herbal products (phytochemicals) - virginia commonwealth university

Herbal Products (Phytochemicals)

Aron H. Lichtman, Ph.D.Associate Professor

Pharmacology and Toxicology

Learning Objectives1. Know Dietary Supplement Health and Education Act

of 1994.2. Know issues involved in evaluating efficacy and side

effects of herbal products.3. Know the uses, potential side-effects, MOAs (if

known), and relevant interactions of: Black Cohosh, Chamomile, Echinacea, Feverfew, Garlic, Ginger, Ginkgo biloba, Ginseng, Green Tea, St. John’s Wort, Saw Palmetto, Valerian.

4. Be familiar with the dangers of: Chaparral, Comfrey, Slimming/dieter's teas, Ephedra (AKA Ma huang), Germander, Kava Kava, Lobelia, Magnolia-Stephania preparation, Willow bark, Wormwood, and Yohimbe.

Public’s Perception of Herbals• Natural products are intrinsically safe

• Sold without a Rx

• Products are reviewed & approved by the FDA

• No warning labels on the products

Current Position and Public KnowledgeCurrent Position and Public Knowledgeof Herbal Medicine in the USAof Herbal Medicine in the USA

Based on data published in JAMA in 1998, • 42.1% of adult Americans use alternative medicine,

12.1% in herbal medicine;• 52% think that supplement and herb are good for people’s

health and wellbeing; • 56% are very familiar or somewhat familiar with alternative

medicine including herbal medicine.• 23% physicians believe herbal medicine is effective

In the USA, patients are increasingly seeking to identify a physician who is solidly grounded in conventional medicine, is also knowledgeable about the value and limitations of alternative treatments.

What Is a Dietary Supplement?Defined in Dietary Supplement Health and Education Act (DSHEA) of 1994.

Product taken by mouth containing "dietary ingredient" to supplement diet.

“Dietary ingredients": vitamins, minerals, herbs/other botanicals, amino acids, and other substances (e.g., enzymes, organ tissues, glandulars, metabolites).

Dietary supplements can also be extracts or concentrates, tablets, capsules, softgels, gelcaps, liquids, or powders.

They can also be in other forms, such as a bar, but if they are, information on their label must not represent the product as a conventional food or a sole item of a meal or diet.

Dietary supplements are in a special category under the general umbrella of "foods," not drugs, and requires that every supplement be labeled a dietary supplement.

Legal Status of Herbal Products

Different set of FDA regulations than those covering "conventional" food and drug products (prescription and OTC).

Generally not patentable • natural products have long history of use for medical

applications• rigorous evaluation of safety and efficacy usually lacking

Dietary Supplement Health and Education Act of 1994 (DSHEA)

A. Manufacturer • responsible for ensuring dietary supplement is safe before marketing.• ensures product label information is truthful and not misleading.• generally, does not need to register with FDA nor get FDA approval

before producing or selling dietary supplements.

B. FDA • responsible for taking action against any unsafe dietary supplement

product after it reaches the market. • post-marketing responsibilities include monitoring safety (e.g. voluntary

dietary supplement adverse event reporting, and product information, e.g. labeling, claims, package inserts, and literature).

C. The Federal Trade Commission• regulates dietary supplement advertising.

How Do Herbs Differ From Drugs?

• Not in our education or experience• Different FDA categories• Constituents - very complex• Plant constituents vary

– Soil, weather, storage, manufacturing process• Active ingredient often unknown• Several constituents may be responsible for effects• Not pure• Unknown pharmacology & toxicology• Nonstandard indications

Problems: Evaluation and Use of Herbal Products• Few properly conducted studies of safety and effectiveness and lack

of long-term studies “natural” does not equal “safe”• avoid in children, elderly, people with chronic diseases• lack of reproductive studies - avoid in pregnant and nursing women• Identification of active constituents (or “balance” of constituents) • Standardization/comparison of products on basis of active

constituents is preferable to quantifying plant material• Manufacturing practices

– widely variable across industry– quality control often lacking

Toxicological Concerns

•Poisonings

•Allergies

•Adverse reactions

•Herb-drug interactions

•Contamination

Overall Caveats• FDA does not evaluate herbal products for safety, effectiveness, or

purity. • Most potential risks and / or advantages are unknown. • No regulated manufacturing standards. • Herbal / health supplements have been contaminated with toxic

metals or other drugs. • Herbal / health supplements should be purchased from a reliable

source to minimize the risk of contamination.• Talk to your doctor if you are pregnant or could become pregnant. • Teratological effects are unknown.• Do not take without first talking to your doctor if breast-feeding.• Do not give to a child without first talking to the child's doctor.

Questions to Ask Patients Who May Be Taking Herbal Products

Are you taking an herbal product, herbal supplement or other "natural remedy?"

If so, are you taking any prescription or nonprescription medications for the same purpose as the herbal product?

Have you used this herbal product before?

Are you allergic to any plant products?Are you pregnant or breast-feeding?

CENTERS FOR COMPLEMENTARY AND CENTERS FOR COMPLEMENTARY AND ALTERNATIVE MEDICINE RESEARCHALTERNATIVE MEDICINE RESEARCH

Release Date: November 29, 1999

PURPOSE Despite the broad use of complementary and alternative medicine (CAM) treatments (Eisenberg et al., 1998) there is a relative paucity of data available to demonstrate convincingly the safety, efficacy, effectiveness and mechanisms of these CAM practices. A similar conclusion was reached in a 1990 report on unconventional cancer treatments by the U.S. Office of Technology Assessment. This report urges a systematic analysis of alternative treatments and their effect on major disease, health and wellness (U.S. Office of Technology Assessment, OTA-H-405, 1990, p.225).

NIH Funded 58 Grants With the Key Word Herbal During this Fiscal Year

LEE, YUE-WEIProject 1 - Chemistry & In Vitro Studies of Chinese Herbal Remedies

LI, XIU-MIN Effect of Chinese herbal medicine on food allergy

LUKAS, SCOTT Project 4 - Chinese Herbal Medicine to Treat Alcohol & Drug Abuse

LEE, YUE-WEI Alternative Therapies for Alcohol and Drug AbuseLI, XIU-MIN Center for Chinese Herbal Therapy (CHT) for Asthma

PIERSON, JULIANN Dietary Supplements and CAM Use in Breast Cancer Survivors

BALICK, MICHAEL Dominican Herbal Medicine: Plants Used for InflammationBENT, STEPHEN Early Identification of Adverse Reactions to Herbs

BERMAN, BRIAN Project 2 - Chinese Herbal Formula for the Treatment of Functional Bowel Disorder

BERMAN, BRIAN Project 3 - A Dose-Ranging Study of Chinese Herbal Medicine in Treating Patients

Black Cohosh (Cimicifuga racemosa)Uses

•Rheumatism (arthritis and muscle pain)•Alleviates menopausal symptoms (hot flashes, night sweats, vaginal dryness)•Eases menstrual discomfort

Do not take if ever been diagnosed with breast cancer

Overdose symptoms might include nausea•Dizziness•Seizures•Visual disturbances •Reduced pulse rate•Increased perspiration•stomach upset (common side effect with therapeutic doses)

.

Newton, K. M. et. al. Ann Intern Med 2006;145:869-879

Adjusted mean number of vasomotor symptoms per day, by study group

Black Cohosh Fails to Reduce Vasomotor Black Cohosh Fails to Reduce Vasomotor Symptoms Associated with MenapauseSymptoms Associated with Menapause

EchinaceaPURPORTED USESPURPORTED USES

•Common cold•Immunostimulation•Infections•Viral infections•Wound healing

Not recommended for use by people with multiple sclerosis, white blood cell disorders, collagen disorders, HIV / AIDS, autoimmune disorders, or tuberculosis.

Echinacea: Side Effects & Drug Interactions

Do not use different formulations together because of overdose risk

Side Effects•Fever•Nausea or vomiting•Allergic Reactions

May alter actions of other medicines that affect the immune system

•Steroids (e.g., betamethasone, dexamethasone, cortisone)•Cyclosporine •Methotrexate•Other immune system suppressants.

In Vitro EffectsIn Vitro Effects• stimulates phagocytosis• enhances mobility of leukocytes• stimulates TNF and interleukin 1 secretion from

macrophages and lymphocytes• improves respiratory activity• Non-specific T cell activation may occur via binding of the

polyacetylene fraction of echinacea binding to cell surface carbohydrate receptors resulting in antiviral and immunostimulant activity

• May also have antiinflammatory, local anesthetic, and antibacterial activity

Copyright restrictions may apply.

Yale, S. H. et al. Arch Intern Med 2004;164:1237-1241.

Echinacea failed to reduce cold durationEchinacea failed to reduce cold duration

Echinacea Failed to Improve URIs in Echinacea Failed to Improve URIs in ChildrenChildren

Efficacy and Safety of Echinacea in Treating Upper Respiratory Tract Infections in Children A Randomized Controlled Trial

Taylor et al., JAMA. 2003;290:2824-2830.

Feverfew (Tanacetum parthenium)Uses•Prevention of migraine headaches.•Prevention and treatment of asthma, rheumatoid arthritis, painful menstrual periods, inflammatory skin conditions such as psoriasis, toothache, and insect bites.

Potential Drug Interations•warfarin (Coumadin)•aspirin; NSAIDs (e.g. ibuprofen, naproxen)

Side effects•Allergic reactions •Dry or sore tongue, loss of taste, unpleasant taste•Indigestion, flatulence,nausea or vomiting.•Following discontinuation: nervousness, tension headache, insomnia, stiffness, joint pain, and tiredness

Feverfew Uses Based on Scientific Evidence Grade*Migraine headache preventionFeverfew is often taken by mouth for the prevention of migraine headaches. Laboratory studies show that feverfew can reduce inflammation and prevent blood vessel constriction (squeezing) that may lead to headaches. Most of the available human studies are not high quality, and report mixed results. However, overall they dosuggest that feverfew may reduce the number of headaches that occur in people with frequent migraines. A large, well-designed study comparing feverfew to other migraine treatments is needed before a strong recommendation can be made.

B

Rheumatoid arthritisIt is not clear if feverfew if helpful for treating rheumatoid arthritis symptoms such as joint stiffness or pain.

C

*Key to grades A: Strong scientific evidence for this use; B: Good scientific evidence for this use; C: Unclear scientific evidence for this use; D: Fair scientific evidence against this use; F: Strong scientific evidence against this use.

Uses:• Enhances memory in Alzheimer's and age-related dementias•• No memory enhancement in healthy individuals > 60 years No memory enhancement in healthy individuals > 60 years

(JAMA, 8/21/03).(JAMA, 8/21/03).• Enhances cerebral and ocular blood flow.• Alleviates congestive symptoms of premenstrual syndrome.• Prevention of altitude sickness. • Treatment of cerebrovascular dysfunctions and peripheral vascular

disorders.

Ginkgo biloba• Active constituents of leaves:

flavonoid glycosides and ginkgolides

• Potent antioxidant• Enhances peripheral, cerebral, and

ocular circulation

Ginkgo Side Effects & Drug Interactions

Drug Interactions• warfarin (Coumadin)• aspirin• NSAIDs (e.g., ibuprofen,

naproxen)• heparin• antioxidants

Overdose • seizures• a loss of consciousness• possibly death.

Serious Side Effects• allergic reaction • irregular heartbeats• muscle spasms or cramps;• seizures• loss of consciousness

Less Serious Side Effects• headache• dizziness• stomach upset

Ginkgo seeds and fruit pulp are toxic, can cause a severe reactiGinkgo seeds and fruit pulp are toxic, can cause a severe reaction on including skin redness, swelling, blistering, and itching for 7including skin redness, swelling, blistering, and itching for 7--10 10 days days

Ginkgo Uses Based on Scientific Evidence Grade*

Claudication (painful legs from clogged arteries)Numerous studies suggest that Ginkgo biloba taken by mouth causes small improvements in claudication symptoms (leg pain with exercise or at rest due to clogged arteries). However, ginkgo may not be as helpful for this condition as exercise therapy or prescription drugs. Additional evidence is needed.

A

Dementia (multi-infarct and Alzheimer's type)The scientific literature overall does suggest that ginkgo benefits people with early stage Alzheimer's disease and multi-infarct dementia, and may be as helpful as acetylcholinesterase inhibitor drugs such as donepezil (Aricept®). Well-designed research comparing ginkgo to prescription drug therapies is needed.

A

Cerebral insufficiencyMultiple clinical trials have evaluated ginkgo for a syndrome called "cerebral insufficiency." This condition, more commonly diagnosed in Europe than the United States, may include poor concentration, confusion, absent-mindedness, decreased physical performance, fatigue, headache, dizziness, depression, and anxiety. It is believed that cerebral insufficiency is caused by decreased blood flow to the brain due to clogged blood vessels. Some research reports benefits of ginkgo in patients with these symptoms, but most have been poorly designed without reliable results. Better studies are needed before a strong recommendation can be made.

B

Acute hemorrhoidal attacksIn early study ginkgo was shown to be effective in the treatment of patients with acute hemorrhoidal attacks. Further research is needed to confirm these results.

C

Age-associated memory impairment (AAMI)Age-associated memory impairment (AAMI) is a non-specific syndrome, which may be caused by early Alzheimer's disease or multi-infarct dementia (conditions for which ginkgo has been shown to have benefit). There is preliminary research showing small improvements in memory and other brain functions in patients with AAMI, although some studies disagree. Overall, there is currently not enough clear evidence to recommend for or against ginkgo for this condition.

C

Ginkgo Uses Based on Scientific Evidence (continued) Grade*

Altitude (mountain) sicknessA small amount of poorly designed research reports benefits of ginkgo for the treatment of altitude (mountain) sickness. Additional study is needed before a recommendation can be made.

C

Chemotherapy side effects reductionIn limited human study, ginkgo has been examined in addition to 5-fluorouracil (5-FU) in the treatment of pancreatic and colorectal cancer, to measure possible benefits on side effects. At this time, there is not conclusive evidence in this area.

C

Deafness (cochlear)Preliminary clinical study has been conducted on the effect of ginkgo in chronic cochleovestibular disorders. Further research is needed before a recommendation can be made.

C

Depression and seasonal affective disorder (SAD)Preliminary study of seasonal affective disorder (SAD) suggests that ginkgo is not effective in preventing the development of winter depression. Other research in elderly patients with depression shows possible minor benefits. Overall, there is not enough evidence to form a clear conclusion.

C

Gastric cancerGinkgo biloba exocarp polysaccharides (GBEP) capsule preparation has been studied for upper

digestive tract malignant tumors of middle and late stage with positive results. However, further research is needed before a recommendation can be made.

C

GlaucomaSeveral small human studies report ginkgo may be associated with mild increases in blood flow to the eyes, vision and intraocular pressure. Well-designed research is needed before a recommendation can be made.

C

Macular degenerationPreliminary research suggests that ginkgo may improve eye blood flow, although it remains unclear if macular degeneration is significantly affected by ginkgo. More research is needed in this area before a conclusion can be drawn.

C

Ginseng: Ancient Remedy, Modern Medicine?

GinsengUses• cancer preventive• alleviation of menopausal

symptoms (hotflashes)• anti-inflammatory• improve the body's resistance• increase vitality• increased immune function• treatment of cardiovascular

diseases• improvement of cognition• enhanced physical performance • enhanced sexual function

Butefficacy of ginseng could not be established beyond doubt for any of these indications

Do not take • bleeding or blood clotting disorder• diabetes• high blood pressure or heart disease• perioperatively

Drug Interactions• any heart or blood pressure

medicines• medicine controlling blood

sugar(e.g., insulin, glipizide, glyburide)

• warfarin • aspirin• NSAIDs (e.g., ibuprofen, naproxen)• heparin

Ginseng Side Effects

Side Effects• Sleeplessness• muscle tension• swelling or fluid

retention• headache• gastrointestinal

disorders

Gingsing Uses Based on Scientific Evidence Grade*

Mental performanceSeveral studies report that ginseng can modestly improve thinking or learning. Mental performance has been assessed using standardized measurements of reaction time, concentration, learning, math, and logic. Benefits have been seen both in healthy young people and in older ill patients. Effects have also been reported for the combination use of ginseng with Ginkgo biloba . However, some negative results have also been reported. Therefore, although the sum total of available scientific evidence does suggest some effectiveness of short-term use of ginseng in this area, better research is necessary before a strong recommendation can be made.

B

Type 2 diabetes (adult-onset) Several human studies report that ginseng may lower blood sugar levels in patients with type 2 diabetes. Long-term effects are not clear, and it is not known what doses are safe or effective. People with diabetes should seek the care of a qualified healthcare practitioner, and should not use ginseng instead of more proven therapies. Effects of ginseng in type 1 diabetes ("insulin dependent") are not well studied.

B

Cancer preventionA small number of studies report that ginseng taken by mouth may lower the risk of being affected by various cancers, especially if ginseng powder or extract is used. Study results are controversial. Additional trials are necessary before a clear conclusion can be reached.

C

Chronic obstructive pulmonary disease (COPD)Ginseng was reported to improve pulmonary function and exercise capacity in patients with COPD in one study. Further research is needed to confirm these results.

C

Congestive heart failureEvidence from a small amount of research is unclear in this area. CCoronary artery (heart) diseaseSeveral studies from China report that ginseng in combination with various other herbs may reduce symptoms of coronary artery disease. Without further evidence of the effects of ginseng specifically, a firm conclusion cannot be reached.

C

Gingsing Uses Based on Scientific Evidence (continued) Grade*

Exercise performanceGinseng is commonly used by athletes with the intention of improving stamina. However, it remains unclear if ginseng taken by mouth significantly affects exercise performance. Numerous studies have been published in this area, with mixed results. Better studies are necessary before a clear conclusion can be reached.

C

FatigueA small amount of research using ginseng extract G115® (with or without multivitamins) reports improvements in patients with fatigue of various causes. However, these results are preliminary, and studies have not been high quality.

C

Fistula (anal)Preliminary evidence in infants with peri-anal abscess or fistula-in-ano suggests that a treatment of GTTC (Ginseng and Tang-kuei Ten Combination) may accelerate recovery. Further research is needed to confirm these results.

C

High blood pressurePreliminary research suggests that ginseng may lower blood pressure (systolic and diastolic). It is not clear what doses may be safe or effective. Well-conducted studies are needed to confirm these early results.

C

Immune system enhancementA small number of studies report that ginseng may stimulate activity of immune cells in the body, improve the effectiveness of antibiotics in people with acute bronchitis, and enhance the body's response to influenza vaccines. Additional studies are necessary before a clear conclusion can be reached.

C

Intracranial pressure (ICP)Preliminary study of Xuesaitong injection (XSTI, a preparation of Panax notoginseng ) reports that it may help to decrease intracranial pressure and benefit coma patients. Further study is needed to confirm these results.

C

Gingsing Uses Based on Scientific Evidence (continued) Grade*

Low white blood cell countsPoorly described preliminary research reports improved blood counts in patients with aplastic anemia using ginseng in combination with other herbs, and improved white blood cell counts in patients with neutropenia using high doses of ginsenosides. Reliable studies are needed before a conclusion can be reached. Notably, there are reports of blood cell counts dropping after ginseng use.

C

Menopausal symptomsEvidence from a small amount of research is unclear in this area. Some studies report improvements in depression and sense of well-being, without changes in hormone levels.

C

Methicillin-resistant Staphylococcus aureus (MRSA)In patients treated with Hochu-ekki-to, which contains ginseng and several other herbs, urinary MRSAhas been reported to decrease after a 10-week treatment period. Further study of ginseng alone is necessary in order to draw firm conclusions.

C

Multi-infarct dementiaA small study conducted in patients with multi-infarct dementia reports that an herbal combination known as Fuyuan mixture, which contains ginseng, may have therapeutic benefits. The effects of ginseng alone are not clear, and no firm conclusion can be drawn.

C

Quality of lifePreliminary research of Siberian ginseng ( E. senticosus ) administration in the elderly suggests that some aspects of mental health and social functioning (and overall health-related quality of life) may improve after four weeks of therapy, although differences appear to attenuate with continued use. Additional study is necessary in this area before a firm conclusion can be reached.

C

Sense of well-beingSeveral studies have examined the effects of ginseng (with or without multivitamins) on overall well-being in healthy and ill patients, when taken for up to 12 weeks. Most trials are not high quality, and results are mixed. However, it remains inconclusive if ginseng is beneficial in this area for anybody.

C

Viral myocarditisPoorly described research in patients treated with a ginseng preparation. More in-depth and reliable studies are needed before a clear conclusion can be drawn.

C

Green TeaGreen Tea

ConstituentsConstituentsCaffeineFlavonoids, theaflavinMethylxanthines: Theophylline,

theobromine, and theaninePolyphenols: Gallic acid and catechins:

gallocatechin (GC), epigallocatechin (EGC), epicatechin (EC), and epigallocatechin gallate (EGCG)

PolysaccharidesProanthocyanidins (tannins)Vitamins: Ascorbic acid, tocopherolOther: Fluoride, chlorophyll, organic

acids

Purported UsesPurported UsesCancer preventionCancer treatmentCardiovascular diseaseCognitive improvementGI disordersHypertensionWeight loss

Green Tea Uses Based on Scientific Evidence Grade*

ArthritisResearch indicates that green tea may benefit arthritis by reducing inflammation and slowing cartilage breakdown. Further studies are required before a recommendation can be made.

C

AsthmaResearch has shown caffeine to cause improvements in airflow to the lungs (bronchodilation). However, it is not clear if caffeine or tea use has significant benefits in people with asthma. Better research is needed in this area before a conclusion can be drawn.

C

Cancer prevention Overall, the relationship of green tea consumption and human cancer remains inconclusive. Evidence from well-designed clinical trials is needed before a firm recommendation can be made in this area.

C

Dental cavity preventionThere is limited study of tea as a gargle (mouthwash) for the prevention of dental cavities (caries). It is not clear if this is a beneficial therapy.

C

DiabetesMore studies are required to determine if green tea, and polyphenols, have any therapeutic benefit for diabetes prevention or treatment.

C

FertilityEarly research using a combination product called FertilityBlend has been associated with some success in helping women to conceive. Further well-designed research on green tea alone for this use is needed before a conclusion can be drawn.

C

Heart attack preventionThere is early suggestive evidence that regular intake of green tea may reduce the risk of heart attack or atherosclerosis (clogged arteries). Further well-designed clinical trials are needed before a recommendation can be made in this area.

C

Green Tea Uses Based on Scientific Evidence (continued) Grade*

High cholesterol or triglyceridesLaboratory, animal studies and limited human research suggest possible effects of green tea on cholesterol and triglyceride levels. Better human evidence is necessary in this area.

C

Memory enhancementSeveral preliminary studies have examined the effects of caffeine, tea, or coffee use on short and long-term memory. It remains unclear if tea is beneficial for this use.

C

Menopausal symptoms A study conducted in healthy postmenopausal women showed that a morning/evening menopausal formula containing green tea was effective in relieving menopausal symptoms including hot flashes and sleep disturbance. Further studies are needed to confirm these results.

C

Mental performance/alertnessLimited, low-quality research reports that the use of green tea may improve cognition and sense of alertness. Green tea contains caffeine, which is a stimulant.

C

Prostate cancer (treatment)One clinical trial showed minimal benefit using green tea extract capsules for the treatment of hormone refractory prostate cancer. Further research is needed before a recommendation can be made.

C

Sun protection/ skin damageThere is limited animal and human study of green tea as a protective agent of skin from ultraviolet light skin injury. Some study results conflict. Comparisons have not been made with well-established forms of sun protection such as ultraviolet protective sunscreen. The effects of green tea on skin damage caused by the sun remain unclear.

C

Green Tea Uses Based on Scientific Evidence (continued) Grade*

Weight loss (maintenance)There are several small human studies addressing the use of green tea extract (GTE) capsules for weight loss or weight maintenance in overweight or average weight individuals. Study results are mixed. Better research is needed before a recommendation can be made in this area.

C

AnxietyL-theanine is a predominant amino acid found in green tea. Preliminary research exists on the effects of this amino acid in comparison with the prescription drug alprazolam on experimentally induced anxiety. No benefit was found.

D


Adverse ReactionsAdverse Reactions

Nausea and GI upset, possibly due to tannin content.

Insomnia, irritability, and nervousness can occur due to caffeine content.

Saw Palmetto (Serenoa repens)Uses

• Benign prostatic hypertrophy (BPH)• Relieve difficult urination that may be associated with BPH • Relieve the symptoms of an irritable bladder

Side effects • Allergic reactions (uncommon)• Cramping• Nausea• Diarrhea• Headache

Do not take this medication without first talking to your doctor if

• Cancer of the prostate• Breast cancer• Other sex hormone-related disease or disorder• Pregnant (may alter hormonal activity)

Saw Palmetto Does Not Improve Benign Saw Palmetto Does Not Improve Benign Prostatic Hyperplasia Symptoms*Prostatic Hyperplasia Symptoms*

*N Eng J Med. 2006 Feb 9;354(6):557-66

Purported Mechanisms of ActionPurported Mechanisms of ActionAntiandrogenic

liposterolic extract of the berries reduced the uptake of both testosterone and DHT(dihydrotestosterone) by more than 40%does not induce changes in the level of testosterone or other hormones in the plasma itself. reduces the conversion of less active testosterone to the more active DHT by inhibiting the enzyme steroid 5 alpha reductase.

antiandrogenic properties, anti-inflammatory and antiedematous activityinhibition of the cyclooxygenase and 5-lipoxygenase pathways thereby preventing the biosynthesis of inflammation-producing prostaglandins and leukotrienes.

St. John’s Wort (Hypericum perforatum)

Uses•treatment of anxiety

mild to moderate depression•stomach upset•Insomnia•fluid retention•hemorrhoids

Topical uses•nerve and muscle pain•skin inflammation•skin wounds•burns

St. John's Wort Uses Based on Scientific Evidence Grade*

Depressive disorder (mild-to-moderate)St. John's wort has been extensively studied in Europe over the last two decades, with more recent research in the United States. Short-term studies (1-3 months) suggest that St. John's wort is more effective than placebo (sugar pill), and equally effective as tricyclic antidepressants (TCAs) in the treatment of mild-to-moderate major depression. Comparisons to the more commonly prescribed selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine (Prozac®) or sertraline (Zoloft®), are more limited. However, other data suggest that St. John's wort may be just as effective as SSRIs with fewer side effects. Safety concerns exist as with most conventional and complementary therapies.

A

Anxiety disorderOverall, there is currently not enough evidence to recommend St. John's wort for the primary treatment of anxiety disorders.

C

Atopic dermatitisEarly study of hypericum-cream in the topical treatment of mild to moderate atopic dermatitis shows positive results. Further studies are needed before a firm recommendation can be made.

C

Depressive disorder (severe)Studies of St. John's wort for severe depression have not provided clear evidence of effectiveness.

C

Obsessive-compulsive disorder (OCD)There are a few reported cases of possible benefits of St. John's wort in patients with obsessive-compulsive disorder (OCD). Currently there is not enough scientific evidence to recommend St. John's wort for this condition.

C

Peri-menopausal symptomsThere is currently not enough scientific evidence to recommend St. John's wort for this indication. C

St. John's Wort Uses Based on Scientific Evidence (continued) Grade*

Premenstrual syndrome (PMS)Further studies are needed before a recommendation can be made. CSeasonal affective disorder (SAD)Despite some promising early data, there is currently not enough evidence to recommend St. John's wort for depressive disorder with seasonal pattern or Seasonal Affective Disorder (SAD).

C

Human immunodeficiency virus (HIV)Anti-viral effects of St. John's wort have been observed in laboratory studies, but were not found in one human study. Multiple reports of significant adverse effects and interactions with drugs used for HIV/AIDS, including protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), suggest that patients being treated for HIV/AIDS should avoid this herb. Therefore, there is evidence to recommend against using St. John's wort in the treatment of patients with HIV/AIDS.

D

Social phobiaResults of early study fail to provide evidence for the efficacy of St. John's wort in social phobia. D


St. JohnSt. John’’s Wort Side Effects and Warningss Wort Side Effects and WarningsSide Effects

•increased skin sensitivity to sunlight•rash•a feeling of fullness in stomach•constipation

Drugs to Avoid•MAO inhibitors (e.g., Nardil, Parnate) •serotonin reuptake inhibitors (e.g., Prozac, Paxil, Zoloft)•tricyclic antidepressants (e.g., Elavil, Norpramin, Tofranil)

•bupropion (Wellbutrin, Zyban)•HIV / AIDS protease inhibitors (e.g., Crixivan, Norvir)•HIV / AIDS nonnucleoside reverse transcriptase inhibitors (e.g., Rescriptor, Viramune).

•Do not take perioperatively

Purported Mechanisms of ActionPurported Mechanisms of Action

Antidepressant activity: • Hypericin (MAO inhibitor)?• Weak inhibition of catechol-O-methyl-transferase

(COMT) and limited reuptake of norepinephrine: whole plant extract

• Inhibits the reuptake of serotonin, dopamine, norepinephrine, GABA, and L-glutamine: Hyperforin

Analgesic and CNS activity: bioflavonoid content.

Valerian (Valerian officinali)Uses

•Anxiety•Restlessness•Insomnia•mental strain•lack of concentration•Reduces excitability•Stress•Headache•Nervous stomach cramps•Uterine spasticity•Menopause•Pain•Emotional distress that may occur with menstruation

Side Effects•Headache•Excitability•Restlessness or uneasiness•Sleeplessness•Dilated pupils•Irregular heartbeats or other heart problems•Allergic reactions

Valerian Uses Based on Scientific Evidence Grade*

InsomniaSeveral studies in adults suggest that valerian improves the quality of sleep and reduces the time to fall asleep (sleep latency), for up to four to six weeks. Ongoing nightly use may be more effective than single-dose use, with increasing effects over four weeks. Better effects have been found in poor sleepers. However, most studies have not used scientific ways of measuring sleep improvements, such as sleep pattern data in a sleep laboratory.

B

Anxiety disorderSeveral studies of valerian have reported benefits in reducing non-specific anxiety symptoms. Valerian has also been given in combination with other herbs, such as passionflower and St. John's wort to treat anxiety. However, most studies have been small and poorly designed. More research is needed before a recommendation can be made.

C

Sedation Although valerian has not been studied specifically as a sedative, evidence from studies conducted for other purposes suggests that valerian may not have significant sedative effects when used at recommended doses. Therefore, even though valerian could be helpful as a sleep aid, it does not appear to cause sedation.

D


Severe Adverse Events: Examples

•HepatotoxicityKava KavaGermanderChaparralComfrey

•Strokes ma hungyohimbe

Kava (Piper methysticum)Uses • induce and improve sleep• decrease anxiety, nervousness, stress, and

restlessness

Interacts with substances that cause drowsiness

• antidepressants• alcohol, sedatives• pain relievers• anxiety medicines• muscle relaxants

Overdose Symptoms• tiredness• Sleepiness• poor coordination

Consumer Advisory (3/25/02): Kava Dietary Supplements

Associated with liver-related injuries – including hepatitis, cirrhosis, and liver failure.

Symptoms include jaundice and brown urine; also nausea, vomiting, light-colored stools, unusual tiredness, weakness, stomach or abdominal pain, and loss of appetite.

Consumers who use a kava-containing dietary supplement and who experience signs of illness associated with liver disease should also consult their physician.

Persons who have liver disease or liver problems, or persons who are taking drug products that can affect the liver, should consult a physician before using kava-containing supplements.

FDA urges consumers and their health care professionals to report any cases of liver and other injuries that may be related to the use of kava-containing dietary supplements.

Ma huang (Ephedra)•Also called squaw tea and Mormon tea of the genus Ephedra.

•Contains various chemical stimulants (e.g., ephedrine, pseudoephedrine and norpseudoephedrine) that are amphetamine-like chemicals used in OTC and prescription drugs, as well as various tannins and related chemicals. The concentrations of these alkaloids varies between species of Ephedra.

•Products often contain other stimulants (e.g., caffeine) which may increase the potential for adverse effects.

•Serious adverse effects, including hypertension, palpitation, neurophathy, myopathy, psychosis, stroke, and memory loss, have been reported to FDA with products containing Ma huang as ingredients.

Ma huang (Ephedra) Purported Uses

• Asthma• Bronchitis • Common cold• Cough• Infections• Promote urination• Strength and

stamina• Weight loss

Ma Huang: Drug Interactions

Aspirin: May increase risk of cerebral hemorrhage.Benzodiazepines and other sedatives: Effects may

be antagonized by ephedra.Beta-adrenergic agonists: may potentiate effects of

beta-adrenergic agonists.CNS stimulants: May increase stimulatory effects.Monoamine-oxidase inhibitors (MAO-I):

Concomitant use can cause hypertensive crisis.Theophylline: May increase stimulatory effects.Digoxin: Concomitant use can cause arrhythmia.

FDA Issues Regulation Prohibiting Sale of FDA Issues Regulation Prohibiting Sale of Dietary Supplements Containing Ephedrine Dietary Supplements Containing Ephedrine

Alkaloids and Reiterates Its Advice That Alkaloids and Reiterates Its Advice That Consumers Stop Using These ProductsConsumers Stop Using These Products

The Food and Drug Administration (FDA) today issued a final ruleprohibiting the sale of dietary supplements containing ephedrinealkaloids (ephedra) because such supplements present an unreasonable risk of illness or injury. The rule will become effective 60 days from the date of publication.

"This FDA rule reflects what the scientific evidence shows - that ephedra poses an unreasonable risk to those who use it," Health and Human Services Tommy G. Thompson said. "The regulations prohibit the sale of dietary supplements containing ephedra, and we intend to take swift action against anyone who puts consumers at risk by continuing to sell such products after the prohibition takes effect.“

FDA News: February 6, 2004

Comfrey (Symphytum officinale)• Internal uses: stomach upset, stomach ulcers, hemorrhoids, and

diarrhea • External uses: bruises, sprains, burns, and swelling • Used as a mouthwash and gargle for gum disease and sore throats.• Contains pyrrolizidine alkaloids, that are firmly established to be

hepatotoxins in animals. • Comfrey and pyrrolizidine alkaloids associated with veno-occlusive

disease (VOD), toxicity to other tissues, and are carcinogens.• The adverse effects are entirely consistent with the known effects of

comfrey ingestion described in the scientific literature. • Should not be used as an ingredient in dietary supplements• Federal Trade Commission (FTC) brought an enforcement action

against a firm for marketing comfrey-containing products.• FDA advises removal of comfrey products from the market (7/6/01)

Yohimbe (Pausinystalia yohimbe)

From tree bark.

Major alkaloid is yohimbine (an α2 adrengergic antagonist)

Used for body building and "enhanced male performance."

Increases blood pressure and heart rate.

Serious adverse effects, including renal failure, seizures and death, have been reported to FDA with products containing yohimbe and are currently under investigation.

Side effects include central nervous system stimulation that causes anxiety attacks.

At high doses inhibits monoamine oxidase (MAO) inhibitor, so serious adverse effects when taken with tyramine-containing foods (e.g., liver, cheeses, red wine).

Should be avoided by individuals with hypertension, diabetes, and heart, liver or kidney disease.

Symptoms of overdosage include weakness and nervous stimulation followed by paralysis, fatigue, stomach disorders, and ultimately death.

Lobelia (Lobelia inflata)Also known as Indian tobacco, contains pyridine-derived alkaloids, primarily lobeline.

Pharmacological actions similar to, though less potent than, nicotine.

Can cause either autonomic nervous system stimulation or depression.

Low doses produce bronchial dilation and increased respiratory rate.

Higher doses result in respiratory depression, as well as sweating, rapid heart rate, hypotension, and even coma and death. As little as 50 milligrams of dried herb or a single milliliter of lobelia tincture has caused these reactions.

Because of its similarity to nicotine, may be dangerous to susceptible populations, including children, pregnant women, and individuals with cardiac disease. But still found in dietary supplements that are marketed for use by children and infants, pregnant women, and smokers.

Willow Bark (Salix species)• Long history of use as a pain reliever

• Little actual research has been done

• Used for its analgesic, antirheumatic, and antipyretic (fever-reducing) properties.

• The pharmacologically active component in willow bark is "salicin,", which like Aspirin (acetylsalicylic acid) is converted to salicylic acid after ingestion.

• Although promoted as an "aspirin-free" analgesic, including in dietary supplement products for children, it shares the same chemical properties and the same adverse effects as aspirin.

Willow Bark Toxicity• The "aspirin-free" claim is particularly dangerous on products marketed,

without warning labels, for use by children and other aspirin-sensitive individuals.

• Major adverse effects: irritation of the gastric mucosa, Pregnancy (including stillbirth, bleeding, prolonged gestation and labor, and low-birth-weight infants), Reye syndrome.

• Salicylate intoxication (headache, dizziness, ringing in ears, difficulty hearing, dimness of vision, confusion, lassitude, drowsiness, sweating, hyperventilation, nausea, vomiting, and central nervous system disturbances in severe cases) may occur as the result of over-medication, or kidney or liver insufficiency.

• Hypersensitivity (approximately 5% population): itching, broncho-spasm and localized swelling (which may be life-threatening), can occur with very small doses of salicylates, and may occur even in those without a prior history of sensitivity to salicylates.

Learning Objectives1. Describe the legal status and regulation of herbal

products.2. Know issues involved in evaluating efficacy and side

effects of herbal products.3. Know the uses, potential side-effects, MOAs (if

known), and relevant interactions of: Black Cohosh, Chamomile, Echinacea, Feverfew, Garlic, Ginger, Ginkgo biloba, Ginseng, Green Tea, St. John’s Wort, Saw Palmetto, Valerian.

4. Be familiar with the dangers of: Chaparral, Comfrey, Slimming/dieter's teas, Ephedra (AKA Ma huang), Germander, Kava Kava, Lobelia, Magnolia-Stephania preparation, Willow bark, Wormwood, and Yohimbe.

herbal products (phytochemicals) - virginia commonwealth university

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