise oil, not Licorice.

  1. Authentic Licorice candy contains between 0.26 mg/g and 7.9 mg/g of glycyrrhizin; while medicinal Licorice products range from 0.30 mg/g to 47.1 mg/g of glycyrrhizin.
  • With MAO inhibitors, Ma Huang (ephedra) also has been shown to increases blood pressure

C. Heart Attack and Sudden Death

  • Ma Huang (ephedra) has caused sudden death from heart attack, tachycardia, stroke and myocardial arrhythmias when taken alone

N.B.: The most commonly reported herbal product to produce adverse reactions with more than 17% of all adverse reactions reported dealing with side effects from Ma Huang

Ma huang, ephedra, contains a number of alkaloids, including ephedrine, from various Ephedra sp. Ma huang is not considered a safe herbal. A potent CNS stimulant, these alkaloids were implicated in over 800 reports of adverse effects including nervousness, insomnia, irritability, psychosis, headache, dizziness, seizures, stroke, premature ventricular contraction, hypertension, myocardial infarction, and death. Much of this is owed to the agent's nonselective adrenergic agonist properties. As a result the FDA proposed limits on the use of ephedrine-containing products: a maximum of 8 mg/dose and 24 mg/day for no more than a week, and combined with no products that contain caffeine. Some states reclassified these agents to control availability, but ephedra-containing alkaloids continue to be widely available. Numerous multi-ingredient products marketed for weight loss or energy, contain ma huang. The Drug Enforcement Agency proposed that products containing over 2% ephedrine be subject to the Controlled Substances Act. Individuals with cardiovascular or thyroid disease and diabetes should avoid the products altogether, as should those consuming caffeine, theophylline, cardiac glycosides, and monoamine oxidase (MAO) inhibitors. (see additional details regarding ephedra in a subsequent section of this module).

4. Internal Organ Damage and Other Considerations

A. St. John’s Wort

  • Can reduce action of concurrent medications because it accelerates liver detoxification centers (i.e., digoxin, theophylline, cyclosporine, phenprocouman, etc.) 
  • Increases risk of photosensitivity-induced dermatitis.

One of at least 300 Hypericum sp, Hypericum perforatum, more commonly known as St. John's wort, has gained increased use for managing mild depressive symptoms. It is being studied in at least one large prospective trial for this indication in comparison with a selective serotonin reuptake inhibitor and placebo. It also has been used for viral infections. It contains many active compounds, such as hypericin, hyperforin, and melatonin, with mechanisms that may contribute to a pharmacologic effect. Although unlikely to be the sole active component, hypericin content is used as a product marker.

Reported adverse effects are allergic reactions, headache, dizziness, restlessness, fatigue, dry mouth, nausea, vomiting, constipation, and photosensitivity. Photosensitivity, in part due to hypericin, and possible nerve damage manifested as reversible subacute toxic neuropathy have been reported. Caution is warranted in combining the herbal with other drugs known to cause photo-sensitivity, and patients should limit sun exposure.

Recent reports described hyperasthesia and a syndrome of dyspnea and hyperventilation with flushing headache, mydriasis, nausea, palpitations, and tremor, as well as significant reductions in cyclosporine levels. A patient with a history of panic disorder taking St. John's wort tincture for 10 days experienced a hypomanic episode that resolved within 2 days of discontinuing the herbal. Until more is known about its mechanism of action it seems prudent to avoid taking it with antidepressant drugs such as MAO inhibitors of either isoform, levodopa, and tryptophan. Also a 2-week washout period between agents is necessary. St. John’s wort appears to be an inducer of an important metabolic pathway, cytochrome P450. As many prescription drugs used to treat conditions such as heart disease, depression, seizures, certain cancers or to prevent conditions such as transplant rejection or pregnancy (oral contraceptives) are metabolized via this pathway, health care providers should alert patients about these potential drug interactions to prevent loss of therapeutic effect of any drug metabolized via the cytochrome P450 pathway.

B. Kava Kava

  • Long-term use can produce abnormal liver function tests, yellow scaly rash and increased cholesterol.

Kava is a botanical product derived from the rhizome and roots of Piper methysticum, a shrub indigenous to the South Pacific. In the United States, kava-containing products are sold as dietary supplements and marketed for the treatment of anxiety, occasional insomnia, premenstrual syndrome, and stress. These supplements often are in the form of raw plant material or concentrated extracts, which are obtained by using either acetone or ethanol extraction or cryoprecipitation. Preparations marketed for human consumption contain a mixture of components collectively known as kava pyrones (i.e., kavalactones). Kava-containing products might differ based on the absolute amount of kava pyrones present and on the relative distribution of kava pyrones. Several countries, including Germany, Switzerland, Canada, Australia, and France, have restricted the sale of kava-containing products based on the occurrence of hepatic adverse events and the documented hepatic toxicity following rechallenge with a kava-containing product.

The FDA has advised consumers and health-care providers about the potential risk for hepatic toxicity associated with the use of kava-containing products. Additional caution by persons who have pre-existing liver disease or are at risk for liver disease might be warranted. Health-care providers should consider questioning patients with evidence of hepatic injury about the use of dietary supplements and herbal products containing kava.

Hepatic Toxicity Possibly Associated with Kava-Containing Products --- United States, Germany, and Switzerland, 1999—2002: Since 1999, health-care professionals in Germany, Switzerland, and the United States have reported the occurrence of severe hepatic toxicity possibly associated with the consumption of products containing kava (i.e., kava kava or Piper methysticum). A total of 11 patients who used kava products had liver failure and underwent subsequent liver transplantation . On March 25, 2002, in response to five such case reports (four in Europe and one in the United States), the Food and Drug Administration (FDA) issued a consumer advisory and subsequently completed an investigation already underway of a similar U.S. case. This report presents the investigation of the two U.S. cases of liver failure associated with kava-containing dietary supplement products and summarizes the European cases. FDA continues to advise consumers and health-care providers about the potential risk associated with the use of kava-containing products. The presence of kava in a supplement should be identified on the product label in the "Supplement Facts" box. The following are commonly used names for kava:

  • ava
  • ava pepper
  • awa
  • intoxicating pepper
  • kava
  • kava kava
  • kava pepper
  • kava root
  • kava-kava
  • kawa
  • kawa kawa
  • kawa-kawa
  • kew
  • Piper methysticum
  • Piper methysticum Forst.f.
  • Piper methysticum G. Forst.
  • rauschpfeffer
  • sakau
  • tonga
  • wurzelstock
  • yangona

Case Reports

Case 1. In May 2001, a previously healthy woman aged 45 years reported the onset of nausea and weakness approximately 8 weeks after beginning use of a kava-containing dietary supplement that listed on the package label, "Kava kava extract (root), standardized to 30% kavalactones (75 mg), hops (strobiles), German chamomile (flower head), passion flower (flower and fruit), gelatin, and natural vegetable fiber." The patient reported taking one tablet twice daily, which was less than the package label recommendation of one tablet three times daily. The patient reported no concomitant medication or dietary supplement use and rare alcohol ingestion (one to two drinks a year). The patient was initially prescribed rabeprazole for acid reflux symptoms, and this drug was taken for 4 days. In addition, the patient discontinued use of the kava-containing supplement. Several days later, the patient was hospitalized with jaundice and hepatitis. Liver biopsy demonstrated subfulminant hepatic necrosis. Autoimmune and infectious hepatitis tests were negative. Liver transplantation was performed in July 2001, and the patient resumed daily activities following recovery from the procedure.

Case 2. In December 2000, a previously healthy girl aged 14 years reported the onset of nausea, vomiting, decreased appetite, weight loss, and fatigue. One week later, the patient had scleral icterus and was hospitalized with acute hepatitis. During late August to mid-December 2000, the patient reportedly used two kava-containing products. One product was taken intermittently in accordance with package directions (two capsules once daily). The patient estimated that she used the product on approximately 44 days during this period. The patient reported taking the second product in accordance with package directions (two capsules once daily) for 7 consecutive days at the beginning of the 4-month period. Because the product labels were unavailable, other product ingredients were unknown. The patient reported no use of alcohol or medications other than occasional ibuprofen. At the time of hospitalization, the patient's liver-function tests were markedly abnormal (alanine aminotransferase: 4,076 U/L, aspartate aminotransfease: 3,355 U/L, gamma-glutamyltransferase: 148 U/L, total bilirubin: 16.2 mg/dL, ammonia: 17 mg/dL, and prothrombin time: 29.4 seconds) (5). Tests for human immunodeficiency virus (HIV), cytomegalovirus, Epstein-Barr virus, Wilson's disease, a-antitrypsin deficiency, antinuclear antibodies, and hepatitis A, B, C, and E were negative. Initial liver biopsy revealed active fulminant hepatitis with extensive centrilobular necrosis, approximately 25% hepatocellular viability, and mixed inflammatory infiltrates consisting of lymphocytes, histiocytes, scattered eosinophils, and occasional neutrophils. No viral cytopathic changes were identified, and immunohistochemical stains for hepatitis B surface and core antigens were negative. The patient underwent successful orthotopic liver transplantation. Pathological examination of the native liver revealed active fulminant hepatitis with total hepatocyte necrosis and extensive parenchymal infiltration by lymphocytes, histocytes, and occasional eosinophils. The patient resumed daily activities following recovery from the procedure.

Summary of European Case Reports

Eight hepatic transplant cases following hepatic failure associated with the use of kava-containing products have been reported in Europe (six in Germany and two in Switzerland). Two male patients aged 32 and 50 years and six females aged 22--61 years required liver transplants after using kava-containing products. The duration of kava use ranged from 8 weeks to 12 months. The products were used at doses ranging from 60 mg to 240 mg per day. Seven patients used kava prepared either by ethanol or acetone extraction methods; one patient used an unspecified type of kava-containing product. The patients had varying symptoms, including influenza-like symptoms and jaundice. Each patient's condition worsened and progressed to fulminant hepatic failure. Four of these cases have been reported in medical literature. Additional information about these cases is available from the German regulatory authority, the Federal Institute for Drugs and Medical Devices, Bonn, Germany, at http://www.bfarm.de. A ninth European transplant case was reported directly to FDA's MedWatch System by a U.S. pharmaceutical manufacturer.

C. Echinacea

  • Can exacerbate autoimmune conditions through overstimulation of the immune system (possibly ginseng as well)

Known by a number of common names, Echinacea purpurea and related species are taken as liquid extracts and tinctures as well as in solid oral dosage forms for short-term immune system stimulation. Products should use above-ground parts of E. purpurea or the roots of E. angustifolia. Allergic reactions can occur and are usually mild, but individuals with a history of asthma, atopy, or allergic rhinitis may experience severe allergic reactions that include dyspnea and anaphylaxis. Other adverse effects are mild and transient tiredness, somnolence, dizziness, headache, gastrointestinal disturbance, and eczema, not significantly different from those with placebo. Flavonoids from this botanical may inhibit cytochrome P450 (CYP) 3A4 activity, but there is little information on interactions with other drugs or nutrients. Echinacea may worsen metabolic control in some diabetic patients and is not recommended in individuals with altered immune function (tuberculosis, human immunodeficiency viral infection, multiple sclerosis, autoimmune diseases) because of altered immunomodulation. Use usually is restricted to 2 weeks for an acute episode and should not exceed 8 weeks as it may lead to immunosuppression. Echinacea should be avoided by patients receiving immunosuppressive therapy.

D. Glucosamine Sulfate

  • Experimental, but not human studies suggest that there is a potential for Glucosamine supplementation to increase insulin resistance in a diabetic patient. As such, diabetic (both type 1 and 2) and prediabetic patients should have their blood glucose monitored during the first month of glucosamine supplementation.

E. Feverfew

Taken most often for migraines, this botanical (Tanacetum parthenium) may suppress prostaglandin and thromboxane production and inhibit serotonin release from platelets. In addition to gastric discomfort, oral ulcers and lip and tongue swelling were reported with use of the leaf and required discontinuation. The mechanism for this effect is unknown. The herb is contraindicated in individuals with an allergy to ragweed or other plants in the daisy family. Nonsteroidal anti-inflammatory drugs may reduce the effect of feverfew, and caution is advised in patients receiving anticoagulants. It is not known whether an interaction exists between feverfew and serotonin agonists used to treat migraines. Few of the North American feverfew products tested contained the proposed minimum content (0.2%) of the predominant active component, parthenolide, with most having less than 0.1%.

FDA (U.S.A.): Special Nutritionals Adverse Event Monitoring System

(searchable database of MedWatch: http://vm.cfsan.fda.gov/`dms/aems)

Of the limited number of dietary supplement adverse event reports to the FDA in 1998:

  • 7% involved St. John’s Wort 
  • 8% involved Ginkgo Biloba 
  • ≥17% involved ephedra-containing products; 800 reports of adverse effects:

Of the limited number of dietary supplement adverse event reports to the FDA in 1998:

  • 7% involved St. John’s Wort 
  • 8% involved Ginkgo Biloba 
  • ≥17% involved ephedra-containing products; 800 reports of adverse effects:
  • Nervousness 
  • Insomnia 
  • Irritability 
  • Psychosis 
  • Headache
  • Dizziness 
  • Seizures 
  • Stroke 
  • Premature ventricular contractions 
  • Increased Blood Pressure 
  • Myocardial Infarction (heart attack) 
  • Death

Final Considerations: Herbal products should be discontinued 2 weeks before elective surgery, and their use reported to the anesthesiologist before any surgical procedure because of the potential for unexpected effects


Herbal products should be stored in a cool, dry place away from children.

References

Drug-Nutrient Interactions In General:
McNeill JR. Interactions between herbal and conventional medicines. Can J CME 1999,11;12:97-110
Boullata J, Pharm D, Nace M. Safety issues with herbal medicine. Pharmacotherapy 2000, 20; 3: 257-269

Bleeding Disorders
McNeill JR. Interactions between herbal and conventional medicines. Can J CME 1999, 11;12:97-110
Heck A, et al. Potential interactions between alternative therapies and warfarin. Am J Health-Syst Pharm 2000,57;13:1221-7
Canadian Guidelines for Cardiac Rehabilitation and cardiovascular Disease Prevention, 11th ed. Canadian Association of Cardiac Rehabilitation 1999
Boon H, Smith M. Health Care Professional Training Program in Complementary Medicine. Institute of Applied Complementary Medicine Inc. 1997
Kinsella, JE, et al. Dietary n-3 polyunsaturated fatty acids and amelioration fo cardiovascular disease: possible mechanisms. Am J Clin Nutr 1990,;52:1-28
Mills S, Bone K. 30 Principles and Practice of Phytotherapy. Churchill Livingstone: 199-200 (Garlic)

Effects on Brain Chemistry
Miller LG. Herbal Medicinals: Selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998;158;20:2200-11
McNeill JR. Interactions between herbal and conventional medicines. Can J CME 1999, 11;12:97-110
Reavley N. New Encyclopedia of vitamins, Minerals, Supplements and Herbs. M. Evans and Company, Inc. NY 1998, Bookman Press (Australia)

Heart Function Disorders
McNeill JR. Interactions between herbal and conventional medicines. Can J CME 1999, 11;12:97-110
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Other Special Considerations

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Patti ME, et al. Activation of the hexosamine pathway of glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle. Diabetes 1999;48;8:1562-71

Escher M, Desmeules J, Giostra E, et al. Hepatitis associated with kava, a herbal remedy for anxiety. BMJ 2001;322:139.
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Food and Drug Administration. Letter to health-care professionals: FDA issues consumer advisory that kava products may be associated with severe liver injury. Rockville, Maryland: U.S. Department of Health and Human Services, Food and Drug Administration, 2002. Available at http://www.cfsan.fda.gov/~dms/addskava.html.
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Walker AM. The relation between voluntary notification and material risk in dietary supplement safety. Food and Drug Administration docket 00N-1200, 2000. Available at http://www.fda.gov/ohrms/dockets/00n1200.

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Drug-Nutrient Interactions

Dr. James Meschino, 

DC, MS, ROHP

Global Integrative Medicine Academy

The Global Integrative Medicine Academy was created to satisfy a need, expressed by many health professionals, to establish credentials as experts in Nutritional Medicine. But, health professionals also needed to be able to complete the programme with a minimum impact on their career, family, and lifestyle. That is why the Advanced Nutritional Medicine and Sports Nutrition Certification Program was created.

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