botanicals & the brain: an update on dietary … · •cite evidence-based data describing the...

© 2013 by the American Pharmacists Association. All rights reserved.

Kelly Orr, PharmD

Clinical Associate Professor

Department of Pharmacy Practice

College of Pharmacy

The University of Rhode Island

BOTANICALS & THE BRAIN: AN UPDATE ON DIETARY SUPPLEMENTS

Disclosures

• Kelly Orr declares she has received research grant funding from Pfizer.

Learning Objectives

• Cite evidence-based data describing the risks and benefits of selected dietary supplements for use in migraine and insomnia

• Educate patients about the safe use of dietary supplements for or use in migraine and insomnia

• Explain regulatory requirements related to dietary supplements and issues related to quality

• Technician: List potential safety concerns with dietary supplements used for migraine and insomnia


Background • Three-fourths of world relies on natural medicines

• Journal of the American Medical Association (JAMA) study1

• 1990 - 34% used > 1 alternative therapy

• 1997 - 42% used > 1 alternative therapy

• Current use approximately 40-62%2,3

• $34 billion spent out of pocket annually on Complementary and Alternative Medicine (CAM)3

• Products, classes, visits to providers

• $15 billion spent on herbs and dietary supplements3

1. Eisenberg et al. JAMA 1998;280:1569-75. 2. Barnes PM et. CDC Advance Data from Vital and Health Statistics No 343; May 2004 3. Barnes PM et al. CDC National Health Statistics Report No 12; Dec 2008.

Trends in Consumer Use of Herbs/Dietary Supplements •2010 NIH and AARP surveyed Americans over the age

of 50 years old 1

• 37% used herbs and dietary supplements

• 67% never discuss CAM use with a health care provider

•2011 Harvard Opinion Research Program 2

• Conducted telephone survey of 1579 respondents

• Approximately 4 out of 10 Americans reported using supplements in past 2 years

1. AARP/NCCAM Survey of U.S. Adults 50+, 2010. Available at URL: http://nccam.nih.gov/news/camstats/2010/findings1.htm. [Accessed April 28, 2015].

2. Blendon RJ et al. Arch Intern Med. 2012; doi:10.1001/2013.jamainternmed.311

Trends in Consumer Use of Herbs/Dietary Supplements •2011 Harvard Opinion Research Program 1

• 36% had not told physician about use of supplements

• 5% had been told by physician or nurse to stop supplement

• 25% reported that they would stop using supplement if public health authorities found it was ineffective



Popular Herbs and Dietary Supplements: 2011 Harvard Survey 1

•Fish oils or omega-3 supplements

•Herbal supplements like ginseng

•Probiotics like acidophilus

•Any other supplements like amino acids, algae derivatives or combination products

•Supplements derived from foods like garlic supplements


2012 National Health Interview Survey • Supplement to the Census Survey

• Asked about use of 18 non-conventional health care practices

• Results: 1,2

• Found that use of non-vitamin/non-mineral dietary supplements was highest used CAM modality

• Increase in use of fish oil, probiotics/prebiotics and melatonin

• Decrease in use of echinacea, garlic, glucosamine/chondroitin

• Use of yoga doubled from 2002 to 2012 survey

• Use of these dietary supplements highest in Pacific, Mountain, and West North Central Regions

1. Peregoy JA al. \. NCHS data brief, no 146. Hyattsville, MD: National Center for Health Statistics. 2014. Available at URL: http://www.cdc.gov/nchs/data/databriefs/db146.pdf. [Accessed April 28, 2015].

2. Clarke TC, Black LI, Stussman BJ, et al. Trends in the use of complementary health approaches among adults: United States, 2002-2012. National health statistics reports; no 79. Hyattsville, MD: National Center for Health Statistics. 2015

2012 National Health Interview Survey1

1. Peregoy JA al. \. NCHS data brief, no 146. Hyattsville, MD: National Center for Health Statistics. 2014. Available at URL: http://www.cdc.gov/nchs/data/databriefs/db146.pdf


REGULATIONS OF HERBS AND DIETARY SUPPLEMENTS

DSHEA: Dietary Supplement and Health Education Act

• Signed into law on October 25, 1994

• Herbal supplements, vitamins and minerals considered dietary supplements not drugs

• Dietary ingredients in supplements no longer subject to pre-marketing safety evaluations

• Labeling criteria

• Body structure and function claims

• Cannot make therapeutic claims

• Must state not approved by FDA

• Must have manufacturer’s name and address

• Not required to have lot numbers, expiration dates or contraindications

Regulatory Role of FDA •FDA responsible for taking action against any unsafe

dietary supplement product after it reaches the market

•Post-marketing responsibilities:

• Monitoring safety

• Product Information

• Labels

• Claims

• Package insert

• Accompanying literature


Background: CAM in Migraine Prevention •> 45 million people in US seek medical attention for

headaches

• Direct costs: $ 11 billion

• Indirect costs: $12 billion • Annual loss of 157 million workdays

•Popular CAM modalities for headaches:

• Mind body interventions

• Massage therapy

• Spinal manipulation

• Dietary supplements

1. Headaches and Complementary Health Approaches. Available at URL:

http://nccam.nih.gov/health/pain/headachefacts.htm [Accessed January 28, 2014].

Dietary Supplements for Migraine Prevention

BUTTERBUR FEVERFEW VITAMIN B2 MAGNESIUM

Butterbur Background •Origin

• Petasites hybridus L. (Gaertner, Meyer & Scherb)

• Member of Compositae/Asteracea family

•Uses

• Migraine prevention, allergic rhinitis

•Mechanism

• Petasin may reduce smooth muscle spasms, leukotriene synthesis

• Isopetasin decreases prostaglandin synthesis, anti-inflammatory properties

Sutherland A, Sweet BV.. Am J Health Syst Pharm. 2010;67(9):705-11.


Butterbur Evidence •Level Evidence A for Migraine Prevention

• American Academy of Neurology and the American Headache Society consider effective

• Level A = established as effective and should be offered for migraine prevention

• Based on two well – designed (Class I) studies

Holland S, Silberstein SD, Freitag F, et. al. Neurology. 2012;78(17):1346-53

Butterbur Evidence • Three-arm, parallel-group, randomized trial of 245

• Petasites extract 75 mg twice daily,

• Petasites extract 50 mg twice daily, or

• Placebo twice daily for a 4 month period

• Primary outcome of decrease frequency as a percentage change from baseline

•Results:

• 48% reduction for Petasites 75 mg (p = 0.0012 vs placebo)

• 68% reported a reduction of ≥ 50% at 4 months (p<0.05 vs. placebo)

• 36% reduction for Petasites 50 mg (p = 0.127 vs placebo)

• 26% reduction for placebo

Lipton RB, et. al. Neurology 2004; 63: 2240– 2244.

Butterbur Evidence • Randomized, group-parallel, double-blind study

• Four week run-in phase of 60 patients:

• Petodolex extract 50 mg twice daily or

• Placebo twice daily for 12 weeks

• Outcomes included frequency, duration, and intensity of migraine attacks

• Frequency decreased by 60% compared to baseline

• Significant reduction in number of attacks vs. placebo

• 3.3 ± 1.5 to 1.8 ± 0.8 at 4 weeks,

• To 1.3 ± 0.9 at 8 weeks,

• To 1.7 ± 0.9 at 12 weeks (p < 0.05)

Grossman W, Schmidramsl H. Altern Med Rev 2001; 6: 303– 310.


Butterbur Safety •Avoid in patients with allergy to ragweed and related

plants to Compositae/Asteracea

•Adverse effects include GI upset (20%)

•Few potential drug/herbal interactions

•Pyrrolizidine alkaloids (PAs) may be present in the extract

• Hepatotoxic and carcinogenic

• Strict manufacturing

•Avoid in pregnancy and lactation

Sutherland A, Sweet BV. Am J Health Syst Pharm. 2010;67(9):705-11.

Butterbur Key Points •Appears to be effective for migraine prevention for 4

– 6 months

•Long – term studies have not been conducted to assess safety and efficacy

•Select products specifically labeled PA – free

•Avoid in patients with allergies to Compositae/Asteracea

Feverfew Background •Origin • Tanacetum parthenium L. (Schultz-Bip.)


•Uses • Migraine prevention; also treatment of dysmennorhea,

arthritis, psoriasis

•Mechanism • Parthenolonide likely contributes to anti-inflammatory

properties

• Other components may influence prostaglandin synthesis, platelet aggregation, serotonin release, histamine release, and vascular smooth muscle contraction

Pareek A, Suthar M, Rathore GS, et al. Pharmacogn Rev. 2011;5(9):103-10


Feverfew Evidence •Level Evidence B for Migraine Prevention

• American Academy of Neurology and the American Headache Society considers MIG – 99 probably effective

• Class I trial and 2 Class II trials

• MIG – 99

• Standardized extract of 0.2 - 0.35% of parthenolide

• CO2 extraction method resulting in a highly stable compound

Holland S, Silberstein SD, Freitag F, et. al. Neurology. 2012;78(17):1346-53

MIG – 99 Evidence • Randomized, double-blind, placebo-controlled, multicentre,

parallel-group trial

• Four week run-in phase of 170 ITT patients:

• MIG – 99 6.25 mg three times daily or

• Placebo twice daily for additional 16 weeks

• Primary outcome was average number of migraine attacks per 28 days in months 2 and 3 vs. baseline

• Migraine frequency decreased from an average of 4.76: • By 1.9 attacks/month for MIG-99 group and

• By 1.3 attacks/month in the placebo group (P = 0.0456)

• Logistic regression analysis demonstrated favorable OR of 3.4 for MIG – 99 (p<0.005)

Diener HC, et. alCephalalgia. 2005; 25(11):1031-41.

Feverfew Evidence •A systematic Cochrane review found insufficient

evidence from randomized, double-blind trials to suggest an effect

•Five studies were included assessing the efficacy of feverfew for preventing migraine

• Total of 343 patients

•Feverfew was well tolerated, but results were mixed

Pittler M, Ernst E. Cochrane Database Syst Rev. 2004;1:CD002286.


Feverfew Safety •Avoid in patients with allergy to ragweed and related


•GI adverse effects most common

• Sore mouth/tongue, abdominal pain

•May have anti-platelet properties, use caution with anti-platelet or anti-coagulant agents

•“Post feverfew syndrome” with abrupt withdrawal may occur after long-term administration

• Joint stiffness, aches, recurring headaches

1. Pareek A, Suthar M, Rathore GS, et al. Pharmacogn Rev. 2011;5(9):103-10 2. Evans RW, Taylor FR. Headache. 2006;46:1012-18.

Feverfew Key Points •Long – term studies have not been conducted to

assess safety and efficacy

•MIG – 99 formulation appears to provide benefit in migraine prophylaxis vs. mixed results with other feverfew products


•GI adverse effects and post-feverfew syndrome possible

Riboflavin Background •Origin

• Vitamin B2, water-soluble

• Found naturally in milk, eggs, meat, enriched flour, and green vegetables

•Uses

• Prevention of riboflavin deficiency, prevention of cataracts

•Mechanism

• By correcting a deficit of mitochondrial energy metabolism migraines may be prevented

MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); Riboflavin (Vitamin B2); [updated 2012 Nov 14; cited 2014 Jan 6]; [about 2 p.]. Available from: http://www.nlm.nih.gov/medlineplus/druginfo/natural/957.html


Riboflavin Evidence •Level Evidence B for Migraine Prevention

• American Academy of Neurology and the American Headache Society considers probably effective

• Class I trial found superior to placebo;

• Class II trial found no benefit with combination of magnesium (300 mg), riboflavin (400 mg), and MIG-99 (100 mg) with placebo (riboflavin 25 mg as sub-therapeutic)

Holland S, Silberstein SD, Freitag F, et. al. Neurology. 2012;78(17):1346-53.

Riboflavin Evidence • High-dose riboflavin 400 mg per day or placebo1

• Placebo controlled, double blind study with 55 ITT patients for 3 months

• Riboflavin significantly reduced frequency (p=0.005) and duration of migraines (p=0.012)

• Responders (≥ 50% reduction) was 59% vs. 19% (p=0.002)

• NNT for effectiveness = 2.3

• High-dose riboflavin 200 mg per day or placebo in children2

• Randomized, double blind, placebo-controlled study

• Forty – eight children received high-dose riboflavin 200 mg per day or placebo for 4 weeks

• Failed to show benefit compared to placebo

1. Schoenen J, et. al. Neurology. 1998;50(2):466-70. 2. MacLennan SC, et. al J Child Neurology. 2008;23(11):1300-4.

Riboflavin Safety •Overall, relatively safe supplement

• Avoid administering through multivitamin due to toxicity of other vitamins

• Not recommended in pregnancy because fetal toxicity is unknown

•Change in urine to yellow – orange color

•High doses may result in diarrhea

•Minor potential drug interactions

Evans RW, Taylor FR. Headache. 2006;46:1012-18.


Riboflavin Key Points •400 mg per day may be an effective dose for

migraine prevention, more well designed studies warranted to confirm

•Well tolerated, low adverse effect profile

•Less evidence to support in comparison to butterbur or feverfew

Magnesium Background •Origin

• Fourth most abundant mineral in the body

• Naturally found in green leafy vegetables, nuts, legumes, and whole grains

•Uses

• Eclampsia/preeclampsia, arrhythmias, asthma, constipation, dyspepsia

•Mechanism

• Some studies link migraine pathophysiology to low levels of magnesium

Guerrera MP, Volpe SL, Mao JJ. Am Fam Physician. 2009;80(2):157-62.

Magnesium Evidence •Level Evidence B for Migraine Prevention

• American Academy of Neurology and the American Headache Society considers probably effective

• Based on 2 positive Class II trials, 1 negative Class III trial

Holland S, Silberstein SD, Freitag F, et. al. Neurology. 2012;78(17):1346-53.


Magnesium Evidence •Small double-blind, placebo controlled studies have

demonstrated inconsistent outcomes • Magnesium pyrrolidone carboxylic acid 360 mg daily on day 15

of the cycle onward vs. placebo1

• Number of days with headache only reduced with Mg2+

• Significant reduction of the Menstrual Distress Questionnaire scores w/ Mg2+

• Magnesium 600 mg (24 mmol) daily or placebo twice daily for 12 weeks2

• Weeks 9 – 12 found reduction in migraine attack frequency with 41.6% Mg+2 and 15.8% placebo vs. baseline (p < 0.05)

• Duration of migraines did not change between groups, only baseline

• Magnesium 10 mmol (486 mg) twice daily (35 patients) or placebo twice daily for 12 weeks3

• No difference between groups

1. Facchinetti F, et. al. Headache. 1991;31(5):298-301. 2. Peikert A, et. al. Cephalalgia. 1996;16(4):257–263. 3. Pfaffenrath V, et al. Cephalalgia. 1996;16(6):436–440.

Magnesium Safety •Generally well tolerated orally • Common adverse effects include GI upset • Nausea, vomiting, and diarrhea

• Overdose potentially fatal • Hypotension, drowsiness, muscle weakness, respiratory depression,

arrhythmia, coma, and death

•Drug interactions • Medications that may increase Mg2+

• Potassium sparing diuretics, calcitonin, or doxercalciferol

• Concomitant administration should be avoided: • Fluoroquinolones, aminoglycosides, bisphosphonates, calcium channel

blockers, tetracyclines, and muscle relaxants

•Avoid in patients with renal insufficiency (< 30cc/min)

Guerrera MP, Volpe SL, Mao JJ. Am Fam Physician. 2009;80(2):157-62

Magnesium Key Points •Probably effective for migraine prophylaxis, though

mixed results

• May be beneficial in women, especially in relation to menstrual migraine

•Lacking long – term data and comparison of different magnesium preparations

•Well tolerated at normal dosages

•Avoid in patients with renal insufficiency

•Number of potential drug interactions

• Absorption binding and additional increases in magnesium


Patient Case • Patient is inquiring about using a “natural” product for

prevention of migraines.

• She reports developing migraines 2 – 3 times per month. She currently has no symptoms.

• Patient has taken divalproex, propranolol, and topiramate for prevention, but discontinued use due to adverse events

•Medications/Dietary supplements: • Sumatriptan 50 mg as needed for acute migraine;

• Ibuprofen 400 mg every 4 – 6 hours as needed for migraine pain;

• Vitamin B2 daily for migraine prevention (she read it may help)

•No known drug allergies

Patient Case Key Points • A trial basis of butterbur could be considered in consult with

provider treating migraines

• Discuss nonpharmacological methods for migraine prevention

• Confirm no allergies to ragweed family

• Select a product free of PAs

• Minor GI adverse effects are most common

• Natural product options are limited for prevention of this condition

• Butterbur studies support use for 12 – 16 weeks, though some monographs support use for 4 – 6 months then taper off

• Prescription alternatives provide more sufficient long – term data on safety and efficacy

Dietary Supplements for Insomnia

• Kava

• Melatonin

• Valerian

• Chamomile

• Lemon balm

• Lavender

Kava. URI Medicinal Garden (K. Orr)


Kava Background •Origin

• Piper methysticum L. (G. Forster)

• Member of the black pepper family (Piperaceae)

•Uses

• Anxiolytic, insomnia

•Mechanism

• Kavapyrones and kavalactones interact with GABA, MOA-B, sodium and calcium channels

• May inhibit reuptake of NE and dopamine

Sarris J, LaPorte E, Schweitzer I.. Aust N Z J Psychiatry. 2011;45(1):27-35

Kava Evidence •Strong evidence to support as an effective anxiolytic

• A systematic Cochrane review found a significant difference in the HAM-A scale score compared with placebo in 345 patients (95% CI, 1.1 to 8.8; p = 0.01)1

• A meta-analysis of kava extract WS 1490 reported efficacy based on an odds ratio of 3.3 (95% CI, 2.09 to 5.22) compared with placebo change in HAM-A2

• However, overall HAM-A scores were not significant

• Women and younger patients showed most improvement

1. Pittler MH, Ernst ECochrane Database Syst Rev. 2003;1:CD003383. 2. Sarris J, Kavanagh DJ, Byrne G, et al.. Psychopharmacology. 2009;205:399–407.

Kava Evidence • Insomnia support is lacking

• Small case series, pilot study with valerian

•Randomized, double-blind, placebo-controlled, internet based trial of 391 patients

• Subjects completed on-line process with documentation of anxiety and reported insomnia over the previous 2 weeks

• No differences were found with either group compared to placebo

Jacobs BP, et. al. Medicine (Baltimore). 2005;84(4):197-207.


Kava Safety – Hepatotoxicity •Center for Food Safety and Nutrition, 20021

• Warning of the risk of severe liver injury associated with kava-containing supplements

• No updates to Consumer Advisory

•Several factors may contribute to origin of liver injury2:

• Aqueous vs. acetone or ethanol extracts;

• Continuous high doses;

• Inappropriate raw products;

• And potential contaminants

1. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 2002;51:1065–7. 2. Teschke R, Lebot V. Food Chem Toxicol. 2011;49(10):2503-16.

Kava Safety • Drowsiness and sedation, avoid combination with other

sedating agents or operating machinery or driving

• High doses may cause ataxia or mental status changes

• Avoid in pregnancy and lactation due to unknown safety

• Kava dermopathy syndrome with chronic high doses, will resolve with discontinuation

• Hematological findings have been observed

1. Ulbricht C, Basch E, Boon H, et. al. Expert Opin Drug Saf. 2005;4(4):779-94. 2. Perez J, Holmes JF. J Emerg Med. 2005;28:49–51.

Kava Key Points •Effective as an anxiolytic, lacking evidence to support

for use in insomnia

•Safety unknown, best to avoid until clear data supporting safety is available

• Hepatotoxicity is a critical concern


Melatonin Background •Origin

• Produced by the pineal gland, synthesized from tryptophan via a serotonin pathway

• Synthetically produced for supplements

•Uses

• Insomnia and prevention of “jet lag”

• FDA orphan drug status for sleep disorders in blind patients

•Mechanism

• Physiologically, melatonin regulates sleep and circadian rhythms

• Administration stimulates these sleep mechanisms van Geijlswijk IM, Korzilius HPL, Smits MG. Sleep. 2010;33(2):1605-14.

Melatonin Evidence • Meta – analysis of randomized, controlled trials in patients

with delayed onset sleep disorder

• 5 trials including 91 adults and

• 4 trials including 226 children

• Results demonstrated:

• Advanced mean endogenous melatonin onset by 1.18 hours (95% CI: 0.89–1.48 h)

• Clock hour sleep onset by 0.67 hours (95% CI: 0.45–0.89 h)

• Melatonin decreased sleep-onset latency by 23.27 minutes (95% CI: 4.83 –41.72 min)

• Wake-up time and total sleep time did not change significantly

van Geijlswijk IM, Korzilius HPL, Smits MG. Sleep. 2010;33(2):1605-14.

Melatonin Evidence • Randomized, placebo-controlled studies in patients with

primary sleep disorders

• 19 studies with 1683 patients (172 children)

• Results demonstrated with melatonin groups:

• Reduction in sleep latency

• WMD =7.06 minutes (95% CI 4.37 to 9.75, p<0.001)

• Increased total sleep time

• WMD=8.25 minutes (95% CI 1.74 to 14.75, p=0.013)

• Overall sleep quality improved in subjects

• Standardized mean difference=0.22 (95% CI: 0.12 to 0.32, p<0.001)

• Trials with longer duration and using higher doses had greater effects on decreasing sleep latency and increasing total sleep time

Ferracioli-Oda E, Qawasmi A, Bloch MH. PLoS One. 2013;8(5):e63773.


Melatonin Evidence •Evaluate safety and efficacy in pediatric patients with

attention-deficit/hyperactivity disorder (ADHD)

• Four studies in children ages 6 – 14 years old

• 3 – 6 mg administered a few minutes before bedtime

• Improved sleep onset and latency

• Limitations of small sample size and short duration

• Mild adverse events reported

Bendz LM, Scates AC. Ann Pharmacother. 2010;44(1):185-91.

Melatonin Safety • Avoid products extracted from bovine pineal glands

• Risk of bacterial contamination and bovine spongiform encephalitis (mad cow disease)

• Avoid in pregnancy and lactation

• Controversial use in children due to potential hormonal effects

• Several potential drug interactions

• Fluvoxamine, TCAs, and MOA-I may increase; benzodiazepines and valproate my decrease melatonin

• Verapamil and nifedipine

• Cisplatin and doxorubicin – may increase effectiveness

• Caffeine and oral contraceptives

1. Bendz LM, Scates AC. Ann Pharmacother. 2010;44(1):185-91. 2. MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); Melatonin; [updated 2013 Oct 3;

cited 2014 Jan 26]; Available from: http://www.nlm.nih.gov/medlineplus/druginfo/natural/940.html

Melatonin Key Points •Appears to have benefit in various sleep disorders,

but some mixed results in some trials

•Emerging use in pediatric patients though long-term studies have not established safety

•Be aware of potential drug interactions


Valerian Background •Origin

• Most common in dietary supplements is Valeriana officinalis L. from the Valerianaceae family

• Over 200 plant species

•Uses

• Insomnia, anxiolytic

•Mechanism

• Valeproates and valeric acid result in sedation

• Valeric acid and other components may effect GABA receptors

Hadley S, Petry JJ. Valerian. Am Fam Physcian. 2003;67(8):1755-1758.

Valerian Evidence •Meta – analysis of 18 trials

• 8 high quality studies

•Primary outcome measures and results:

• Sleep quality (yes/no)

• RR of 1.37 (95% CI, 1.05-1.78) vs. placebo

• Sleep quality improvement through visual analog scales

• -0.02 (95% CI, -0.35 to 0.31)

• Latency Time (LT) in minutes to sleep

• 0.70 min (95% CI, -3.44 to 4.83)

• Subjective improvements only demonstrated

Fernández-San-Martín MI, Masa-Font R, Palacios-Soler L, et al. Sleep Med. 2010;11:505–11.

Valerian Safety •Generally well tolerated

•Possible headache or paradoxical excitement

•CNS depressant, avoid with medications that can potentiate this effect

•Possible withdrawal symptoms

•Avoid in pregnancy and lactation

Ulbricht C, Chao W, Costa D, et al. Curr Drug Metab. 2008;9:1063–120.


Valerian Key Points •Evidence to support use is limited

• Subjective improvements, lacking quantitative data to demonstrate effectiveness

•Well tolerated, be aware of potential adverse effects and drug – herb interactions

Valerian. URI Medicinal Garden (K. Orr)

Chamomile Background •Origin

• Chamomilla recutita L.

• Matricia chamomilla and Matricaria recutita


•Uses

• GI spasms, inflammation of GI, skin, mucous membranes, anxiolytic, and sedative

•Mechanism

• Binding to GABA receptors, modulation of monoamine neurotransmission

1. McKay DL, Blumberg JB. Phytother. Res. 2006.20;519-30. 2. Sarris J, et. al. Eur Neuropsychopharmacol..2011;21(12):841-60.

Chamomile Evidence •Though popular through teas for inducing sleep,

overall lacking evidence of efficacy

•Randomized, double-blind, placebo-controlled pilot study with DSM-IV primary insomnia for ≥ 6-months

• 34 patients taking 270 mg of chamomile twice daily or placebo twice daily

• No significant changes with sleep diary measures, daytime symptoms, and safety assessments

•Controlled studies to support tea not available

Zick SM, Wright BD, Sen A, Arnedt JT. BMC Complement Altern Med. 2011;11:78.


Chamomile Safety •Avoid in patients with allergy to ragweed and related


•Contact dermatitis, contact urticaria, and angioedema have been reported

• Unknown if underlying allergy

•Theoretical drug/herbal interactions

• Coumarin may potentiate anti-platelet or anti-thrombotic effects

•Mild sedative effect, avoid with benzodiazepines, opioids, and alcohol McKay DL, Blumberg JB. Phytother. Res. 2006.20;519-30.

Chamomile Key Points •Evidence is limited to support efficacy in the

treatment of primary insomnia

•Well tolerated, be aware of potential adverse effects and drug – herb interactions


Chamomile. URI Medicinal Garden (K. Orr)

Lemon Balm Background •Origin

• Melissa officinalis L. of the family Lamiaceae

•Uses

• Insomnia, agitation related to dementia, GI complaints, or topically for cold sores

•Mechanism

• Volatile oils: citronellal, geranial, and neral have demonstrated sedative effects

• Thought to inhibit GABA and MOA-B

1. Ulbricht C, Brendler T, Gruenwald J.et. al. J Herb Pharmacother. 2005;5(4):71-114. 2. Wheatley D. J Psychopharmacol. 2005;19:414.


Lemon Balm Evidence •Lacking rigorous evidence to support for sleep

• Most trials are small, pilot studies

• Many studies are with combination products such as valerian

• Subjective improvements in sleep quality have been significant and well tolerated

1. Taavoni S, Nazem Ekbatani N, Haghani H. Complement Ther Clin Pract. 2013;19(4):193-6. 2. Cases J, Ibarra A, Feuillère N, Roller M, Sukkar SG. Med J Nutrition Metab. 2011;4(3):211-218. 3. Müller SF, Klement S. Phytomedicine. 2006;13(6):383-7.

Lemon Balm Safety •Generally well tolerated

•Caution with other medications or natural products with sedative properties

•Topical administration has been association with hypersensitivity reactions

•Potential for thyroid inhibition, avoid in patients with underlying problems

Ulbricht C, Brendler T, Gruenwald J.et. al. J Herb Pharmacother. 2005;5(4):71-114.

Lemon Balm Key Points •Small studies to support potential benefit for sleep

disorders, overall lacking

• Unknown if lemon balm or other contributing natural product combinations

•Well tolerated, be aware of sedative properties


Lavender Background •Origin

• Lavandula angustifolia Miller of the family Lamiaceae

•Uses

• Insomnia, digestive disorders, topically as antiseptic or rubefacient

•Mechanism • Linalyl acetate and linalool are active constituents thought to have

calming/sedative effects

• May have effects on cholinergic, dopaminergic, glutamate, opioidergic, and GABA transmission

Denner SS. Holist Nurs Pract. 2009;23(1):57-64.

Lavender Evidence •Prospective, randomized study of 67 women from

ages 45 – 55 years old for 12 weeks

• CPSQI (Chinese version of Pittsburgh Sleep Quality Index) greater than 5

• Twice a week were given lavender aromatherapy or control group provided sleep hygiene education

• Results:

• Significant decrease from baseline in CPSQI in lavender group (p<0.001) vs. control (p=0.776)

• No change in resting heart rate or heart rate variability

Chien LW, Cheng SL, Liu CF. Evid Based Complement Alternat Med. 2012;2012:740813.

Lavender Evidence • Single – blinded, randomized, controlled study of 64 patients

in the CCU over 3 days1 • Nine hours lavender aromatherapy vs. no intervention

• Lavender group score: 20.12 ± 5.76 at baseline vs. 13.97 ± 2.58 (p < 0.001) vs. control group score: 18.31 ± 4.44 at baseline vs. 18.68 ± 3.52 (p = 0.27)

• After aromatherapy, the lavender group score was also significantly less than the control score (p<0.001)

• Randomized, controlled, pilot study of 50 patients in the intermediate care unit2

• Patients received 3 mL 100% lavender oil from 10 pm – 6 am while control group received usual care

• BP was significantly lower between 12 pm - 4 am in the lavender group vs. control group (P = 0.03)

• Average overall sleep score was higher in lavender group (48.25) vs. control group (40.10), but not significant

1. Moeini M, et. al. Nazari F. Iran J Nurs Midwifery Res. 2010;15(4):234-9 2. Lytle J, Mwatha C, Davis KK.. Am J Crit Care. 2014;23(1):24-9.


Lavender Safety •Well tolerated, no established contraindications or

drug interactions

•Caution with other medications or natural products with sedative properties

•Mild dermatitis and photosensitivity has been reported with topical use

•Case reports of gynecomastia combined with tea tree oil, resolved upon discontinuation

•Another more recent case report in 14-month female

•Historically avoided in pregnancy and lactation

Denner SS. Holist Nurs Pract. 2009;23(1):57-64.

Lavender Key Points •Evidence from small trials, many pilots, to support

aromatherapy for improved sleep

•Often favored as aromatherapy because well tolerated, minimal side effects, and lack of drug interactions

Lavender. URI Medicinal Garden (K. Orr)

DS Adverse Event Reporting •Dietary Supplement and Nonprescription Drug

Consumer Protection Act of 2006 •Requires labeling and mandatory adverse events (AE)

reporting of DS • Packaging will display name and address of entity collecting AE data

and state they are responsible for FDA reporting

•Definition of “serious adverse events”: • Death • A life-threatening experience • Inpatient hospitalization • A persistent or significant disability or incapacity • A congenital anomaly or birth defect • Medical or surgical intervention

US Food and Drug Administration. Dietary Supplement and Nonprescription Drug Consumer Protection Act. Pub L No. 109 – 462. 109th Congress. December 22, 2006.


AE Reporting System • January 2014 - Department of Health and Human

Services' Safety Reporting Portal to simplify and improve reports: www.safetyreporting.hhs.gov

• Manufacturers

• Consumers and health – care providers

•Reports forwarded to Center for Food Safety and Applied Nutrition (CFSAN)

• CFSAN AER system (CAERS)

• Reviewer evaluates and characterizes event

Frankos VH, et. al. Clin Pharmacol Ther. 2010;87(2):239-44.

Recalled Supplements •Analysis from January 1, 2009 – December 31, 2012

recalled supplements

•Purchased supplements through internet or in retail stores which were previously recalled

• Total of 274 recalled

•Tested products showed:

• 18/27 (67%) had ≥ 1 adulterated ingredient

• Sports enhancement

• Weight loss

• Sexual enhancement

• Greater enforcement and awareness needed

Cohen P, Neal-Kababick J. JAMA. 2014;321:1691-3.

In the News– New York Investigation of Dietary Supplements

O’Connor A. New York Attorney General Targets Supplements at Major Retailers. New York Times [February 3, 2015]. Accessed Feb. 3, 2015 at: http://well.blogs.nytimes.com/2015/02/03/new-york-attorney-general-targets-supplements-at-major-retailers/?_r=0


Recent Findings – New York Investigation of Dietary Supplements • February 2015 – New York State attorney general’s office accused 4

major retailers of mislabeling, contamination, and false advertising

• The following products were tested:

• Gingko biloba, St. John’s Wort, ginseng, echinecea, saw palmetto, valerian root, and garlic

• Approximately 1/3 of those tested did not result in labeled contents using DNA testing

• All retailers named were sent cease-and-desist letters, with requests of procedures used to verify contents

• March 2015 – CT, IN, and Puerto Rico join

• Some experts question DNA barcode analysis as inappropriate for identification purposes for DS contents

1. O’Connor A. New York Times [February 3, 2015]. Accessed Feb. 3, 2015 at: http://well.blogs.nytimes.com/2015/02/03/new-york-

attorney-general-targets-supplements-at-major-retailers/?_r=0 2. O’Connor A. New York Times [March 9, 2015]. Accessed Mar. 19, 2015 at: http://well.blogs.nytimes.com/2015/03/09/safety-of-herbal-

supplements-pulls-prosecutors-together/ 3. Morrell A. Forbes [March 16, 2015]. Accessed Mar. 19, 2015 at:http://www.forbes.com/sites/alexmorrell/2015/03/14/did-the-ny-ag-flub-

its-testing-in-herbal-supplement-smackdown/

Council for Responsible Nutrition. New white paper on DNA barcode testing refutes results from New York Attorney General’s investigation of botanical supplements. [March 9, 2015] Available at: http://www.crnusa.org/prpdfs/CRNPR15-NewWhitePaperonDNABarcodeTesting031115.pdf. Accessed on: March 19, 2015.

Quality Assurance Resources Quality Entity Websites

ConsumerLab.com www.consumerlab.com

United States Pharmacopeia

Dietary Supplement Verification Program

www.usp-dsvp.org

NSF International www.nsf.org/consumer/consu

mer_dietary.html


Self- Assessment Question 1 •Which of the following dietary supplements has the

strongest level of evidence to support use for prevention of migraine?

•A. Butterbur

•B. Feverfew

•C. Riboflavin (vitamin B2)

•D. Magnesium

•E. All are equally effective

Self- Assessment Question 1 •Which of the following dietary supplements has the

strongest level of evidence to support use for prevention of migraine?

•A. Butterbur

•B. Feverfew

•C. Riboflavin (vitamin B2)

•D. Magnesium

•E. All are equally effective

Assessment Question 2 •Which of the following dietary supplements could be

safely used in a patient with underlying ragweed allergy?

•A. Butterbur

•B. Feverfew

•C. Chamomile

•D. Lavender

•E. None of the above are safe


Assessment Question 2 •Which of the following dietary supplements could be

safely used in a patient with underlying ragweed allergy?

•A. Butterbur

•B. Feverfew

•C. Chamomile

•D. Lavender

•E. None of the above are safe

Self-Assessment Question 3 •Which of the following statements is correct

regarding dietary supplements recalled by the FDA?

•A. The FDA strictly enforces products are not remarketed until recalled ingredient is removed.

•B. The majority of products recalled are those used for insomnia

•C. More aggressive enforcement capability of recalled ingredients should be given to the FDA

Self-Assessment Question 3 •Which of the following statements is correct

regarding dietary supplements recalled by the FDA?

•A. The FDA strictly enforces products are not remarketed until recalled ingredient is removed.

•B. The majority of products recalled are those used for insomnia

•C. More aggressive enforcement capability of recalled ingredients should be given to the FDA

botanicals & the brain: an update on dietary … · •cite evidence-based data describing the...

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