Chapter 2  Section 2: Top Ten Herbals Products used in the United States

Section 2

Top Ten Herbals Products used in the United States

Word Drug links to herbal healing, this came from German meaning drogue which means to dry herbs.   This is the first step in processing herbs into medicines.  

Brief History:

US Pharmacopeia is a standard drug reference established in 1820. Approximately two-thirds of the reference included botanicals. In 1880, approximately 3/4th were botanicals; which was a little over 100 herbs.  Then in the 19th century, medication was laced with alcohol, cocaine, and even heroin. Due to that action, required drug regulation.  But when Jungle an expose on meat packing industry to convince congress to establish the Food and Drug Admission in 1928.  The role is to address adulteration and mislabeling of food and drugs.  In 1937, Sulfanilamide killed 107 people due to toxicity, and in 1959 Thalidomide caused over 8000 toxic effects on European infants.  That was when the FDA became more stringent in enforcement and the Food, Drug and Cosmetic Act in 1938 was established to provide our first United States drug regulations. 

In 1972, The FDA developed Over Counter Review Panels to ensure that over-the-counter pharmaceutical companies can prove that their medications are safe and effective in studies.  The panel consisted of a pharmacist, physicians, and pharmacologist that would review and develop monographs and grandfathered in the herbs.  Initially, they evaluated over 100 herbs. The panel did not review medical literature at that time but the only information they reviewed was what the over-the-counter pharmaceutical companies provided in support of products they wanted to keep on the pharmacy shelves.  In the end, only two dozen herbs were added to the US Pharmacopeia.  Some examples include laxatives like Senna and psyllium and a few decongestants like peppermint oil and eucalyptus.

So, my question is why only a few herbs were evaluated.  First of all, there were only a few herb companies.   Many mom-and-pop companies brewed medicinal teas.  Many just did not know about the OTC review panels.  Herbalists felt uncomfortable with the word drug and felt the products were more of a food. But a large part was due to the stigma of current medications very much like today. After 1985 when the OTC review process was completed, any new drug or herb would have to undergo the expensive and time-consuming test required of new prescription medications.  So, since herbs are not patented, there is no way to recoup the huge investment for the approval process.

Supplement and Health Education Act (DSHEA) 1994:

 The role of the Dietary Supplement and Health Education Act is to evaluate vitamins, herbals, amino acids, and other botanicals.  They regulate supplements more like food rather than medication.  Note that herbal products cannot be put on the same shelf as OTC or meds and before 1994, all products were grandfathered. The main purpose is to shift the burden of proof to the FDA.

 We have two key players of DSHEA:

• Manufacturers do not need to register or get FDA approval, they are responsible to ensure the product is safe, ensuring product label information is truthful and not misleading, 

• US Food and Drug Administration (FDA) takes action if the product is unsafe, once on the market. Note that supplements will be removed from the market if proven to be unsafe but prescriptions can only be approved if they are safe and effective BEFORE being available on the market.   FDA also monitors the safety of products via the Adverse Drug Reaction Med Watch reporting system as well as monitors product information of labeling of products, manufactory of claims, package inserts, and any accompanying literature.

In February 2019, a press release from the FDA about proposed changes to how dietary supplements regulation oversight has been since the Dietary Supplement and Health Educational act of 1994. The goal is to strengthen regulation by these three priorities; 1. Ensure safety by continuing to protect the consumer from harmful products, 2. Maintain Product Integrity to ensure that the product contains what it says it contains and 3. Informed decision-making so we have a fostered environment where consumers and professionals can make informed decisions before recommending or using.

Adverse Event Reporting: 

The FDA Med Watch Reporting System (http://www.fda.gov/medwatch/report/hcp.htm) is a voluntary system submitted online or via mail of adverse reactions to any regulated drugs, Biologics, Medical devices, or Dietary supplement. The reporting allows the FDA to evaluate and determine patient safety of available products and if interventions are needed.  

Labeling Requirements and other aspects to help determine a higher quality of supplements:

The FDA requires that manufacturers include the required disclaimer on every bottle of supplements for sale. “This statement has not been evaluated by the FDA. This product I not intended to diagnose, treat, cure or prevent any disease”.  In addition, manufacturers can include structure-functional claims to educate consumers on what the supplement can be used for. 

In June 2010 and forward the FDA and Federal Trade Commission created the Good Manufacturing Practices (GMPs) which have more stringent practices, better record keeping, quality control, testing, good quality production, and verifying the quality of raw materials.  This practice also allows increased inspecting of facilities by FDA inspectors to see if manufacturers comply. 

As there are hundreds of products available, the Supplement Seals of Approval included four independent companies that evaluate bottle to bottle pill to pill; what’s on the label is indeed in the product they can display a supplement seal of approval.  The four companies include Good Manufacturer Practices (GMPs), Consumer Labs (CL), United States Pharmacopoeia (USP), and National Sanitation Foundation (NSF). If product A has a seal and product B does not; always pick the one with the seal.  If a product does not have a seal this might be because the product has yet to be evaluated or didn’t meet the requirement for the seal.              

Supplements can be further distinguished from each other based on the Four P’s of Quality.  1. Positive Identity, are you buying what is on the label? Does it have a Supplement Seals of Approval? 2. Potency, is the dosage form in the right amount? Too much, too little, or none at all? 3. Purity, Is there anything else contained in the supplement like metals, pesticides, mold, or pharmaceutical ingredients? 4. Performance, the Pharmacokinetic and Pharmacodynamics of the product.

Now that we discuss how to find a “better” quality product you might as if there is any evidence of IHM.  Efficacy has been evaluated by folklore, anecdotes, and small studies.  We also have to look at the safety of use. Do we have any inherent toxicity?  Any interaction with conventional therapy?  But if we look at mainstream medicine; we have many products that are prescription that originated from plants.  Some examples include  Poppies = Morphine, Foxglove = Digoxin, Willow bark = Aspirin, and Pacific yew tree = Tamoxifen®.

We have some things to keep in mind when starting supplement use; start low and go slow. Discontinue the product if ineffective or unsafe.  Know that herbs interact with prescription and over-the-counter products.  Ideally, it is best to use single active ingredients vs combinations due to the risk of reaction and dose adjustment. Always buy a product from a reliable source.   For certain patient populations, we should use caution in pregnancy, nursing patients, elderly, children, and patients with serious health problems.

Most commonly used Supplement in the United States per

 the National Health Interview survey.

Fish Oil / Omega 3 Fatty Acid Supplement (Nonprescription)

Common Indication: Hypertriglyceridemia

Mechanism of action: 

1. Decrease in the hepatic secretion of VLDL-C, increase in VLDL-C clearance and reduces TG transport.

2. In addition, omega-3 fatty acids compete with arachidonic acid in the cyclooxygenase & lipoxygenase pathways

Efficacy: 20-50% reduction of triglyceride levels.  A meta-analysis of 10 trials                 ( N=78,000) concluded that supplements do little to protect patients with CV disease, stroke, or all-cause mortality

Adverse reactions: Fish taste, GI upset, heartburn, and belching

Drug interactions: Antihypertensive (lower BP), contraceptives, and Orlistat (moderate)

Herb interactions: Garlic, Ginger, Ginkgo, and Ginseng

Dosage: 1 – 15 g daily of DHA and EPA.  Note that most fish oil capsules are 120 mg DHA and 180 mg EPA.

• Food as medicine: Specific omega 3 fatty acid content of fish in a 3 oz. service of the following:

  • Catfish = 0.15-2 grams

  • Cod = 0.13-0.24 grams 

  • Flounder/Sole = 0.42 grams 

  • Halibut = 0.4-1 grams 

  • Herring = 1.71-1.81 grams 

  • Mackerel = 0.34-1.57 grams 

  • Rainbow trout = 0.84-0.98 grams 

  • Salmon (Atlantic, Farmed) = 1.09 - 1.83 grams 

  • Salmon (Atlantic, Wild) = 0.9 - 1.56 grams 

  • Salmon (Chinook) = 1.48 grams 

  • Salmon (pink) = 1.09 grams 

  • Salmon (sockeye) = 0.68 grams 

  • Sardines = 0.98-1.70 grams 

  • Tuna (light, canned) = 0.26 grams

• Food as medicine as dietary forms

  1. Omega 3 Fatty acid is found in fish, flaxseed, and walnuts

  2. Omega 6 fatty acid is found in corn, safflower, and sunflower oil

  3. Omega 9 fatty acids are found in olive oil, avocados, peanuts, and almonds

• Clinical pearls: 

  1. To decrease the fishy taste you can take with food, use an enteric-coded product or place it in the freezer and take it frozen. Best to take with food due to increased bioavailability.  If a history of GERD then taken immediately before a meal.

  2. It is generally recognized as safe (GRAS) where the FDA created a list in 1962 of herbs used as food additives for over 250 products. Generally, we have fewer concerns about complications than a concentrated supplement.  

  3. Using dietary forms when pregnant, the patient should limit consumption to 12 oz. per week and avoid shark, swordfish, and tilefish due to high levels of mercury.  

  4. We want to use caution in patients allergic to shellfish. 

  5. This is a treatment option for patients who cannot take niacin due to gout and flushing reactions. 

  6. Two-three fishy meals weekly but uncertain of beneficial effects of supplements as of now.   

  7. A point of care test called Omega Quant HS–Omega-3 Index test by metagenic is available for the patient to test how much DHA and EPA are in their red blood cells.

Glucosamine Sulfate / Chondroitin:

Common indication: Osteoarthritis

• Derived from Marine Exoskeleton (shrimp, lobster, and crab) or synthetically produces

• Quality of supplements: Previous evidence suggested that it was not orally absorbed.  Current data suggest that 8 - 18% is absorbed.

Efficacy:

1. Slow onset of 4-8 weeks.  

2. Most studies look at weight-bearing joints.  

3. Some have shown improved joint space narrowing but might not prevent flare-ups.   

4. Decrease pain scores by 28-41% and Improve functionality by 21-46%

Glucosamine / Chondroitin Arthritis Intervention Trail (GAIT)

1. Design: Multicenter, RDB, celecoxib Controlled, N = 1583, Groups: 1500mg glucosamine, 1200 chondroitin, both, 200 mg celecoxib, or placebo

2. Outcome: Primary - 20% reduction in knee pain from baseline to 24 weeks

3. Results: Glucosamine and chondroitin alone or in combination did not reduce pain

4. Data is mixed and controversial. Patients continue to take the supplement and report excellent outcomes. But the GAIT trial used Sulfate form rather than hydrochloride with is now more extensively studied. 

Effect of Oral Glucosamine on Joint Structure in Individuals with Chronic Knee Pain: A Randomized, Placebo-Controlled Clinical Trial

1. Design: N 201, Mild to Moderate pain in one or both knees, 24 weeks, 1500mg Glucosamine HCL

2. Outcome: Primary – Worsening cartilage damage in all knees using 3T magnetic imagining

3. Results: Glucosamine showed no evidence of structural benefits in patients with chronic knee pain

Adverse reactions: Nausea, Diarrhea, Constipation & Heartburn

Drug interactions: Diabetic medications, etoposide, doxorubicin, and warfarin

Disease interactions: Asthma and increase the spread or recurrence of prostate cancer 

Lab interactions: High doses can affect INR

Dosage: 1500 mg daily or 500 mg tid of Glucosamine and 1000 – 1200 mg daily chondroitin

• Clinical pearls: 

  1. Caution with shellfish allergy

  2. Glucosamine sulfate and Glucosamine hydrochloride may not be interchangeable

  3. FDA-approved ophthalmic product (Viscoat)® 

  4. Low-cost products may contain very little chondroitin

Prebiotics & Probiotics:

Common indications: treating and preventing diarrhea

Mechanism of action: good bacteria that re-colonizes areas of the body that has an infection

1. Lactobacillus & Bifidobacterium, species

Efficacy: Data is mixed. varies by dose, frequency & organisms in the product.

Adverse reactions: Flatulence

Drug interactions: Cyclosporine & Cisplatin

Disease interactions: Immunocompromised patients\

Dosing: 1-10 million colony forming units (CFUs) TID-QID

• Clinical Pearls:  

1. No generic equivalency between products

2. We can consider food as medicine like Pickles, Yogurt, Kefir, Cheese, Miso, etc. 

3. Might hold off on introducing probiotics too soon.  Have a plan like bitters (Kale, black coffee, and chards) to stimulate the digestive juices and pancreases to enhance bile flow from the gall bladder.

Melatonin

Indications: Circadian Rhythm Sleep disorders, Short term Primary Insomnia, and Jet lag

Mechanism of action: Regulate the body’s circadian rhythm, endocrine secretions, and sleep patterns. L-tryptophan converted to 5-HTP then to Serotonin and then to Melatonin

Efficacy: Helpful in elderly patients when levels are low.  Studies have shown it can reduce the time of sleep onset by 12 minutes.     However, it doesn’t appear to improve sleep efficiency

Adverse reactions: Daytime drowsiness, Headache, and Dizziness

Drug interactions: Anticoagulants & Antiplatelet increase the risk of bleeding, CNS Depressants

Herb interactions: Valerian, Kava & St. John’s Wort

Disease interactions: Seizures, DM, Depression, HTN (can increase and decrease blood pressure)

Dosage: 

Insomnia 2 - 5 mg qhs use short term 

Jet lag = 0.5 - 8 mg day of arrival and then 2-5 days afterward.

• Clinical pearls:

1. Good sleep hygiene. 

2. Use an Immediate release product to help you fall asleep or a sustained release product to stay asleep.  

3. Some cases of contaminants in products have been found which are associated with Eosinophilia- myalgia syndrome.  

4. FDA Orphan Drug status for indication of circadian rhythm sleep disorders.

Coenzyme Q-10

Indications: Congestive heart failure and Preventing statin-induced myopathy

Mechanism of action: Has antioxidant properties to stop damage and give energy to cells.  Also a cofactor in metabolic pathways.

Efficacy: Increase exercise capacity & reduces mortality by 31%. No change in EF or NYHA classification.  No significant benefit for myopathy or statin tolerability

Adverse reactions: GI upset, heartburn, and appetite loss

Drug interactions: anticoagulants

Lab interactions: Prostate-Specific antigen (PSA) might be reduced by 33% if taking 100 mg x 12 weeks

Disease interactions: may lower blood pressure, cigarette smoking may deplete body stores

Dosage: 100 mg daily for Heart Failure.  Max daily dose of 300 mg daily.  A lower dose taken 2-3 times a day may decrease side effects

• Clinical pearls: 

1. Some medications can lower Co Q 10 levels like Statins, beta-blockers, and diuretics.  

2. Best to take it with a fatty meal.

Echinacea (Echinacea angustifolia)

Indications: Common cold and Upper respiratory infection

Mechanism of action: Stimulates the immune system by increasing phagocytosis and lymphocyte activity

Efficacy: Evidence is mixed. In a 2019 meta-analysis - 22% decreased risk of URI. In a 2015 meta-analysis - 35% decreased the risk of recurrent URI.

Adverse reactions:  Fever, GI upset, sore throat, dizziness, and unpleasant taste

Drug interactions: Inhibits cytochrome P450 3A4, Inhibits cytochrome P450 1A2, and Corticosteroids.

Disease interactions: Autoimmune disease

Dosage: 

Crude extract - 6.75 mg (95% herb & 5% root) 2 tab tid

Juice - 20 drops Q2hrs 1st day, then 20 drops tid 

Tea - 5-6 cups 1st day, then 1 cup x 5 days

• Clinical pearls:

1. Part of the Chrysanthemum family which can increase the risk of rash.  

2. It was included in the US National Formulary from 1916 – 1950.  

3. Products should be discontinued product 2 - 3 weeks before surgery due to the risk of bleeding.  

4. The patient will have a tingling sensation on the tongue. 

5. Currently AT RISK per the united plant savers organization.

Cranberry

Indications: Urinary tract infections (UTIs)

Mechanism of action: Contain condensed tannins that interfere with bacterial adherence in the urinary tract. Wrap around E.coli to prevent adhering to the wall.

Efficacy: About a 33-38% reduction of UTIs in women. There is mixed data verse the use of juice verse extracts.  The society of OBGYN of Canada recommends for prevention of UTI recurrences.

Adverse reactions: GI (N/V/D) & risk of kidney stones when consumed more than one liter a day.

Drug interactions: Warfarin

Dosing: 10-16 oz. daily with 26% cranberry juice or 400-5000 mg bid orally

A proximally 1500grams of fresh fruit will make one liter of juice

Garlic (Allium sativum)

Indications: Hypertension and Hyperlipidemia 

Mechanism of action: Inhibits hepatic cholesterol synthesis and activates the production of endothelium-derived relaxation factor to relax smooth muscle and vasodilation

Efficacy: Effect of Raw Garlic versus Commercial Garlic Supplements on Plasma Lipid Concentration in Adults with Moderate Hypercholesterolemia

Design: RDBPC, N = 220, Product: fresh garlic, dried powder, extract tablets or placebo

Outcome:

Primary – LDL-C at baseline, one month, and post-intervention

Secondary – HDL-C, TG, BP, and platelet aggregation

Results: Not statically significant to reduce LDL-C or secondary endpoints after 6 months

Adverse reactions: Halitosis, body odor, heartburn, and GI upset

Drug interactions: Anticoagulant, Antiplatelet, CYP3A4 and CYP2E1

Herb interactions: Ginger, ginkgo, and vitamin E

Dosage: 

DL 600 mg – 1800 mg/day in tid doses

HTN – 600-900 mg daily

1 fresh clove (4 g)

Standardized to 0.65 - 1.3 % allicin

• Clinical pearls:

1. When using fresh product needs to sit for 10 minutes and chopped up before use for best results

2. Generally recognized as safe (GRAS) 

3. Discontinue 2 - 3 weeks before surgery

4. Products marketed as odorless, may not contain allicin

Ginseng (Panax ginseng)

Indications: Adaptogen, Diabetes, and Erectile Dysfunction

Mechanism of action: Increase serum cortisol and stimulate adrenal function

Efficacy: Use the short-term, data to decrease the risk of repeat colds in a season

Korean red ginseng (Panax ginseng) improves glucose and insulin regulation in well-controlled. Patients maintained good glycemic control.  Safety and compliance were unchanged

Adverse reactions: insomnia, BP changes, appetite loss, rash, dizziness, and mood changes

Drug interactions: anticoagulants, diabetic meds, Digoxin, Estrogen, CYP 2D6

Herb interactions: capsaicin, chamomile, feverfew, garlic, ginger, and bitter orange ( might prolong the QT interval

Disease interactions: schizophrenia where we see an increase in insomnia and agitation

Dosage: We need to have a > 7% ginsenoside standardized product

ED 900 mg tid

DM 3 – 6 grams 2 hours before meals

Common Cold 200 mg daily for 4 wks. before vaccination and then 8 wks. Afterward

• Clinical pearls:

1. Generally recognized as safe (GRAS) products

2. Should be discontinued 2 - 3 weeks before surgery due to bleeding risk.  

3. Ginseng is extremely difficult and expensive to grow.  It needs to be at least six years old before harvesting for optimal results.

Ginkgo (Ginkgo biloba)

Indications: Dementia

Mechanism of action: Protects tissues from oxidative damage

Efficacy: Some results were seen in 2 - 3 weeks. Ideally 12 weeks of use for optional results 5-year study with N 3000

Patients ≥75 yo, 240 mg daily.

Prevent dementia or Alzheimer's disease, Ginkgo Evaluation of Memory (GEM) Study

Design: RDBPC, 6 year study, N = 3069, intervention was 120 mg bid ginkgo verses placebo

Outcome: incident dementia and AD

Results: was not effective in reducing the incidence rate of dementia (95% confidence interval [CI], 0.94-1.33; P=.21) or AD 1.16 (95% CI, 0.97-1.39; P=.11). Follow up to GEM study in 2009

Adverse reactions: GI, HA, dizziness, palpitations, and allergic skin reactions

Drug interactions: Antiplatelet and anticonvulsants, and thiazides

Herb interactions: St John's Wort can increase the risk of hypomania

Disease interactions: Possible interference with fertility

Dosage: 120 – 240 mg daily in divided doses. Needs to be a standardized leaf extract of 24% ginkgo heterosides flavonoids and 6% terpenoids

• Clinical pearls: Discontinue 2 - 3 weeks before surgery

Conclusions

Evidence continues to evolve regarding legitimate IHM uses. We have a lack of FDA regulation that necessitates informed decisions to find safe and effective products. It is important to emphasize self-care and self-empowerment. As health professionals must be educated about IHM or at least know where to find the information. Most importantly we “Do no harm” approach.