TOP SUPPLEMENTS:LATEST EVIDENCE

Gregory Shumer, MD, MHSA

University of Michigan

Department of Family Medicine – Integrative Medicine

OBJECTIVES & OUTLINE

Objectives: Review evidence for commonly-used supplements

Understand when supplements may be appropriate to recommend in outpatient setting

Outline Case-based learning and supplement review

Conclusions / Questions

CASE 1

27-year-old previously healthy male

Has had mild headaches for years, but always resolved with ibuprofen

Started working a new job with more stress over the summer, and started developing new, more severe headaches

Describes headaches as starting on left side, frontal/temporal. Feels throbbing, made worse by bright lights. 6-8/10 in intensity. Symptoms last 1-2 days then resolve. Happening about once per week and sometimes causes him to miss work. Ibuprofen no longer effective

CASE 1 - MIGRAINE

Diagnostic criteria:

A. At least five attacks fulfilling criteria B-D

B. Headache attacks lasting 4-72 hr

C. Headache has at least two of the following four characteristics: unilateral location pulsating quality moderate or severe pain intensity aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs)

D. During headache at least one of the following: nausea and/or vomiting photophobia and phonophobia

E. Not better accounted for by another ICHD-3 diagnosis.

International Classification of Headache Disorders, 3rd Edition: https://www.ichd-3.org/1-migraine/1-1-migraine-without-aura/

MIGRAINE PREVENTION: MAGNESIUM

Low levels of ionized magnesium levels in patients with migraines, especially menstrual migraines (1-2)

Daily magnesium supplementation reduces migraine frequency and intensity (3-4)

Dose for migraine prevention: 400-1000 mg daily

Potential side effects: Loose stools & diarrhea, more common with magnesium oxide and magnesium citrate

Types to look for: magnesium glycinate, magnesium taurate, magnesium malate, chelated magnesium

1. Mauskop A, Altura BT, Altura BM: Serum ionized magnesium levels and serum ionized calcium/ionized magnesium ratios in women with menstrual migraine. Headache. 2002 Apr;42(4):242-8. 2. Mazzotta G. et al. Electromyographical ischemic test and intracellular and extracellular magnesium concentration in migraine and

tension-type headache patients. Headache. 36:357-361 1996 3. Teigen L, Boes CJ: An evidence-based review of oral magnesium supplementation in the preventive

treatment of migraine. Cephalalgia. 2014 Dec 22. 4. Peikert A, Wilimzig C, Kohne-Volland R: Prophylaxis of migraine with oral magnesium. Results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia. 16:257-263 1996

MAGNESIUM

Magnesium is also useful for: Fibromyalgia-related pain (1)

Magnesium levels (serum, erythrocyte) lower in fibromyalgia patients than controls

Treatment with magnesium decreased tender points and pain scores

Diabetes and metabolic syndrome (2)

Magnesium intake inversely associated with metabolic syndrome and diabetes

Hypomagnesemia more common in individuals with type 2 diabetes

Premenstrual syndrome (2)

Taking magnesium orally can reduce mood change, anxiety symptoms, and premenstrual migraines

GI Symptoms: Constipation, GERD

1. Bagis S et al. Is magnesium citrate treatment effective on pain, clinical parameters and functional status in patients with fibromyalgia? 2013 Jan;33(1):167-72. doi: 10.1007/s00296-011-2334-8. Epub 2012 Jan 22. 2. https://naturalmedicines-therapeuticresearch-com.proxy.lib.umich.edu/databases/food,-herbs-supplements/professional.aspx?productid=998#effectiveness

MIGRAINE PREVENTION:VITAMIN B2 (RIBOFLAVIN)

Precursor for two coenzymes involved in redox reactions. May improve mitochondrial energy reserves in neurons

Studies show improvement in preventing migraines compared to placebo (1-2)

May have synergistic preventive effects when used with beta blocker (3)

Safe in children and in pregnancy

1. C. Boehnke, U. Reuter, U. Flach, S. Schuh-Hofer, K.M.Einhaupl, G. Arnold: High-dose riboflavin treatment is efficacious in migraine prophylaxis: an open study in a tertiary care centre. Eur J Neurol. 11:475-477 2004 2. J. Schoenen, J. Jacquy, M. Lenaerts: Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial, Neurology. 50 (2):466-470 1998 3. P.S. Sandor, J. Afra, A. Ambrosini, J. Schoenen: Prophylactic treatment of migraine with beta-blockers and riboflavin: differential effects on the intensity dependence of auditory evoked cortical potentials. Headache. 40:30-35 2000

CASE 1 TREATMENT RECOMMENDATIONS

Look for potential triggers and avoid triggers if possible Aim for quality sleep

Stress management

Look for dietary or environmental triggers

Imitrex (sumatriptan) 50 mg at onset of migraine, repeat x 1 if needed 2 hours later

Magnesium (as magnesium glycinate, taurate, malate or chelated): 400-500 mg daily

Vitamin B2 200 mg twice daily

CASE 2

22-year-old female college student coming in for symptoms of bloating, intermittent diarrhea, abdominal pain, and overall discomfort

Symptoms present most days per week, have been ongoing for about a year. Bowel movements are variable, sometimes normal, sometimes diarrhea 2-3 times per day

Triggers: Stress (exams, relationships), certain foods (sweets, carbs)

Alleviating Factors: Symptoms were not as severe over summer vacation

Otherwise generally healthy; no chronic medical conditions

IRRITABLE BOWEL SYNDROME (IBS)

Rome IV Diagnostic Criteria Recurrent abdominal pain at least 1 day per week for the past 3 months, with symptom

onset at least 6 months prior to diagnosis

PLUS at least 2 of the following:

Symptoms related to bowel movements (either better before or after bowel movements)

Symptoms associated with change in stool frequency

Symptoms associated with change in stool form

Subtypes

IBS-C, IBS-D, IBS-M, IBS-U

Based on Bristol Stool Scale Types

Schmulson MJ, Drossman DA. What is New in Rome IV. J Neurogastroenterol Motil. 2017 Apr; 23(2): 151–163.

PROBIOTICS

Probiotics significantly reduce bloating, pain, flatulence, and fecal urgency symptoms Very few studies on prebiotics and synbiotics

Studies are heterogenous, and cannot make conclusion on specific strains or species of probiotics

Dosing: At least 20 billion CFU daily, including species of Lactobacillus and Bifidobacterium

Dietary Supplements: Fiber Meta-analysis of 14 studies found significant improvement in IBS scores with soluble

fiber interventions

Improves microbiome diversity

Examples in studies: Psyllium, Wheat Bran

1. Didari T et al. World J Gastroenterol. Mar 14 2015. 2. Ford AC et al. Am J Gastroenterol. Oct 2014. 3. Moayyedi P, et al. Am J Gastroenterol. Sept 2014.

PROBIOTICS

Also useful for:

Prevention of antibiotic-associated diarrhea (1) Cochrane Review showed lower incidence of diarrhea (8 vs. 19%) with probiotics groups

Infant Colic (2) Systematic review of 5 RCTs found 2.3-fold reduction with probiotics for infant colic

Depression & Anxiety (3) 2017 RCT of 10 studies found improvement of depression, anxiety, and fatigue scores

compared to placebo

Other areas of research Diabetes, obesity, asthma, hypertension, IBD, autism, ADHD, GERD, hyperlipidemia…

1. Cochrane Review 2015: Probiotics for the prevention antibiotic-associated diarrhea in children 2. Bird AS et al, Probiotics for the Treatment of Infantile Colic: A Systematic Review, 2016 3. Wallace CJ, Malev R. The effects of probiotics on depressive symptoms in humans: a systematic review. Ann Gen Psychiatry. 2017; 16: 14.

CASE 2 TREATMENT RECOMMENDATIONS

22-year-old female with IBS-D Identify triggers and pro-actively avoid triggers.

Discuss stress management and mindfulness

Start daily probiotics: At least 20 billion CFU daily, including species of Lactobacillus and Bifidobacterium

Increase fiber in diet, or start daily Metamucil or Benefiber

For acute episodes of frequent diarrhea, can use Imodium as needed

CASE 3

49-year-old male with history of ulcerative colitis presenting with worsening knee pain

X-rays confirm moderate-to-severe osteoarthritis in bilateral knees

Asking for alternative remedies to help with pain control

TURMERIC & CURCUMIN

Curcumin is the active phytochemical contained within the spice turmeric

Has been shown to exhibit anti-inflammatory and anti-oxidant effects

Displays mild immunosuppressant effects by inhibiting IL-2, TNF-α, and IFN-γ

Has anti-inflammatory effects in the gut through inhibiting chemokines and neutrophil activity

Rakel D. Integrative Medicine Fourth Edition. Elsevier Inc. Philadelphia, PA. 2018

CURCUMIN FOR OSTEOARTHRITIS

2016 meta-analysis of turmeric (curcumin) for alleviating arthritis pain

8 RCTs included in analysis

Turmeric superior to placebo in reducing pain scores mean difference in pain visual analogue scores of -2.04 [-2.85, -1.24] (p < 0.00001)

No statistically significant difference in pain scores between turmeric and NSAID medications (ibuprofen, diclofenac)

Average dose in study: 1000 mg daily dose

Daily JW, Yang M, Park S. Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Journal of Medicinal Food, 19:8, August 2016

CURCUMIN FOR ULCERATIVE COLITIS (UC)

Useful both as primary treatment and adjuvant therapy for ulcerative colitis 90% symptomatic improvement on curcumin compared to placebo

RCT: 89 UC patients on mesalamine therapy randomized to curcumin 1000 mg BID or placebo

Reduced symptoms, UC flares, and endoscopic inflammation in curcumin group

Useful in active UC on optimized mesalamine therapy

Clinical remission achieved in 54% of patients who had curcumin added to regimen, compared to 0% of placebo group

Dose for ulcerative colitis treatment: 1000 mg twice daily

1. P.R. Holt, S. Katz, R. Kirshoff: Curcumin therapy in inflammatory bowel disease: a pilot study. Dig Dis Sci. 50 (11):2191-2193 2005. 2. H. Hanai, et al.: Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 4(12):1502-1506 2006. 3. A. Lang, et al.: Curcumin in combination with mesalamine induces remission in patients with mild-to-moderate ulcerative colitis in a randomized controlled trial. ClinGastroenterol Hepatol. 2015

CASE 3 TREATMENT RECOMMENDATIONS

49-year-old with history of ulcerative colitis on mesalamine presenting with worsening knee pain related to osteoarthritis

Refer to physical therapy

Curcumin 1000 mg as daily supplement. If still symptomatic, or if UC is active or worsening –increase to 1000 mg twice daily

CASES 4

36-year-old female coming in with recurrent urinary tract infection (UTI)

Frequently develops UTI after intercourse, and UA in clinic confirms UTI

Third infection in the past year

Asking for alternative remedies to help prevent future urinary tract infections

CRANBERRY EXTRACT

Use dates back to Native American tribes for urinary conditions

Inhibits bacterial adhesion to the bladder wall and decreases bacterial virulence (1,2)

1. A.B. Howell, H. Botto, C. Combescure, et al.: Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study. BMC Infect Dis. 10:94 2010. 2. D.G. de Llano, A. Esteban-Fernández, F. Sánchez-Patán, et al.: Anti-adhesive activity of cranberry phenolic compounds and their microbial-derived metabolites against uropathogenic Escherichia coli in bladder epithelial cell cultures. Int J Mol Sci. 16(6):12119-12130 2015

CRANBERRY EXTRACT

2012 Cochrane Review (1) Cranberry juice or capsules may decrease

frequency of UTI in susceptible women

High drop-out rate due to difficulty adhering to daily juice consumption

Cranberry extract 400-800mg BID reduces frequency of UTI (2,3)

Similar efficacy of cranberry extract 500 mg BID vs. trimethoprim 100 mg daily for UTI prevention (4)

1. R.G. Jepson, G. Williams, J.C. Craig: Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev. 10:CD001321 2012 Oct 17. 2.E.B. Walker, D.P. Barney, J.N. Mickelsen, et al.: Cranberry concentrate: UTI prophylaxis. J Fam Pract. 45:167-168 1997. 3. E.E. Mazokopakis, C.M. Karefilakis, I.K. Starakis: Efficacy of cranberry capsules in prevention of urinary tract infections in postmenopausal women. J Altern Complement Med. 15:1155 2009. 4. M.E. McMurdo, I. Argo, G. Phillips, et al.: Cranberry or trimethoprim for the prevention of recurrent urinary tract infections? A randomized controlled trial in older women. J Antimicrob Chemother. 63 (2):389-395 2009

CRANBERRY EXTRACT

Has been studied for treatment of UTI May be effective, though results are not

consistent

Cranberry for lower urinary tract symptoms (LUTS) in men Small study (n = 21) showed greater

improvement in symptom reduction in cranberry group versus control

500 mg three times daily

A. Vidlar, J. Vostalova, J. Ulrichova, et al.: The effectiveness of dried cranberries (Vaccinium macrocarpon ) in men with lower urinary tract symptoms. Br J Nutr.104:1181-1189 2010

CASE 4 - TREATMENT

Treat current UTI with antibiotics

Behavioral ways to reduce recurrent infections: Eliminate use of spermicides

Urinate after intercourse

Start cranberry extract: 500 mg BID

CASE 5

60-year-old male with worsening lower urinary tract symptoms (LUTS) Waking up 4-5 times overnight to urinate

Slower stream and difficulty initiating stream

Difficulty emptying bladder

PSA has been checked and has been stable long-term

Would like to try something natural before committing to a prescription medication

SAW PALMETTO

Small palm that grows in Southeastern United States

Weak inhibitor of 5-alpha-reductase

Anti-inflammatory effect on prostate gland

Reduction of androgen receptors on prostate

Rakel D. Integrative Medicine Fourth Edition. Elsevier Inc. Philadelphia, PA. 2018

SAW PALMETTO

Mixed evidence: Improved symptom scores, nocturia,

residual urine volume, and urinary flow in patients with BPH (1)

Large RCT (over 1000 men): Saw palmetto as effective as finasteride –37% reduction in symptoms (2)

Cochrane Review 2012:

No significant difference between saw palmetto and placebo for LUTS related to BPH (3)

Recommended Dose: 160 mg twice daily

Allow 8 weeks to see full benefit1. G.S. Gerber, G.P. Zagaja, G.T. Bales, et al.: Saw palmetto (Serenoa repens) in men with lower urinary tract symptoms: effects on urodynam parameters and voiding symptoms. Urology. 51:1003-1007 1998. 2. J.C. Carraro, J.P. Raynaud, G. Koch, et al.: Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients. Prostate. 29:231 1996. 3. J. Tacklind, R. Macdonald, I. Rutks, J.U. Stanke, T.J. Wilt: Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev. 12 2012

CASE 5 - TREATMENT

Start supplement with saw palmetto at dose of roughly 160 mg twice daily

If still symptomatic at 2-month follow-up, discuss starting Flomax

CASE 6

23yo male with worsening depression, lack of energy, over-sleeping

Low self-esteem, has difficulty leaving home. Still functioning OK at work but has difficulty concentrating; reports good social support. Lives at home with parents.

Otherwise healthy. Not on any medications. Does not want to start SSRI due to concern for sexual side effects

Not in therapy; has not tried other therapies

PHQ-9 = 12

GAD=7 = 4

SUPPLEMENTS: RHODIOLA ROSEA

Traditional medicine cultures have used Rhodiola rosea as an herb to promote work endurance, resistance against fatigue, depression, and other conditions

May enhance mood via effects on central biogenic amines and endorphins

May stimulate norepinephrine, serotonin, dopamine, and acetylcholine receptors in brain

Good safety profile

Mao JJ et al. Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial

SUPPLEMENTS: RHODIOLA ROSEA

High-quality RCT compared Rhodiolaversus sertraline 50 mg for mild-moderate depression and found both better than placebo, and equally effective

Rhodiola with fewer side effects and smaller drop-out rate

Dosing: 200-400 mg 1-2 times daily

Side effects: anxiety / jitteriness

Mao JJ et al. Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial

CASE 6 - RECOMMENDATIONS

Lifestyle: Need to pursue something in terms of hobbies and exercise. Encouraged leaving the house for walks outdoors – most days per week. Discussed light box for SAD. Healthy diet.

Medications/Supplements: Rhodiola 400 mg once daily in the morning

Meet with SW for psychotherapy

CONCLUSIONS

Consider recommending supplements when appropriate

Examples discussed today: Magnesium

B2

Probiotics

Curcumin

Cranberry extract

Saw Palmetto

Rhodiola

Good resources Consumerlab.com (less than $4 per month)

Natural Medicines (through UM Library)

REFERENCES

International Classification of Headache Disorders, 3rd Edition: https://www.ichd-3.org/1-migraine/1-1-migraine-without-aura/

Mauskop A, Altura BT, Altura BM: Serum ionized magnesium levels and serum ionized calcium/ionized magnesium ratios in women with menstrual migraine. Headache. 2002 Apr;42(4):242-8.

Mazzotta G. et al. Electromyographical ischemic test and intracellular and extracellular magnesium concentration in migraine and tension-type headache patients. Headache. 36:357-361 1996

Teigen L, Boes CJ: An evidence-based review of oral magnesium supplementation in the preventive treatment of migraine. Cephalalgia. 2014 Dec 22.

Peikert A, Wilimzig C, Kohne-Volland R: Prophylaxis of migraine with oral magnesium. Results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia. 16:257-263 1996

Bagis S et al. Is magnesium citrate treatment effective on pain, clinical parameters and functional status in patients with fibromyalgia? 2013 Jan;33(1):167-72. doi: 10.1007/s00296-011-2334-8. Epub 2012 Jan 22

https://naturalmedicines-therapeuticresearch-com.proxy.lib.umich.edu/databases/food,-herbs-supplements/professional.aspx?productid=998#effectiveness

C. Boehnke, U. Reuter, U. Flach, S. Schuh-Hofer, K.M.Einhaupl, G. Arnold: High-dose riboflavin treatment is efficacious in migraine prophylaxis: an open study in a tertiary care centre. Eur J Neurol. 11:475-477 2004

J. Schoenen, J. Jacquy, M. Lenaerts: Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial, Neurology. 50 (2):466-470 1998

P.S. Sandor, J. Afra, A. Ambrosini, J. Schoenen: Prophylactic treatment of migraine with beta-blockers and riboflavin: differential effects on the intensity dependence of auditory evoked cortical potentials. Headache. 40:30-35 2000

Schmulson MJ, Drossman DA. What is New in Rome IV. J Neurogastroenterol Motil. 2017 Apr; 23(2): 151–163.

Ford AC et al. Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis. Am J Gastroenterol. Oct 2014.

Moayyedi P, et al. The effect of fiber supplementation on irritable bowel syndrome: a systematic review and meta-analysis. Am J Gastroenterol. Sept 2014.

Didari T et al. Effectiveness of probiotics in irritable bowel syndrome: Updated systematic review with meta-analysis. World J Gastroenterol. Mar 14 2015.

REFERENCES

Rakel D. Integrative Medicine Fourth Edition. Elsevier Inc. Philadelphia, PA. 2018

Daily JW, Yang M, Park S. Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Journal of Medicinal Food, 19:8, August 2016

P.R. Holt, S. Katz, R. Kirshoff: Curcumin therapy in inflammatory bowel disease: a pilot study. Dig Dis Sci. 50 (11):2191-2193 2005.

H. Hanai, et al.: Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 4(12):1502-1506 2006.

A. Lang, et al.: Curcumin in combination with mesalamine induces remission in patients with mild-to-moderate ulcerative colitis in a randomized controlled trial. Clin Gastroenterol Hepatol. 2015

A.B. Howell, H. Botto, C. Combescure, et al.: Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study. BMC Infect Dis. 10:94 2010.

D.G. de Llano, A. Esteban-Fernández, F. Sánchez-Patán, et al.: Anti-adhesive activity of cranberry phenolic compounds and their microbial-derived metabolites against uropathogenic Escherichia coli in bladder epithelial cell cultures. Int J Mol Sci. 16(6):12119-12130 2015

R.G. Jepson, G. Williams, J.C. Craig: Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev. 10:CD001321 2012 Oct 17.

E.B. Walker, D.P. Barney, J.N. Mickelsen, et al.: Cranberry concentrate: UTI prophylaxis. J Fam Pract. 45:167-168 1997.

E.E. Mazokopakis, C.M. Karefilakis, I.K. Starakis: Efficacy of cranberry capsules in prevention of urinary tract infections in postmenopausal women. J Altern Complement Med. 15:1155 2009.

M.E. McMurdo, I. Argo, G. Phillips, et al.: Cranberry or trimethoprim for the prevention of recurrent urinary tract infections? A randomized controlled trial in older women. J Antimicrob Chemother. 63 (2):389-395 2009

A. Vidlar, J. Vostalova, J. Ulrichova, et al.: The effectiveness of dried cranberries (Vaccinium macrocarpon ) in men with lower urinary tract symptoms. Br J Nutr.104:1181-1189 2010

G.S. Gerber, G.P. Zagaja, G.T. Bales, et al.: Saw palmetto (Serenoa repens) in men with lower urinary tract symptoms: effects on urodynam parameters and voiding symptoms. Urology. 51:1003-1007 1998.

J.C. Carraro, J.P. Raynaud, G. Koch, et al.: Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients. Prostate. 29:231 1996.

J. Tacklind, R. Macdonald, I. Rutks, J.U. Stanke, T.J. Wilt: Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev. 12 2012

Mao JJ et al. Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial