Release Date: April 15, 2008
Expiration Date: April 15, 2009
TARGET AUDIENCE
Internists, family practitioners, geriatricians, cardiologists, and others who care for older patients.
MEDIUM USED & METHOD OF PARTICIPATION
Read the article, complete the evaluation and post-test, and return both to: NACCME via fax at (610) 560-0502. You will receive your certificate in 6-8 weeks. If you would like to print your certificate immediately, go to http://cme.naccme.com, register as a NACCME user, and access the activity test and evaluation online.
SUCCESSFUL COMPLETION
Successful completion entails participants obtaining a score of at least 70% on the post-test. A certificate of completion will be mailed to the address listed on your post-test/evaluation form within 6-8 weeks of receipt of the documents.
ACCREDITATION
MD/DO:
This activity is sponsored by the North American Center for Continuing Medical Education (NACCME). NACCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NACCME designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.
SPONSOR
This activity is sponsored by The North American Center for Continuing Medical Education.
DISCLOSURES
All those with control over the content of continuing education programs sponsored by NACCME are expected to disclose whether they do or do not have any real or apparent conflict(s) of interest or other relationships related to the content of their presentation(s). It is not assumed that these relationships will have an adverse impact on presentations; they are simply noted here to fully inform participants.
Drs. Thomas and Gambert have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of the subject of their article.
Reviewer: Dr. Christmas has disclosed no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of the subject of this article.
Editor: M. Edwards has disclosed no significant financial relationship.
All NACCME employees involved in the planning and editing of this educational activity have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of this educational activity.

CONFLICT OF INTEREST RESOLUTION-CONTENT VALIDATION
In compliance with ACCME Standards for Commercial Support and NACCME’s policy and procedure for resolving conflicts of interest, this continuing medical education activity was reviewed by a member of the Advisory Board in March, 2008 for clinical content validity, to ensure that the activity’s materials are fair, balanced, and free of bias, and that the activity materials represent a standard of practice within the profession in the U.S. and that any studies cited in the materials upon which recommendations are made are scientifically objective and conform to research principles generally accepted by the scientific community.
Learning Objectives
Upon completion of this educational activity, participants should be able to:
1. Discuss the most commonly ingested water-soluble vitamins, essential fatty acids, and herbs available in the United States.
2. Identify the dietary sources of water-soluble vitamins and essential fatty acids.
3. Describe the nutritional importance of the most commonly used supplements.
4. Explain the main hazardous side effects of the most commonly used over-the-counter supplements.

This is Part II of a two-part article. Part I discussed commonly used minerals and trace elements and fat-soluble vitamins.
 
In an attempt to live healthier and longer lives, millions of Americans are increasingly purchasing organic foods and “natural” supplements, vitamins, minerals, and herbs from health food stores. While under certain circumstances these products may have beneficial effects, in many cases there is little evidence to support their use. In fact, they may have significant health risks associated with their use—and may even be life-threatening. Not everything bought in a health food store is “healthful,” as illustrated by the following case. (We repeat the clinical case from Part I [published in the March issue of Clinical Geriatrics] to help illustrate the potential outcome of such practices.)
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Mrs. S was an 86-year-old woman who had immigrated to the United States from Russia 60 years earlier. Throughout her life, she practiced home remedies and believed in living a “natural life.” She and her husband enjoyed reading popular health food magazines, and they found a local health food store that sold them a variety of vitamins, minerals, and other supplements that they had read about that week. They had two shelves in their kitchen: one with the products and the other with cross-referenced articles that listed claimed “benefits” for each item stored on their other shelf.
It was a cold, snowy night when the telephone rang, asking me (SRG) to make a house call to see Mrs. S. That morning, she had awoken with a headache, and by afternoon she was “not her usual self,” according to her family. I remember ringing the doorbell and the front door opening to her apartment; I immediately smelled vinegar and heard an older woman moaning. Upon entering the living room, I saw Mrs. S sitting naked and draped in dish towels that had been soaked in vinegar, “a home remedy” that her family claimed she frequently used; her feet were placed in a bucket of ice water. I asked the family to help her lie down on the sofa and cover her with a blanket while I went into the kitchen to discard the bucket of water. On the way into the kitchen, I tripped over two 100-pound bags of kelp—seaweed to some, sodium iodide to me—and then I saw the shelves. There, carefully arranged in alphabetical order, was a cornucopia of vitamins and minerals from A to zinc. I remembered learning in medical school about the “cold pressor test”; the ice water likely contributed to her high blood pressure, now 240/120 mm Hg. Mrs. S was in severe congestive heart failure; not helped by her daily intake of two cups of kelp she took in an attempt to be “healthy.” We took her to the hospital, where she was also found to have renal failure, hyperkalemia, and hypermagnesemia, among other toxicities. Mrs. S died shortly thereafter.
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While it is beyond the scope of this two-part series to review in detail all aspects of the products mentioned, the articles do address the key aspects of each, with a particular focus on potential comorbidities, side effects, and hazards that may result from taking some commonly available products sold at health food stores. Part I discussed commonly used minerals, trace elements, and fat-soluble vitamins. Part II discusses commonly used water-soluble vitamins, essential fatty acids, and herbs.
Water-Soluble Vitamins
Vitamin B1 (Thiamine)
Vitamin B1, or thiamine, plays a role in energy formation by helping derive energy from alcohol, carbohydrates, and fats. It is a coenzyme required for the oxidative decarboxylation of alpha-keto acids and for the activity of transketolase in the pentose phosphate pathway. Thiamine is rapidly absorbed, largely in the proximal small intestine and excreted in the urine as thiamine acetic acid and as the metabolites pyrimidine and the thiazolic moiety. The more carbohydrates consumed, the greater the requirement for vitamin B1, and thus the potential for worsening a deficiency state. During severe deficiency states, plasma and tissue levels of pyruvate are increased. The classic deficiency state is called beriberi, primarily associated with symptoms related to the nervous and cardiovascular systems. Mental confusion, anorexia, muscular weakness, ataxia, peripheral paralysis, ophthalmoplegia, edema, muscle wasting, tachycardia, and cardiomegaly may result. Carbohydrate ingestion in someone who is already deficient in vitamin B1 can precipitate the thiamine deficiency state known as Wernicke-Korsakoff syndrome.
Vitamin B1 is present in many food sources including unrefined cereals, peas, whole-wheat flour, wheat germ, brown rice, soya beans, organ meats, lean cuts of pork, and legumes and seeds/nuts. As with rice, the majority of vitamin B1 is removed with the husk during the milling process, and, thus, white flour is naturally deficient in vitamin B1. For this reason, vitamin B1 is usually added in the preparation process prior to distribution. Deficiency states are common, especially in persons who are alcoholics in whom decreased consumption and absorption and increased requirements play a role. The Recommended Dietary Allowance (RDA) for thiamine is 1.22 mg per day for men and 1.03 mg per day for women.
Toxicity from excessive intake is not common since most of the excess ingested is excreted in the urine. There have been cases of hypersensitivity reactions and drowsiness reported from parenterally administered vitamin B1, but no cases of thiamine toxicity by oral administration have been reported—even at doses as high as 500 mg daily for periods as long as 1 month.
Vitamin B2 (Riboflavin)
Vitamin B2, or riboflavin, is used in generating energy from carbohydrates and also plays a role in maintaining healthy eyes, skin, tongue, mouth, and nervous system function. It also promotes proper growth and development. It functions primarily as a component of two flavin coenzymes, flavin mononucleotide and flavin adenine dinucleotide, that catalyze many oxidation-reduction reactions. It is involved in the conversion of tryptophan to niacin. Riboflavin is absorbed primarily in the proximal small intestine and is excreted with its metabolites in the urine. It is found in large amounts in eggs and other dairy products such as cheese. It is also found in wholemeal products, wheat germ, broccoli, turnips, spinach, and brewer’s yeast, as well as poultry, fish, and meat. Deficiency states may lead to oral-buccal cavity lesions such as cheilosis and angular stomatitis, a generalized seborrheic dermatitis, scrotal and vulvar skin changes, and a normocytic anemia. While uncommon, ingestion of large quantities may lead to nausea, vomiting, and dark urine. The RDA for riboflavin is currently 1.2 mg per day for adults. No cases of serious toxicity from ingested riboflavin have been reported.
Vitamin B3 (Niacin)
Niacin is a water-soluble vitamin and may be found in either of two forms, nicotinic acid or nicotinamide. It is used in the body as a component of two coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). These coenzymes are present in all cells and participate in metabolic processes including glycolysis, fatty acid metabolism, and tissue respiration. A deficiency of niacin results in the disease pellagra, which is characterized by dermatitis, diarrhea, inflammation of the mucous membranes, and, in severe cases, dementia. Niacin is present in meats, though can be formed in the body by the conversion of dietary tryptophan to niacin. Tryptophan is present in milk and eggs, with 60 mg of tryptophan considered equivalent to 1 mg of niacin; both are considered to be equivalent to 1 niacin equivalent (NE) unit. It has been recommended that a diet contain at least 6.6 NE per 1000 kcal and not less than 13 NEs at caloric intakes of less than 2000 kcal for adults of all ages. Individuals receiving nicotinic acid or nicotinamide to treat lipid abnormalities may be prone to toxicity.

Ingestion of nicotinic acid, but not of the amide, most commonly produces vascular dilation or flushing. Ingestion of doses ranging from 3 grams to 9 grams of nicotinic acid daily may result in various metabolic effects, including increased utilization of muscle glycogen stores, decreased serum lipids, and decreased mobilization of fatty acids from adipose tissue during exercise. Other signs of overdose/toxicity that may occur include nausea, vomiting, peptic ulcers, abdominal cramps, diarrhea, weakness, light-headedness, headache, fainting, sweating, high blood sugar, gout, heart rhythm disturbances, and jaundice. High-blood-pressure medication effects may be potentiated; blood pressure should be monitored while on nicotinic acid to avoid hypotension.
Vitamin B6
Vitamin B6 consists of three related compounds, pyridoxine, pyridoxal, and pyridoxamine, all converted in the liver, erythrocytes, and other tissues to pyridoxal phosphate and pyridoxamine phosphate (coenzymes in transamination reactions). The requirement for vitamin B6 increases as the intake of protein increases. Deficiency rarely occurs alone but may present in persons who are deficient in several B-complex vitamins. Chicken, fish, kidney, liver, pork, and eggs are good sources of vitamin B6, as are soy beans, oats, whole-wheat products, peanuts, and walnuts. The RDA for vitamin B6 is 2.0 mg per day for men and 1.6 mg per day for women. While not common, toxicity may result from doses exceeding 100 mg or more per day, and may present as an ataxia and severe sensory neuropathy.
Folate 
Folate and folacin are compounds that have nutritional properties and chemical structures similar to folic acid. Folates function as coenzymes that transport single carbon fragments from one compound to another in amino acid metabolism and nucleic acid synthesis. Deficiency leads to impaired cell division and to alterations of protein synthesis. Clinically, megaloblastic anemia is the most common finding associated with deficiency states, although dementia has also been reported to occur. Low levels of folic acid have also been implicated in age-related hearing loss.1 The RDA for folate is 3 mcg/kg body weight or approximately 200 mcg for adult men and 180 mcg for adult women. This level allows for liver storage to protect against the development of a deficiency during short periods of inadequate intake.
Folate is present in a wide variety of foods including liver, yeast, leafy vegetables, legumes, and some fruits. Very large doses of folic acid, 100 or more times the RDA, may precipitate convulsion in persons whose epilepsy has been under control with phenytoin, as both inhibit uptake of each other at the gut cell membrane, and possibly at the brain cell membrane. Animal data suggest that intake of large doses of folic acid may precipitate in the kidneys, producing kidney damage and hypertrophy.
Vitamin B12
Vitamin B12 and cobalamin refer to a number of cobalt-containing corrinoids that can be converted to methylcobalamin or 5’-deoxyadenosylcobalamin, the two cobalamin coenzymes active in metabolic pathways. Cyanocobalamin is the commercially available form of vitamin B12 used in vitamin pills. Animal products are the primary dietary source of vitamin B12, with 1 to 3 mcg per day required to maintain an adequate body pool of this vitamin. Deficiency states may result from either an inadequate quantity in the diet or increased utilization, as may result from bacterial overgrowth in the intestine or the presence of an intestinal tapeworm. Vitamin B12 deficiency states may also result if there is a problem with intestinal absorption at receptor sites in the ileum mediated by a specific binding glycoprotein known as intrinsic factor, secreted by the stomach. This autoimmune process leads to the vitamin B12 deficiency state, pernicious anemia. A macrocytic, megaloblastic anemia may result and neurological symptoms may also be present due to demyelination of the spinal cord and brain and the optic and peripheral nerves. Weakness, sore tongue, and even dementia may be noted.
While no specific toxicity has been described for excessive intake of vitamin B12, there have been anecdotal reports of persons taking vitamin B12 who complain of having a “dry mouth” and bleeding from the nose and ear.
Vitamin C
Vitamin C (L-ascorbic acid) is a water-soluble vitamin with antioxidant properties that cannot be synthesized by humans. It serves as a co-substrate for hydroxylations requiring oxygen, such as the hydroxylation of lysine and proline to form collagen, dopamine to form norepinephrine, and tryptophan to form 5-hydroxytryptophan. It also plays a role in reactions involving tyrosine, folic acid, histamine, corticosteroids, and bile acids, among others, and plays a role in the function of leukocytes and macrophages. It serves to promote wound healing. Vitamin C is absorbed in the intestine by a sodium-dependent transport process. At low doses, absorption remains high but plasma concentrations plateau between 1.2 mg/dL and 1.5 mg/dL with intake of between 90 mg and 150 mg per day. Body stores appear to reach their maximum with intakes at 200 mg per day. Excretion is mainly in the urine. At daily intakes up to 100 mg, oxalate is the major product excreted. When larger amounts are ingested, ascorbic acid is also excreted unchanged. Major dietary sources of vitamin C include vegetables and fruits, with particularly high concentrations found in citrus fruits, strawberries, tomatoes, broccoli, peppers, potatoes, and collard greens. In order to prevent a deficiency state or scurvy, a minimum level of 10 mg per day for adults has been established. Intakes of more than 200 mg per day have been associated with increased levels of oxalate and ascorbic acid in the urine. While there continues to be debate over the benefits of relatively high doses of vitamin C, kidney stones remain a risk, especially in persons who have increased amounts of oxalate in their diet or who have hypercalciuria. Ingestion of doses exceeding 1 gram per day has also been associated with gastric irritation and diarrhea. A rare disorder known as “rebound scurvy” has been described in persons taking very high doses of vitamin C for prolonged periods of time who suddenly reduce their intake.
Essential Fatty Acids
Fish Oils
Commercially available supplements of fish oil and ocean fish from cold waters are excellent sources of omega-3 fatty acids. While not conclusive, studies suggest that omega-3 fatty acids may potentially reduce the risk of developing cardiovascular disease and inflammation.2 Oily fish such as mackerel, cod, salmon, herring, and sardines have high amounts of these fatty acids and are thought to be relatively safe to consume in reasonable quantities. Other fish rich in omega-3 fatty acids, such as swordfish, albacore tuna, and marlin, have a higher chance of having toxic levels of dioxins and mercury, and, therefore, their intake should be more limited. Depending on the source of a commercially available supplement and the method of processing used, these same risks may exist even for supplements. Fish oils may also potentiate the action of warfarin, leading to an increased risk of bleeding, and they may also present a risk to persons with hemophilia. Fish oil supplements may lead to mild gastrointestinal upsets such as nausea and diarrhea, halitosis, eructation, and “fishy-smelling” breath, skin, and urine. Nosebleeds and easy bruising have also been reported.
Herbs
Saw Palmetto
Saw palmetto was used by the Mayans and Seminole Indians for a variety of reasons, including as an antiseptic and an expectorant. It is the most commonly used herbal preparation for the treatment of benign prostatic hypertrophy, with a number of studies supporting its use.3 It is thought to inhibit the conversion of testosterone to dihydrotestosterone. Inhibitory effects on androgen receptors and anti-inflammatory properties have also been suggested, although supportive data are sparse in this regard. Allergic reactions are rare and may include throat swelling and difficulty breathing. The most common complaints following its use involve the gastrointestinal tract and include stomach pain, nausea, vomiting, halitosis, constipation, or diarrhea. Rare reports of jaundice, headache, dizziness, insomnia, depression, difficulty breathing, muscle pain, increased blood pressure, chest pain, and abnormal heart rhythm have been reported. Severe bleeding during saw palmetto use has also been reported.4 Rarely, saw palmetto is associated with erectile dysfunction, testicular discomfort, breast tenderness, and reduced libido.
Ginkgo Biloba
Ginkgo leaves or ginkgo biloba preparations have been advocated as a way to improve memory, blood flow, dizziness, and tinnitus. While some studies have demonstrated benefit in the early stages of Alzheimer’s disease, with improvement or a slowing of progression noted,5 others have failed to demonstrate any benefit from ginkgo consumption.6 While different doses, preparations, and populations studied make it difficult to reach any definite conclusion, a meta-analysis gave some credence to its positive effect. Starting with 50 clinical studies in persons with dementia and cognitive dysfunction, four studies met the inclusion criteria for the meta-analysis, mainly due to differences in criteria for diagnosing dementia.7 When the four studies were combined, 212 patients were in the placebo and ginkgo groups. Based on the quantitative analysis of these trials, the authors concluded that 120 mg to 240 mg of ginkgo biloba extract for 3-6 months had a small but significant effect on objective measures of cognitive function in Alzheimer’s disease without significant side effects.7 Common side effects include stomach upset, nausea, headache, and diarrhea. Ginkgo has also been associated with an increased risk of bleeding, although this too is controversial. It is suggested that individuals with blood circulation disorders and those taking anticoagulants such as aspirin and warfarin avoid its use.
Kava Kava Root 
Kava is related to the black pepper and has been used in the Pacific region by indigenous people for hundreds of years as part of religious rites. Chewed or mixed with water to create an extract, it was used for its “psychoactive properties.” It has been advocated in the West as a way to reduce anxiety, stress, and even depression. Drinking kava extract frequently causes the lip and tongue to become numb. This is thought to be due to a contraction of blood vessels in this region. It may also lead to either euphoric or calming behavior. While not fully understood, the mechanism of action is thought to be due to a potentiation of gamma-aminobutyric acid neurotransmission; serotonin and dopamine may also be affected. Liver toxicity and even failure have been described due to kava use, leading several countries to ban its sale. The U.S. Food and Drug Administration has issued an advisory to consumers about the potential risk of using products containing kava. A kava-induced dermopathy has also been reported in those persons using large quantities of this herb.
Licorice Root
Licorice is a perennial herb that is widely cultivated throughout Europe, the Middle East, and Asia. The roots and stolons contain glycyrrhizin or glycyrrhizinic acid, a compound that is approximately 50 times sweeter than sucrose. Licorice extracts are commonly used to flavor food and liquors, though in certain parts of the world licorice root is used as a medicinal tea for chronic gastritis and bronchitis, and as a laxative and expectorant. It has also been used as a treatment of hepatitis C to reduce the risk of developing hepatocellular carcinoma.8 Glycyrrhizic acid has been identified as having a “pseudo-aldosterone-like effect.” It has been shown to cause inhibition of peripheral metabolism of cortisol and be capable of binding to ineralocorticoid receptors in the same way as aldosterone.9 The end result may be sodium and water retention, potassium loss, hypertension, edema, and even myoglobinuria. These potentially serious side effects usually subside within several weeks of discontinuing its use. Most licorice sold in the United States contains minimal licorice content and uses artificial flavoring and corn syrup. “Natural licorice,” more commonly sold in Europe and elsewhere, does present a risk if eaten to excess and should be considered in any patient who presents with symptoms of hyperaldosteronism.
Echinacea
Echinacea species are a group of native American wildflowers from the daisy family. It is primarily used for the prevention and treatment of uncomplicated upper respiratory tract infections.10 Echinacea was the most commonly used natural product in 2002 (7.6% of American adults).11 It has been noted to have antiviral activity against influenza, herpes, and poliovirus, as well as antioxidant12 and anti-inflammatory activity through inhibition of lipoxygenase and cyclooxygenase.13 In addition, Echinacea has been demonstrated to increase phagocytosis, lymphocyte activity, and cytokine production, as well as modulate apoptosis.14,15
Overall, Echinacea  is usually well tolerated. Potential side effects include dyspepsia, diarrhea, “bad taste,” fever, nausea, and vomiting. Patients with allergies to ragweed, chrysanthemums, marigolds, and daisies may have reactions to Echinacea.16 Small trials and case reports have reported rash,17 anaphylaxis,18 pemphigus vulgaris,19 and renal tubular acidosis.20 There have been concerns regarding the use of Echinacea in patients with autoimmune disorders due to its immune-stimulating effects.21 Because of its immunostimulating activity, Echinacea may interfere with immunosuppressant therapy.16 The data on the safety of duration of use vary from 8 to 12 weeks.22
St. John’s Wort
St. John’s wort (Hypericum perforatum) is a yellow flower that has been used for its antidepressant, anti-inflammatory, and wound-healing properties for generations.23 St. John’s wort was the sixth most popular natural product in the United States in 2002 (2.2% of American adults).11 Hyperforin is thought to be primarily responsible for St. John’s wort’s effect on mood due to its effect on norepinephrine and dopamine.24
Gastrointestinal symptoms, dizziness, confusion, fatigue, sedation, dry mouth, urinary frequency, anorgasmia, and swelling are the most commonly noted side effects.25,26 Reports of photosensitivity have also been documented.27 The use of St. John’s wort should be avoided during pregnancy and lactation due to a lack of safety data. Caution is needed with medications that are metabolized by the CYP3A4 and/or P-glycoprotein, including protease inhibitors, cyclosporine, theophylline, digoxin, simvastatin, verapamil, irinotecan, imatinib, tacrolimus, warfarin, and methadone, due to the risk of decreased drug levels. These interactions are likely due to induction of the CYP3A4 system by the hyperforin component and of P-glycoprotein by hypericin.28,29 Cases of breakthrough bleeding and undesired pregnancy in women taking oral contraceptive pills have been reported due to decreased estrogen levels.28
St. John’s wort should not be used in combination with other antidepressants to avoid the potential for developing serotonin syndrome.30 Several cases of serotonin excess (agitation, hyperthermia, diaphoresis, tachycardia, and neuromuscular disturbances) have been reported in elderly individuals taking St. John’s wort and selective serotonin reuptake inhibitors together.31 It is recommended that St. John’s wort be discontinued at least 5 days prior to a planned operative procedure.32
Black Cohosh
Black cohosh (Actaea racemosa or Cimicifuga racemosa) is one of the most widely used amongst the alternatives available for the management of hot flashes.33 Black cohosh contains phytoestrogens, botanical compounds that mimic estrogens and have mild estrogenic-binding effects. Salicylic acid is also found in small quantities in black cohosh, contributing to its anti-inflammatory and analgesic properties. A potential safety concern is its possible estrogenic effect on the breast. It is not considered safe therapy for patients with breast cancer, those at high risk for breast cancer,34 or in patients with a history of estrogen-dependent tumors. Phytoestrogen-containing herbs have not been associated with the negative health effects seen with synthetic estrogen, but it should be used with caution in individuals taking hormone replacement therapy or oral contraceptives, or those with a history of thromboembolic disease or stroke.34 Black cohosh may cause nausea, vomiting, headache, and hypotension at higher dosages. It should also be used with caution in individuals allergic to salicylates. Its use is contraindicated in pregnancy and lactation.35 Monitoring of serum hormone levels (estrogen) is recommended after 6 months of use of black cohosh.
Conclusion
The risks and benefits of any drug should be reviewed collaboratively by clinician and patient. In addition, as many patients often take multiple medications and supplements together, obtaining the detailed medication history from the patient is critical. Subsequently, utilizing resources to assess for known potential drug interactions and toxicities is essential. Many of these interactions are not well described. As more patients seek out medicines that may be considered out of the mainstream (or out of the mainstream dosing), it becomes even more critical for the clinician to be well versed in the benefits and toxicities of these commonly used medicines.
 
Resources
www.nlm.nih.gov/medlineplus/druginfo/herb_All.html
www.micromedex.com/products/altmeddex/