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HERBAL MEDICATIONSAND OLDER ADULTS

Gayle Nicholas ScottPharmD, FASCP, BCPS, ELS, CMPP

gscottphar@cox.net

Disclosure

I have no relevant conflicts of interest.

Learning Objectives

1. Discuss uses, scientific evidence, potential drug interactions and adverse reactions of dietary supplements commonly used by older adults.2. Explain the differences in regulation of drugs, dietary supplements, medical foods, and functional foods.3. Describe effective methods of advising patients/families about dietary supplement use.

GlucosamineChondroitinStrontiumFish oil Coenzyme Q10Garlic ProbioticsCinnamonGinseng Ginkgo Melatonin Valerian

Legal Definition:Dietary Supplement

• Substances intended to supplement the diet • Vitamins, minerals, hormones, whole plant material, extract of

plants, amino acids, misc. other “natural” products (e.g. creatine, glucosamine, melatonin)

• Not required to provide dietary or nutritional benefit

• Terms used interchangeably • Dietary supplement• Herbal medication • Natural product • Nutraceutical

Vitamins and Dietary Supplements:Frequency of Use

• About half of Americans use some type of vitamin or dietary supplement (DS) regularly

• 38% take a DS other than a vitamin• 13–20% of Americans use herbal products• Most users would continue supplement

even if clinical trial/FDA reported ineffectiveness

Why US Adults Use Dietary Supplements

JAMA Intern Med. 2013;173;74-6 *Significant difference among age groups (P<0.05)

Reported motivations for dietary supplement use by age group 2007- 2010

Heart Health Eye Health Joint Health Bone Health

Dietary Supplement Regulation

• Dietary supplements are regulated by Dietary Supplement Health & Education Act (DSHEA)

• FDA regulates both drugs and dietary supplements, but under different laws with vastly different requirements

Directions for Use:Take 3 capsules daily until desired comfort level is reached. Then gradually reduce number of capsules taken daily to maintain comfort level. Capsules may be taken all at once or divided with meals throughout the day.*

Supplement Facts Serving Size: 3 CapsulesAmount Per Serving % Daily Value

Calories 15Sodium 105 mg 4%Total Carbohydrates 1.5 g < 1%**

Vitamin C (from Manganese Ascorbate) 6 mg 10%

Manganese (from Manganese Ascorbate) 1 mg 50%

Glucosamine Hydrochloride 99% 1.5 g †

Sodium Chondroitin Sulfate(Contains approximately 8% moisture)

1.2 g †

**Percentage Daily Values are based on a 2,000 calorie diet†Daily Value Not Established

Dietary Supplement Labelling

Structure and Function Claims

• Nonmedical claims• Helps your brain perform at its

best• Supports memory & concentration

• Medical claim is illegal• Treats dementia or ADHD

Proprietary Blend

Total amount of various ingredients• Synergistic and Proprietary

Formulation 692 mg • Dimethylaminoethanol, l-glutamine,

bacopin, l-phenylalanine, phosphatidylserine, docosahexaenoic acid (DHA) concentrate, choline, inositol, n-acetyl tyrosine, bilberry (vaccinium myrtillus) extract, gamma aminobutyric acid, grape skin extract, vinpocetine, Trace Lyte [?], water, boron, vanadium

• Plus 23 additional vitamins and minerals with labelled amounts

• Vitamin A 4000IU, manganese 2 mg

Comparison of Drug versus Dietary Supplement Regulation

Dietary Supplement DrugProof of efficacy no yesUse structure & function claim medical indicationSafety presumed safe presumed unsafeBurden of proof FDA manufacturer

Bioavailability no yesActive ingredient amounts on label

proprietary blend allowed yes

Patentable no yes

Advertising FTC FDA

Medical Foods: FDA Definition• Dietary management of diseases/conditions

with distinctive nutritional needs that can’t be met by diet alone–Labelled for specific medical conditions with

distinctive nutritional requirements• Intended for use under medical supervision

–Patient receiving active and ongoing medical supervision for a condition that requires medical care on a recurring basis for instructions on the use of the medical food

Medical Foods• Designed for unique nutritional needs of

patients with genetic metabolic disorders• Examples:

• Phenylalanine free formulas for babies with phenylketonuria –Enfamil Phenyl Free 1

• Branched-chain amino acid free products for maple syrup urine disease– Ketonex 1 and 2, MSUD Express

• Nonessential amino acid free products for urea cycle disorder (ornithine translocase deficiency)– Cyclinex 1 and 2

Comparison of Medical Foods andDietary Supplements

• Medical foods are not required to be proven safe or effective

• FDA does not require approval before marketing

• Using medical food designation allows manufacturer to make medical claim• Eg, treatment of dementia vs supports

memory function

Medical Foods Labelling• Packaging similar to

prescription products• Package insert

• FDA specifies products are for use with medical supervision; no prescription required

• "Caution: Federal law prohibits dispensing without prescription" is NOT required on product labeling

• Product marketer may request dispensing only on physician requestNDC number, “Rx only”

usually on label

Questionable Medical Foods• Axona (caprylic triglyceride) for mild to

moderate Alzheimer’s• Medium chain triglyceride found in coconut oil • MOA: increase energy to brain, provide raw materials

for cholesterol and acetylcholine synthesis• Small industry sponsored phase II

study: 90 days, ADAS-cog similar in patients receiving Axona, placebo

• Coconut oil less expensive • No studies to support

• More info: Medscape coconut oil

Questionable Medical Foods

Limbrel (flavocoxid) for osteoarthritis• Proprietary blend of flavonoids such as

baicalin and catechin (from Scutellaria baicalensis and Acacia catechu)

• “Found in common foods such as soy, peanuts, cauliflower, kale, apples, apricots, cocoa and green tea”

• Purported MOA: cyclooxygenase and 5-lipoxygenase inhibitor

• 2 company-sponsored noninferiority trials• Associated with acute liver injury

Functional Foods

• FDA does not define “functional food”• Foods marketed for purposes other than

nourishment • Activia, probiotic yogurt marketed “to regulate

the digestive system” • Contains Bifidobacterium animalis, marketed with

trademarked name Bifidus Regularis in US • “Eat twice daily for 4 weeks to reduce the

frequency of minor digestive issues like bloating, gas, discomfort and rumbling”

Approach to Dietary Supplement Use

• Reliable evidence for efficacy is often absent• May not fit evidence-based

medicine model• Patient perception is important• Safety is the primary concern

• Safety, particularly in older adults, is largely unknown

Glucosamine for Osteoarthritis

• Manufactured from chitin in shells of shellfish or produced synthetically

• Available as glucosamine sulfate and glucosamine hydrochloride• HCl most common in US (as

dietary supplement)• SO4 more common in Europe

(as Rx medicine)

“It used to be ‘Rock Around the Clock’, now it’s ‘Limp Around the Block’!”

Chondroitin Sulfate for Osteoarthritis

• Manufactured from bovine cartilage or produced synthetically

• Low bioavailability <5%–15%• Sodium salt available in US as dietary

supplement, drug in Europe• Sulfate is covalently linked to

chondroitin molecule

Glucosamine and Chondroitin• Often sold as combination product• Both found naturally in joint cartilage• Both appear to be safe with low incidence

of adverse effects• Mechanism is unknown

• May have disease-modifying effect• Reduced cartilage loss, joint space narrowing• Lower C-reactive protein

– Indicator of lower systemic inflammation?

Glucosamine and Chondroitin Clinical Trials

• Results have been conflicting• Some research suggests pain reduction,

increased mobility, disease-modifying effect• Other studies, no effect on pain, function, or

structure• Glucosamine sulfate salt may be more

effective than HCl salt• Once daily dosing glucosamine 1500 mg +

chondroitin 1200 mg may be more effective than TID

Glucosamine and ChondroitinOsteoarthritis Guidelines

• Not recommended• American College of Rheumatology (ACR)• American Society of Orthopedic Surgeons (ASOS)• National Institute for Health and Clinical Excellence (NICE)

• Uncertain• Osteoarthritis Research Society International (OARSI)

• Recommended• European League Against Rheumatism (EULAR)• European Society for Clinical and Economic Aspects of

Osteoporosis and Osteoarthritis (ESCEO)

OsteoarthritisThe Other Ingredients

• Insufficient or negative evidence • Methylsulfonylmethane (MSM)• Manganese• S-adenosylmethionine (SAMe)• Avocado/soybean unsaponifiables

Strontium for Osteoarthritis

• Ranelate salt widely promoted in Europe as a prescription drug

• Strontium ranelate may have disease-modifying effect• May inhibit bone resorption, stimulate bone formation • Slowed joint space narrowing• Decreased pain, increased physical function

• In US, strontium marketed as a dietary supplement available as carbonate, chloride, citrate, gluconate, sulfate salts

• Questionable bioavailability• All clinical research is on strontium ranelate

Omega-3 Fatty Acids• AKA: polyunsaturated fatty acids (PUFA),

n-3 fatty acids, ω-3 fatty acids• Essential fatty acids (not made by body) • 3 nutritionally important

• Eicosapentaenoic acid (EPA)• Docosahexaenoic acid (DHA)• Alpha linolenic acid (ALA)

–Don’t confuse with alpha linoleic acid (an omega-6)–Body has limited ability to make EPA/DHA from ALA

Fish Oil for Cardiovascular Disease

• Prescription products • Lovaza: 1 g omega-3s/capsule

–3 to 4 times amount in most supplements

• Vascepa: EPA only• Fish oil dietary supplements often

do not contain labelled amount of EPA/DHA• 79% contained less EPA than labelled• 75% contained less DHA than labelled

Fish Oil for Cardiovascular Disease• Fish consumption associated with

• Reduced stroke risk in women, but not men• Reduced risk of acute coronary syndrome

• Mediterranean Diet may lower CV risk• Benefit of omega-3s somewhat controversial

for lowering overall CV risk• 2 meta-analysis: omega-3 supplements did not

reduce risk of CV events, all-cause mortality, or sudden cardiac death

• Systematic review of same studies found benefit

Fish Oil for Dementia and Alzheimer’s Disease

• Proposed mechanisms• Maintenance of neuronal membrane, function• Antioxidant activity – may reduce inflammation,

vascular responses and thrombosis• Meta-analysis of 3 large studies (3536 total)

found no benefit of fish oil on cognitive function in healthy older adults

• Would longer trials (>40 months) show benefit?• Small trials found benefit in patients with AD

• Slowed cognitive and functional decline

Co-enzyme Q10

• Also called ubiquinone, CoQ10• In all human cells, esp heart, liver, kidney• Cofactor in mitochondrial electron transport

• Appears to be safe• Minor GI adverse effects have been reported

• Some reports of warfarin interaction• Both increased and decreased effect

Co-enzyme Q10

• Statin myopathy• Statins reduce CoQ10 levels• Mixed evidence of efficacy for myopathy

• Heart failure • Some evidence of improved ejection fraction

• Hypertension• Effect if any is small

• Parkinson’s disease• No benefit

Garlic (Allium sativum)• Active constituents allicin, s-allyl cysteine• Statin-like activity

• HMG-CoA reductase inhibitor • Antiplatelet activity• Antihypertensive activity• Products: garlic powder, oil, aged garlic

extract• Much interproduct variability• Clove of garlic is ~ 5 g

Garlic Safety• Appears to be safe for most people

• Used in studies for up to 7 years• Breath and body odor (some products)• Gastrointestinal adverse effects• Drug interactions

• May vary among products• Antiplatelet/anticoagulant drugs• Some HIV, antirejection drugs

–CYP3A4 induction

Garlic for Cardiovascular Disease

• Hypertension• Reduces systolic ~12 mmHg,

diastolic 9 mmHg• Effect on risk of mortality and

cardiovascular morbidity unclear

• Hypercholesteremia–No significant effect on LDL

• Peripheral artery disease• No reliable evidence of efficacy

“Gravity has lowered my chest, my stomach, and my butt. Why hasn’t it lowered my cholesterol?!” 

Probiotics• Yeasts or bacteria

• Lactobacillus bulgaricus, Streptococcus thermophilus in yogurt

• Bifidobacterium sp, Lactobacillus sp, Saccharomyces cerevisiae in dietary supplements

• None approved by FDA as a drug• Appear to be safe for most people

• Possibly unsafe in severe immunosuppression• May be inactivated by concurrent antibiotic

or antifungal therapy

Probiotics• Prevention of antibiotic-associated Clostridium

difficile infection • Equivocal or weak evidence in older adults

• Prevention of ventilator-associated pneumonia• Low quality evidence suggests possible effect• No difference in ICU stay or mortality

• Irritable bowel syndrome, constipation• Possibly effective, but most effective type of

bacteria/yeast is unclear

Probiotics• Modest effect on BP in hypertension

• >8 weeks for onset of effect• Higher dose for effectiveness

– ≥1011 colony-forming units (cfu)–Compare with serving of Yoplait yogurt 5.7 x 108 cfu

• Mechanism• ?May affect renin-angiotensin system

• Modest effect on lipids• ↓total cholesterol 6.4 mg/dl, LDL 4.9 mg/dl• No effect on HDL or triglycerides

• Much less effective than statins

Cinnamon• Cinnamomum cassia., C. zeylanicum,

C. burmanii species• May increase insulin sensitivity• Cinnamon available as a spice is often a

mixture of species• About 5g in 1 teaspoon• Also available in capsules

• Probably safe for most people

Cinnamon for Diabetes• Studied for both type 1 and type 2 diabetes

• Dose 0.12–6 g daily for 4–18 weeks• Heterogeneous study designs• Questionable, but possible effect on fasting

blood glucose, ? HbA1C• More research needed

Ginseng (Panax ginseng)

• AKA Asian, Korean, red ginseng• Don’t confuse with other ginsengs

• Siberian (Eleutherococcus senticosus)• American (Panax quinquefolius)• Thai (Kaempferia parviflora)

• Appears to be safe for short term-use for most people• Mild GI effects, insomnia

Ginseng for Diabetes

• Few studies, short term studies• 30 days - 12 weeks• Small study populations (<69 subjects)

• No significant effect on HbA1C

Ginkgo (Ginkgo biloba)• Leaf extract EGb761 used in most studies• Proposed mechanisms

• Antioxidant activity• Augment cerebral blood flow

• Appears to be safe for most people• Warfarin interaction probably

overstated

Ginkgo for Cognitive Impairment/AD

• 2 large studies in adults >70 yrs with normal or mild cognitive impairment

• Ginkgo extract (EGb761) no better than placebo for slowing cognitive decline, reducing overall incidence of dementia or AD over > 5 yrs

Melatonin• Pineal hormone regulates circadian rhythm

• Secretion decreases with aging• Elevation of endogenous melatonin with

exogenous administration• May be more pronounced in elderly

–More effect on peak concentration than half-life–Sustained release may promote daytime drowsiness

• Long-term safety is unknown• Ramelteon (Rozerem) binds to melatonin

receptors appears safe for 1 year

Melatonin for Insomnia• For insomnia in elderly

• 0.3 mg to 2 mg of immediate release product 1 hr before bedtime may best mimic normal circadian rhythm

• May be effective for REM sleep behavior disorder

• No reliable evidence for improvement of sleep in Alzheimer’s disease

Valerian for Insomnia• Modestly reduces time to sleep onset • May improve sleep quality• Slow onset off effect

• May require several weeks for onset of effect • Dose: 400-900 mg valerian

up to 2 hours before HS• Long-term safety is unknown

TALKING WITH PATIENTS ABOUT DIETARY SUPPLEMENTS

Try to maintain open communication with patient about dietary supp use

ACTIONRecommend

TolerateMonitor closelyAdvise against

• Unless safety is a concern, “probably won’t hurt, might help” attitude might be best

SAFE? EFFECTIVE?Yes YesYes ???? YesNo No

Dietary Supplements:Questions to Ask Patients

• Are you taking other medicines for the same purpose?

• Have you used the product before? How long?

• Has it improved your condition? Have you noticed any side effects?

• How do you take the product?

Product SelectionGuidelines

• Avoid complex herbal mixtures• “Proprietary blend” is a yellow flag

• Select brands used in a clinical trials• Select reputable manufacturers

• ask for quality control data• Chose “standardized” products or extracts• Look for batch numbers, expiration dates

Emphasize safety!

• “Natural” ≠ “safe”• Dietary supplements

do have side effects and should be monitored like drugs

• Dietary supplements can interact with drugs and other supplements

For More Information• National Center for Complementary and

Alternative Medicine (NCCAM)• Established by US Congress in 1998• www.nccam.nih.gov http://nccam.nih.gov (free)

• FDA Center for Food Safety and Applied Nutrition (free)• http://www.cfsan.fda.gov/~dms/supplmnt.html

• www.NaturalDatabase.com ($299/yr)• www.consumerlab.com ($33/yr)• Consumer Reports

Posttest Questions

1. True or False: Dietary supplements must be tested for efficacy in randomized controlled trials before marketing.

FALSE

Posttest Questions

2. Glucosamine is used to treat which of the following conditions?

A. Type 2 diabetesB. Intermittent claudicationC. OsteoarthritisD. Alzheimer’s disease

Posttest Questions

3. Which of the following is most important in considering dietary supplement use?

A. SafetyB EfficacyC. PharmacokineticsD. Drug interaction potential

Questions??