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Understanding Nutrition, Herbs, and Drug Interactions Michael Davidson, Pharm.D., ACN Integrative Pharmacist Clinical Nutritionist Phytotherapist Disclaimer The information provided in this lecture should not be construed as a claim or representation that any formula, procedure, or product mentioned constitutes a specific cure, palliative, or ameliorative for any condition. The material contained in this lecture has not been reviewed by the FDA and is not for the diagnosis or treatment of any disease. Disclaimer This lecture and the information it contains is for educational purposes only; it is not a substitute for individualized guidance from a qualified healthcare professional. Audiences are cautioned not to use any substance or product mentioned herein without reviewing it with their qualified healthcare professional to determine if it is appropriate for them. What is an Herbal Product? It is a mixture of organic chemicals that are made from raw or processed plant parts, that may include leaves, stems, flowers, roots, and seeds of plants. Different Forms: Extracts, Juices, Teas, Lozenges, Inhalants, Oils, Salves, Capsules, and Herbal Baths In the US, under current law, they are categorized as Dietary Supplements. Herbal Products and Medications 1/3 to 1/2 of drugs commonly prescribed today contain at least one active ingredient derived from plants. Examples: Aspirin: Botanical origin from white willow bark and acid meadow sweet plant. Codeine and Morphine: Botanical original from opium/poppy. Digoxin: Botanical origin from foxglove. Source: Barrett B, Kiefer D, Rabago D. Assessing the risks and benefits of herbal medicine: an overview of scientific evidence. Altern Ther Health Med. 1999;5:40–9. Consumer Education Use of dietary supplements is increasing in the US. Supplement use in adults (20 years and above): 1988–1994: over 40% 2003–2006: over 50% Standardization of Active Ingredients The potency of herbs depends on: geographic location soil sunlight rainfall altitude harvesting drying process storage Standardization of Active Ingredients Therefore, necessary for manufacturers to test their products to ensure standardized amounts of suspected active ingredients Most companies do not do perform these tests. Some research is required to ascertain the quality of supplements and/or of the supplement company Quality Problems Many of the purported side effects and drug interactions of herbs are not due to the herb itself. Actually due to: Chemicals added in the manufacturing process (eg. solvents, preservatives, etc.) Wrong species or wrong part of plant used Contaminants Possibility of Contamination Herbal products imported from Asia may have a high risk of containing contaminants. A study examining the contents of 260 Asian patent medicines found that 25% of products contained high levels of heavy metals and another 7% contained undeclared drugs, purposefully and illegally added to elicit a desired effect. Source: Bent, Stephen. “Herbal Medicine in the United States: Review of Efficacy, Safety,and Regulation”. 2004. Regulations of Herbal Products in the U.S. Regulation is currently the predominant factor affecting the reliability of herbal products that are manufactured in the U.S. The Dietary Supplement Health and Education Act (DSHEA) of 1994 classifies herbs as dietary supplements. Supplement manufacturers are required to fulfill the FDA’s Good Manufacturing Practices (GMPs) for foods, which describe conditions under which products must be prepared, packed, and stored. Regulations of Herbal Products in the U.S. GMPs do not address all issues influencing supplement quality. This raises concerns regarding the quality of herbal supplements. Remember, quality and potency of herbal products is affected by: geographic location, soil, sunlight, rainfall, altitude, the methods used to grow, harvest, dry, and store the herbs. DSHEA Restricts regulation of herbal products by the FDA, enabling supplements to be produced, and marketed without having to undergo rigorous evaluations for safety and efficacy. Source: Bent, Stephen. “Herbal Medicine in the United States: Review of Efficacy, Safety,and Regulation”. 2004. Regulations of Herbal Products in other Countries In contrast, some other countries have government regulatory bodies responsible for ensuring safety and efficacy of herbal products on the market Eg. Australia, Germany Regulations of Herbal Products in Australia The Therapeutic Goods Administration was established in 1990 to “safeguard and enhance the health of the Australian community through effective and timely regulation of therapeutic goods” TGA “provides a national system of controls relating to the quality, safety, efficacy and timely availability of therapeutic goods used in, or exported from, Australia” Source: Australian Government Department of Health: Therapeutic Goods Administration http://www.tga.gov.au/pdf/presentations/tga-education-introduction.pdf Regulations of Herbal Products in Germany In Germany herbs are routinely prescribed by physicians and sold in pharmacies. The German Commission E gives scientific expertise for the approval of substances and products previously used in traditional, folk and herbal medicine. Regulations of Herbal Products in Germany The commission became known beyond Germany in the 1990s for compiling and publishing 380 monographs evaluating the safety and efficacy of herbs for licensed medical prescribing in Germany These monographs serve as the basis for the medical usage of herbs within the German health care system Outline acceptable manufacturing processes on the basis of available scientific and clinical evidence. Source: Mark Blumenthal. The German Commission E Monograph System for Phytomedicines: A Model for Regulatory Reform in the United States. American Botanical Council, P.O. Box 201660, Austin, TX 78720. Herb-Drug Interactions Other herb-drug interactions are due to an actual interaction between the plant and drug ingredients In general, 2 different types: PK: interaction causes a change in the amount of herb or drug in the body PD: interaction causes a change in the degree of effect of the herb or drug on the body These can be beneficial or harmful ST. JOHN’S WORT (Hypericum Perforatum) Percentage use in US: 2.1% Main Actions: Antidepressant, nervine tonic, antiviral (against enveloped viruses), vulnerary, antimicrobial (topically) Scientific evidence for efficacy: Likely effective for mild-moderate depression Safety: Numerous Amounts of Drug Interaction. Not recommended for pregnant or lactating women. ST. JOHN’S WORT Most interactive herbal product Interaction with drugs metabolized by liver Increases the rate of metabolism of certain pharmaceutical agents, causing a reduction in blood levels. ST JOHN’S WORT May reduce levels of the following drug types: certain antivirals chemotherapeutic agents oral contraceptives warfarin Anti-seizure medications, cardiovascular meds (eg. digoxin) transplant rejection drugs many others Source: Hammerness P, Basch E, Ulbricht C, et al. St John’s wort: a systematic review of adverse effects and drug interactions for the consultation psychiatrist. Psychosomatics. 2003;44:271–82. GINKGO BILOBA Commune Use: Improvement of Memory and Concentration, and treatment of dementia and peripheral vascular disease, reduce the incidence of plaque formation associated with atherosclerosis, Antioxidant, Glaucoma, Menopausal symptoms, Multiple Sclerosis, Sexual Dysfunction Main Actions: Antioxidant, anti-PAF activity, tissue perfusion enhancing, circulatory stimulant, cognition enhancing, neuroprotective Percentage use in U.S.: 3.7% Scientific Evidence for Efficacy: Likely Effective for Alzheimer’s Prevention Side Effects: generally mild and may include headache, GI upset, nausea/vomiting GINKGO BILOBA Some possible Drug Interactions with: anticonvulsants (may reduce effects) antipsychotics (may increase effects) hypoglycemic meds (may increase effects) certain acid lowering drugs (may reduce effects) certain anxiolytic/sleep meds (may increase or decrease effects) Ernst, Edzard. “The Risk-Benefit Profile of Commonly Used Herbal Therapies: Ginkgo, St. John’s Wort, Ginseng, Echinacea, Saw Palmetto, and Kava” 2002. GINSENG (PANAX GINSENG): Background Information Historically, ginseng has been used to improve endurance, concentration, alertness, and general well-being. P. ginseng has a range of pharmacological activities, including CNS stimulation, immune system modulation, and anabolic effects. Main Actions: adaptogenic, tonic, immune modulating, cardiotonic, chemopreventive, cognition enhancing GINSENG (PANAX GINSENG): Efficacy recent epidemiological study of a ginseng growing region in Korea: the risk for cancer of persons who consumed fresh Korean ginseng on a regular basis was reduced to about 30% of those who did not consume it. a dose-response correlation between regular ginseng consumption and risk for cancer was observed. Source: Ernst, Edzard. “The Risk-Benefit Profile of Commonly Used Herbal Therapies: Ginkgo, St. John’s Wort, Ginseng, Echinacea, Saw Palmetto, and Kava” 2002. GINSENG (PANAX GINSENG): Safety Some possible Drug Interactions with: warfarin (may decrease effect) digoxin (may increase digoxin levels) anti-diabetic meds (may increase effect) blood pressure lowering meds (may decrease or increase effects depending on drug) MAO inhibitors like phenelzine (CI: may cause HA, tremor, mania) moreover, since the quality of numerous commercial ginseng products sold in the US is unknown, adverse effects / drug interactions might be caused by contaminants. Ernst, Edzard. “The Risk-Benefit Profile of Commonly Used Herbal Therapies: Ginkgo, St. John’s Wort, Ginseng, Echinacea, Saw Palmetto, and Kava” 2002. Standardization of Active Ingredients: Ginseng A number of recent studies have documented significantly different levels of suspected active ingredients in the same types of herbal products. For instance, a recent analysis of 25 available ginseng products found a 15- to 200-fold variation in the concentration of 2 ingredients (ginsenosides and eleuthrosides) believed to have biological activity. Source: Harkey MR, Henderson GL, Gershwin ME, Stern JS, Hackman RM. Variability in commercial ginseng products: an analysis of 25 preparations. Am J Clin Nutr.2001;73:1101–6. Standardization of Active Ingredients: Echinacea Three species of echinacea are used to prepare commercially available herbal supplements: Echinacea angustifolia, E. pallida, and E. purpurea. Main actions: immune enhancing/modulating, depurative, lymphatic, anti-inflammatory, vulnerary, sialogogue. Although roots are used most frequently, the dramatic variability of echinacea products may be ascribed to the varying plant parts used in different preparations. Echinacea History Information regarding the therapeutic use of Echinacea first came from Native American tribes. The eclectic physicians (a groups of doctors that reached prominence around the late 19th to early 20th century in the US) then adopted this use. The most common treatment prescribed by the Eclectics was the root of E. angustifolia, by 1921. Source: Wagner H. Z Phytother 1996; 17: 79-95 Echinacea History Native Americans preffered E. angustifolia and used only the root The Eclectics used only lilophilic extracts (high alcohol concentration) of dried roots of E. angustifolia. Eclectics described good quality Echiancea root as “imparting a persistent tingling sensation”. Tingling caused by active ingredients in E. angustifolia known as alkylamides; presence of tingling sensation indicates presence of active constituents (quality marker). Sources: Felter HW, Lloyd JU. King’s American Dispensatory. 18th Edn, 3rd revision. First published 1905, reprinted Eclectic Medical Publications, Portland, 1983. Bauer R, Wagner H. In Wagner H, Farnsworth NR eds. Economic and Medicinal Plant Research, Vol 5, Academic Press, London, 1991. Echinacea History In the 1930s, German herbalist Madaus had trouble growing E. angustifolia ; used E. purpurea instead. Used the stabilized juice of fresh E. purpurea tops (aerial parts), likely due to his background in homeopathy. This hydrophilic extract of echinacea contains very low levels of alkylamides (no tingling sensation). Only echinacea roots are likely to contain sufficient concentrations of active ingredients (alkyl-amides) necessary for therapeutic benefit. Echinacea: Quality Problems This contributed to today's multitude of preparations available on the market, often: Non-traditional species of echinacea used Wrong plant part used Improper extraction method Improper manufacturing process Echinacea: Clinical Research NK cells decline in number and function with age and this is thought to be one factor behind the increase in various diseases with age. Experiments in healthy, elderly mice found that 2 weeks of oral doses of Echinacea root returned NK cell number and function to the levels normally found in young adults In addition, for mice fed Echinacea purpurea root from 7 weeks of age to 13 months, lifespan was significantly extended compared to controls. Sources: Currier NL, Miller SC. Exp Gerontol 2000; 35: 627-639 Brousseau M, Miller SC. Biogerontology 2005; 6: 157-163 Echinacea: Clinical Research An Echinacea root formulation was compared against a herbal adaptogenic formulation and a placebo in the prevention of winter colds over a 90-day period. The trial recruited 260 medical students who were under stress from their studies. The placebo group averaged an infection rate of 10%, whereas this dropped to as low as 2% by day 70 (p=0.013) in the Echinacea group. Source: McIntosh A et al. AANP Convention, Coeur d’ Arlene, 1999. Echinacea: Clinical Research Randomized, double blind, placebo-controlled clinical trial: 175 participants travelling return from Australia to North America, Europe or Africa for 1 to 5 weeks. Active tablets each contained extract from 1.275 g Echinacea root (4.4 mg alkylamides) Priming dose was 2/day, travel dose was 4/day, and dose when ill was 6/day The Echinacea group exhibited significantly lower average respiratory infection symptom score (about half) compared with the placebo group (p<0.05) after return from travel. Tiralongo E et al. Evid Based Complement Alternat Med 2012; 2012: 417267 Echinacea: Clinical Research Tiralongo E et al. Evid Based Complement Alternat Med 2012; 2012: 417267 Tribulus History As an herb which improves libido and male sexual performance, Tribulus terrestris has grown in popularity. Main Actions: tonic, aphrodisiac, oestrogenic in females (indirectly), androgenic in males (indirectly), fertility agent It is used by phytotherapists to: improve male and female fertility for menopausal symptoms to enhance physical performance and fitness. Source: Morgan M, Bone K.Tribulus terrestris. Professional ReviewAug 2001; No. 76, pp 1-4. Tribulus History A common weed found in many parts of the world, Tribulus has been employed therapeutically in traditional medical systems such as Ayurveda and Chinese medicine. Bulgarian research using a standardized Tribulus leaf preparation which is rich in furostanol saponins (especially the marker phytochemical protodioscin) lead to the modern uses noted above. Since furostanol saponins are important, active constituents, the Bulgarian extract was standardized to contain at least 45% of these saponins as protodioscin. Tribulus: Phytochemistry Meticulous analytical studies (using HPLC), have determined the following: There is a substantially higher content of protodioscin in the leaves (1.337%), than in the stem (0.276%) or fruit (0.245%) (plant samples taken from Bulgaria). Plant material from Eastern Europe is higher in protodioscin than material from India, China or Australia. Sources: Lehmann RP et al. Rev de Fitoterapia 2002; 2(S1): 217 (Abstract B006) Ganzera M et al. J Pharm Sci 2001; 90: 1752 Tribulus: Quality Problems Most Tribulus products on the market are very different from the Bulgarian extract. As demonstrated in one study, Tribulus leaf from Australia and India did not contain protodioscin. Morgan M, Bone K.Tribulus terrestris. Professional ReviewAug 2001; No. 76, pp 1-4. In an assessment of products selected from the US market, deficiencies of protodioscin were discovered in the majority. Sources: Morgan M, Bone K.Tribulus terrestris. Professional ReviewAug 2001; No. 76, pp 1-4. Ganzera M, Bedir E, Khan IA. Determination of steroidal saponins in Tribulus terrestris by reversed-phase high-performance liquid chromatography and evaporative light scattering detection.J Pharm Sci 2001; 90(11): 1752-1758. Tribulus: Clinical Research In an unblinded, placebo-controlled study, treatment with concentrated extract of Tribulus terrestris leaf from Bulgaria had a beneficial effect on menopausal symptoms: improvement in hot flushes, sweating, insomnia and depression in 98% of the 50 participating women Improvement in libido in nearly 70% of women. Intake of placebo was ineffective. Zarkova S. Tribestan: Experimental and Clinical Investigations. Chemical Pharmaceutical Research Institute, Sofia, Bulgaria. Tribulus: Clinical Research A number of uncontrolled clinical trials have been conducted by Bulgarian research teams including over 300 men with fertility problems and impotence. Concentrated extract of Tribulus terrestris leaf, containing furostanol saponins (predominantly protodioscin, at least 45%) was found to have a stimulating effect on sexual function. Treatment with Tribulus extract increased serum testosterone in some patients with lowered levels, (levels were not increased in those with normal values of testosterone) Concentrated extract of Tribulus terrestris leaf was found to be well tolerated, with gastrointestinal upset occurring in only a few patients. Sources: Protich M et al. Akush Ginekol 1983; 22: 326 Kumanov F et al. Savr Med 1982; 4: 211 Viktorov IV et al. MBI: Medicobiologic Information 1982, cited in Zarkova S. Tribestan: Experimental and Clinical Investigations. Chemical Pharmaceutical Research Institute, Sofia, Bulgaria. Nikolova V, Stanislavov R. Dokl Bolg Akad Nauk 2000; 53: 113 Stanislavov R, Nikolova V. Dokl Bolg Akad Nauk 2000; 53: 107 Nutrition and Herbal Therapy When used correctly by a healthcare professional knowledgeable in phytotherapy / herbalism and nutrition, herbal therapy, appropriate nutrition, and nutritional supplements can be used to: Reduce drug side effects / toxicities Reduce drug-related organ impairment Reduce drug-induced nutrient depletion Improve drug therapeutic effects Drug-Induced Nutrient Depletion some commonly prescribed medications, when taken chronically, can deplete the body’s reserves of essential vitamins, minerals, enzymes, co-factors, and other nutrients. “To carry on the life process, each of the 80 to 100 trillion cells must digest constructive food, excrete wastes, repair itself, and carry on other essential functions. Every cell requires all the known and unknown elements of nutrition.” -- Dr. Janet Lang Prolonged nutrient depletion can result in diseases of any organ system depending on the specific nutrients being depleted. Likely contributes to leading causes of death in the US including heart disease, cancer, dementia, etc. Drug-Induced Nutrient Depletion Drug-Induced Nutrient Depletion What to do about nutrient depletion? Is taking a synthetic nutrient supplement the solution? What is the difference between chemically synthesized nutritional supplements and those derived from a whole-food source? Not All Supplements are Created Equal When you take a synthetic vitamin supplement, your body is merely getting isolated chemicals. Examples include: Vitamin A (as beta carotene or as Vitamin A palmitate or acetate) Vitamin C (as ascorbic acid, or as calcium ascorbate) Vitamin E (as d-alpha-tocopherol, tocotrienols, or as mixed tocopherols) Not All Supplements are Created Equal In food or herbs, nutrients are never isolated; they are always in complexes with other nutrients, without which they cannot function, and therefore, cannot enable the body to function. “Nutrients in foods are highly synergistic interactive complexes. Synergy means that the whole is greater than the sum of its parts, that the relationship which the parts have to each other is the most catalytic, most empowering, most unifying, most functional or effective part. Synergy means that 1 + 1 may equal 8, 24, or even 1,600. Synergistic function produces more and better results than any action of any part separated from the whole…” "Separating the group of compounds (in a vitamin complex) converts it from a physiological, biochemical, active micronutrient into a disabled, debilitated chemical of little or no value to living cells. The synergy is gone."-- Dr. Judith DeCava Not All Supplements are Created Equal Whole Food Complex Synthetic Isolates Not All Supplements are Created Equal To give an analogy, a vitamin taken from food is part of a complex machine like a clock. Many interlocking gears and other parts are necessary for a clock to function correctly, which are all found in the food. Manufacturers who make synthetic vitamins are analogously gathering large quantities of several types of these gears, throwing them together in no particular order within a pill, and trying to convince you that they will work like a clock within your body. Furthermore they try to convince you that more of a particular vitamin (a huge daily value) is better; this is like saying that having more of a particular part needed to make a clock is more important than having all of the necessary parts of that clock in their correct arrangement. Thus, 50 mg of vitamin C (or A, E, etc.) from a food (or whole food supplement) is more nourishing and contains far more functional components than 1000 mg of ascorbic acid (the antioxidant wrapper that protects the functional components) from a synthetic supplement. Not All Supplements are Created Equal Vitamin C complex structure includes: Ascorbinogen and bioflavonoid complexes Tyrosinase (copper-bearing enzyme) (Most Functional Part) P, K, and J factors Ascorbic acid - this antioxidant wrapper is the only part of the vitamin C complex found in synthetic supplements Not All Supplements are Created Equal Vitamin E complex structure includes: Xanthine Selenium Manganese Lipositols Polyunsaturated fatty acids Alpha, Beta, Gamma, and Delta Tocopheral – these antioxidant wrappers are the only part of the vitamin E complex found in synthetic supplements (only some of them eg. delta and alpha tocophreal). Synthetic “vitamins” increase cancer risk in smokers Results: Unexpectedly, we observed a higher incidence of lung cancer among the men who received beta carotene than among those who did not (change in incidence, 18 percent). Fewer cases of prostate cancer were diagnosed among those who received alphatocopherol than among those who did not. Beta carotene had little or no effect on the incidence of cancer other than lung cancer. Alphatocopherol had no apparent effect on total mortality, although more deaths from hemorrhagic stroke were observed among the men who received this supplement than among those who did not. Total mortality was 8 percent higher among the participants who received beta carotene than among those who did not, primarily because there were more deaths from lung cancer and ischemic heart disease. Conclusion: We found no reduction in the incidence of lung cancer among male smoker after 5-8 years of dietary supplementation with alpha-tocopherol or beta carotene. In fact, this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects. N Engl J Med. 1994 Apr 14;330(15):1029-35. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. Not All Supplements are Created Equal In effect, when large quantities of synthetic vitamins are ingested, your body treats them more like drugs or xenobiotics (foreign substances) than nutrients. To prevent them from causing biochemical imbalances, the body attempts to quickly excrete them (eg. high-dose synthetic B vitamins are rapidly excreted after ingestion, turning the urine a bright yellow color) Moreover, the parts that are retained are still missing many of the components required to make them functional. The body is forced to scavenge these missing components from its own tissue reserves This is why synthetic supplements seem to work in the shortterm, but stop working once these tissue reserves are depleted, sometimes resulting in a larger imbalance than before starting on the supplements. Not All Supplements are Created Equal To prevent these imbalances, choose supplements made from real food (whole food concentrates) rather than chemicals. Must research quality of supplement production process from the growing and harvesting of foods used to make the supplements to the manufacturing and quality control process. Best to have guidance of health care professional in choosing a supplement. Adverse Drug Reactions (ADRs) in the U.S. Over 2 MILLION serious ADRs yearly 100,000 DEATHS yearly ADRs 4th leading cause of death ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents and automobile deaths Ambulatory patients ADR rate—unknown Nursing home patients ADR rate— 350,000 yearly Sources: Institute of Medicine, National Academy Press, 2000 Lazarou J et al. JAMA 1998;279(15):1200–1205 Gurwitz JH et al. Am J Med 2000;109(2):87–94 COMMONLY USED DRUGS AND ASSOCIATED TOXICITY MANAGEMENT: EXAMPLES Reducing Drug-Related Toxicity / Organ Impairment Not only can nutrients (especially from whole food sources) and high quality herbs be used to support Pts. with various health problems, they can also be used to minimize the adverse effects of any drugs these Pts. are taking. Functional Approach: Address underlying cause of why Pt. is taking drug Minimize ADRs and drug associated toxicity Pts. Taking Statin Drugs Statin drugs are known to deplete a molecule critical for cellular respiration (energy production) called Coenzyme Q Address underlying cause Nutrition/exercise/lifestyle Cardiovascular health Inflammation Protect against drug-induced organ impairment: cardiovascular Hepatic Musculoskeletal CNS Pts. Taking ACE-I/ARB Drugs ACE-I/ARB are a class of antihypertensive drugs known to cause renal impairment Address underlying cause Nutrition/exercise/lifestyle Cardiovascular health Endocrine balance Protect against drug-induced organ impairment: Renal system Cardiovascular system Pts. Taking Antibiotics Broad spectrum antibiotics (especially) will eliminate essential intestinal flora Address underlying cause: Nutrition/exercise/lifestyle Immune System support Reduce adverse drug effects: GI system restore/rebuild healthy gut flora to the extent possible Pts. Taking NSAIDS Non-Steroidal Anti Inflammatory Drugs Known to deplete folic acid (vitamin B9), which is involved in a number of functions in the body a few of which include DNA synthesis, repair, and methylation, and erythrocyte maturation. Address underlying cause: Assess cause of pain and undertake correcting measures Manage pain meanwhile Protect against drug-induced organ impairment: Cardiovascular System GI system Renal System Pts. Taking Acid-Suppressing Drugs Prolonged administration of acid-lowering drugs is known to inhibit digestion and result in nutrient deficiency (B-12, folate, vitamin D, calcium, iron, zinc). Address underlying cause: Nutrition/exercise/lifestyle Improve digestion Protect against drug induced organ impairment: Digestive Immune Musculoskeletal Thank You Questions? References Australian Government Department of Health: Therapeutic Goods Administration http://www.tga.gov.au/pdf/presentations/tga-education-introduction.pdf Barrett B, Kiefer D, Rabago D. Assessing the risks and benefits of herbal medicine: an overview of scientific evidence. Altern Ther Health Med. 1999;5:40–9. Bauer R, Wagner H. In Wagner H, Farnsworth NR eds. Economic and Medicinal Plant Research, Vol 5, Academic Press, London, 1991. Bent, Stephen. “Herbal Medicine in the United States: Review of Efficacy, Safety,and Regulation”. 2004. Blumenthal, Mark. The German Commission E Monograph System for Phytomedicines: A Model for Regulatory Reform in the United States. American Botanical Council, P.O. Box 201660, Austin, TX 78720 Brousseau M, Miller SC. Biogerontology 2005; 6: 157-163 Currier NL, Miller SC. Exp Gerontol 2000; 35: 627-639 "Dietary Supplement Fact Sheet: Folate". Office of Dietary Supplements, National Institutes of Health. Drug-Induced Nutrient Depletion Handbook, by R. Pelton et al.; Physician’s Desk Reference Ernst, Edzard. “The Risk-Benefit Profile of Commonly Used Herbal Therapies: Ginkgo, St. John’s Wort, Ginseng, Echinacea, Saw Palmetto, and Kava” 2002. Felter HW, Lloyd JU. King’s American Dispensatory. 18th Edn, 3rd revision. First published 1905, reprinted Eclectic Medical Publications, Portland, 1983. Ganzera M et al. J Pharm Sci 2001; 90: 1752 References Gurwitz JH et al. Am J Med 2000;109(2):87–94 Hammerness P, Basch E, Ulbricht C, et al. St John’s wort: a systematic review of adverse effects and drug interactions for the consultation psychiatrist. Psychosomatics. 2003;44:271–82. doi: 10.1176/appi.psy.44.4.271. Harkey MR, Henderson GL, Gershwin ME, Stern JS, Hackman RM. Variability in commercial ginseng products: an analysis of 25 preparations. Am J Clin Nutr.2001;73:1101–6. Institute of Medicine, National Academy Press, 2000 Jaime Gahche et al. Dietary Supplement Use Among U.S. Adults Has Increased Since NHANES III (1988–1994). NCHS Data Brief. No. 61, April 2011. Krinsky, Daniel L. et al., “Natural Therapeutics Pocket Guide”. 2nd Edition. 2003. Kumanov F et al. Savr Med 1982; 4: 211 Lazarou J et al. JAMA 1998;279(15):1200–1205 Lehmann RP et al. Rev de Fitoterapia 2002; 2(S1): 217 (Abstract B006) Magee, Katrina. “Herbal Therapy: A review of Potential Health Risks and Medicinal Interactions” 2005. Markman, Maurie. “Safety Issues in Using Complementary and Alternative Medicine” 2002. McIntosh A et al. AANP Convention, Coeur d’ Arlene, 1999. Messina, Barbara. “Herbal Supplements: Facts and Mythes- Talking to your Patients about Herbal Supplements” 2006. Morgan M, Bone K.Tribulus terrestris. Professional ReviewAug 2001; No. 76, pp 1-4. References N Engl J Med. 1994 Apr 14;330(15):1029-35. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. Nikolova V, Stanislavov R. Dokl Bolg Akad Nauk 2000; 53: 113 Protich M et al. Akush Ginekol 1983; 22: 326 Stanislavov R, Nikolova V. Dokl Bolg Akad Nauk 2000; 53: 107 Tiralongo E et al. Evid Based Complement Alternat Med 2012; 2012: 417267 Viktorov IV et al. MBI: Medicobiologic Information 1982, cited in Zarkova S. Tribestan: Experimental and Clinical Investigations. Chemical Pharmaceutical Research Institute, Sofia, Bulgaria. Wagner H. Z Phytother 1996; 17: 79-95 Weinstein SJ, Hartman TJ, Stolzenberg-Solomon R, et al. (November 2003). "Null association between prostate cancer and serum folate, vitamin B(6), vitamin B(12), and homocysteine". Cancer Epidemiol. Biomarkers Prev. 12 (11 Pt 1): 1271–2. PMID 14652294. Zarkova S. Tribestan: Experimental and Clinical Investigations. Chemical Pharmaceutical Research Institute, Sofia, Bulgaria.