DIETARY SUPPLEMENTS
Definitions:
· Dietary supplement - regulatory term. Includes vitamins, minerals, herbs, botanicals, fatty acids, and amino acids as long as they are prescribed in dosage forms, such as capsules, tablets, liquids, gels or powders.
· Nutraceutical - includes dietary supplements and foods with therapeutic value
· Medical food – a specific combination of whole food macronutrients (carbohydrate, fat, protein) with micronutrients and botanical extracts, designed with a specific therapeutic goal in mind, prepared in powder form.
· Functional food – foods that provide health benefits beyond basic nutrition. Many occur naturally (i.e. tomatoes, broccoli), and others are commercially prepared, such as calcium-fortified orange juice or omega 3 fortified eggs.
· Vitamins - complex organic substances (i.e. carbon containing compounds) not made in the body, essential in small quantities for normal functioning of the body. (Vitamin D is an exception; it is made in the body from cholesterol if there is sun exposure. Niacin is an exception too; it is synthesized in small amounts in the body from tryptophan).
· Minerals - non-organic (i.e. no carbon atoms), homogenous substances found in the earth's crust.
Popularity: Sales of all dietary supplements, including vitamins, minerals, herbs, and a variety of other compounds defined in the U.S. as dietary supplements was estimated at $8.8 billion in 1994, $15.7 billion in 2000, $17.8 billion in 2001.
Fatty acids - molecular building blocks of fats. Clinical features of deficiency include alopecia, atopic dermatitis, brittle nails, dandruff, dry hair, fatty liver, , polydipsia, polyuria, and slow wound healing.
·
o This is derived entirely from plants, but is not efficiently converted into EPA and DHA in the human body.
§
Only about 15% of
§
Conversion of
§ Omega 6 fats and omega 3 fats compete for metabolic conversion via the D6D enzyme.
§ The D6D enzyme requires a number of cofactors, including magnesium, zinc, biotin, and vitamins B3, B6, and C.
§
Trans fat intake, diabetes, aging, excess
alcohol, excess cholesterol intake, and excess sugar intake all interfere with
conversion of
§ PCBs damage the D5D and D6D enzymes.
o Benefits
§ Seed husks are a good source of fiber, and will be beneficial in those with constipation.
§
According to Barry Sears, PhD,
§
Dietary
§ Associated with reduced risk of heart disease death in 5 prospective observational studies, and in particular the Lyon Diet Heart Study, and also in 3 open label trials, with a meta-analysis of these trials showing a relative risk of CAD death of 0.79 in association with ALA intake (J Nutr. 2004. 134. 919).
o Negative study – a 12 week RCT in 60 healthy adults found that 30 ml of flaxseed oil provided few additional benefits for adults participating in a resistance training program (Appl Physiol Nutr Met. 2009. 34. 49-59).
o Risks
§ A systematic review and meta-analysis identified 8 prospective and 8 retrospective studies (including the large prospective cohort PLCO study) identified a relative risk (RR) of prostate cancer of 1.2 among individuals with the highest quantile intakes of ALA, as well as the highest blood or adipose tissue ALA concentrations (Am J Clin Nutr. 2009. 89. 1558S-1564S as cited in Alt Med Alert. 2009. 12. 129-130).
§ The pooled RR was 1.02 in prospective studies, 1.51 in retrospective studies (p=0.08 for the 51% increased risk in the retrospective studies).
§
The pooled RR was 1.09 in studies assessing
dietary intake, 1.54 in studies assessing whole blood, serum, or adipose tissue
levels of
§ The RR dropped from 1.2 to 0.94 after adjustment for publication bias.
§
At 5.1 years of follow up in the PLCO trial,
with ~30,000 participants, men in highest quintile of
§
Authors identified 6 additional studies that
could not be included in the meta-analysis; 5 of these 6 showed no association
between
§
Nine cohort and case control studies show an
association between either
§
In vitro data shows that
§ Seed husks contain cyanogens, which is converted to thiocyanate, which inhibits iodine uptake by the thyroid, possibly leading to goiter. Note cyanogen is destroyed by cooking, and flax oil is free of cyanogen.
· CLA
o May promote lean body mass and may support healthy glucose metabolism through a PPAR agonist effect.
o Exists in supplement form in either a free fatty acid form or as a stabilized form which is resistant to oxidation.
· Fish oil capsules – contain EPA (eicosapentanoic acid) and DHA (docosahexanoic acid), which are anti-inflammatory omega 3 fatty acids.
o For information on dietary sources and mechanism of action, return to Home Page and click on “Nutrition” and scroll to polyunsaturated fats.
o Excellent review article: J Am Board Fam Pract. 2005. 18. 28-36.
o Safety:
§ Bleeding – theoretical risk; EPA binding to platelets is reversible, and only partially inhibits platelet aggregation.
§ In a RCT in 511 patients undergoing CABG and on aspirin or warfarin, those randomized to 4 grams per day of omega 3 fatty acids did not show elevation of the bleeding time or of bleeding episodes (Blood Coagul Fibrinolysis. 1995. 6. 17-22).
§ In a 1 year RCT of 610 patients undergoing CABG, those who received 4 grams per day of fish oil concentrate showed no increase in bleeding. All patients in this trial received antithrombotic treatment, either aspirin or warfarin. (Am J Cardiol. 1996. 77. 31-36).
§ There are no published reports of clinically significant abnormal bleeding events (Am Fam Physician. 2004. 70. 133-140).
§ A review of 19 studies of omega 3 fatty acids in patients undergoing CABG, carotid endarterectomy, or femoral artery catheterization found that none of these studies identified an increased bleeding risk in those taking fish oil (Am J Cardiol. 2007. 99. 44C-46C).
§ Retrospective review of medical records in 182 patients, most with coronary artery disease, taking high dose fish oil (mean dose 3 gm) and aspirin (mean dose 161 mg) and clopidogrel (Plavix - mean dose 75 mg) identified 1 major and minor bleeding episodes over 33 months of follow up. In comparison, a retrospective review of medical records in 182 age and sex matched controls taking aspirin and Plavix, but not taking fish oil identified 1 major and 7 minor bleeding episodes in the control group over the same 33 months. “In conclusion, high dose fish oil is safe in combination with aspirin and clopidogrel…” (Am J Cardiol. 2009. 104. 1052-1054).
§ In 1523 patients at 24 US centers whose omega 3 indexes were assessed at the time of acute MI, there was no relation between omega 3 index and bleeding, suggesting that regular consumption of omega 3 fatty acids does not increase bleeding risk (Am J Cardiol. 2012. 109. 13-18).
§ Glucose elevation - conflicting reports regarding effect on glucose levels in diabetics – one RCT showed a slight increase in fasting glucose but no increase in glycosylated hemoglobin (Am J Clin Nutr. 2002. 76. 1007-1015), but another study showed no effect on glucose (Ann N Y Acad Sci. 1993. 683. 337-340).
§ LDL - may increase LDL by approximately 5%, especially in those with elevated triglycerides. The additional LDL is large, dense LDL which is thought to be less pathogenic (J Lipid Res. 1990. 31. 1549-1558).
§ Mercury – manufacturing process removes most mercury that might have been present in the fish itself.
o ADHD – a review concludes that the data on fish oils and ADHD is encouraging, but not conclusive (Prostaglandins Leukot Essent Fatty Acids. 2006. 75. 299-308).
o Alzheimer’s prevention
§ Animal studies in transgenic mice show that oral intake of DHA reduces Alzheimer-like amyloid beta and tau pathology (J Neurosci. 2007. 27. 4385-4395).
§ Studies of plasma levels of omega 3 fatty acids have shown higher levels correlated with a reduced risk of Alzheimer’s (Am J Clin Nutr. 2003. 77. 803-808; Arch Neurol. 2006. 63. 1545-1550).
§ Several studies have reported that dietary intake of omega 3 fatty acids is associated with a reduced risk of cognitive decline (Am J Epidemiol. 1997. 145. 33-41; Ann Neurol. 1997. 42. 776-782; BMJ. 2002. 325. 932-933; Arch Neurol. 2003. 60. 940-946; Am J Clin Nutr. 2007. 85. 1142-1147), with a protective benefit suggested in a Cochrane analysis (Cochrane Database Syst Rev. 2006. CD005379).
§ However, an 18 month multisite RCT in 402 individuals randomized to take 2 grams per day DHA (from algae) versus a matched placebo failed to show any differences in cognitive or functional decline despite elevation of plasma phospholipid levels and CSF DHA (in a subgroup). Furthermore, in another subgroup which underwent baseline and follow up brain MRI imaging, there was no effect of DHA supplementation on total brain or hippocampal volume changes in the treatment group versus the placebo group (JAMA. 2010. 304. 1903-1911 and editorial 1952-1953).
§ A 6 month, 3 arm RCT in 50 individuals over age 65 and with mild cognitive impairment, comparing a supplement rich in EPA (1.67 g EPA+0.16 g DHA/day), a supplement rich in DHA (1.55 g DHA+0.40 g EPA/day) and a safflower oil control group found minimal effect of either fish oil supplement (no effect on memory or cognition in the high EPA supplement group, improved scores for verbal fluency but not any other measure of memory or cognition in the high DHA group). However, the high DHA group, and to a lesser extent, the high EPA group, showed less depressive symptoms, based on scores on the Geriatric Depression Scale (Sinn N et al. Br J Nutr. Epub 9/20/11).
o Anxiety in a population of substance abusers – a 3 month RCT in 24 patients found improvement in anxiety symptoms in patients treated with 3 grams/day of EPA + DHA (J Clin Psychopharmacol. 2006. 26. 661-665).
o Arrhythmia – review article (Reiffel JA, McDonald A. Am J Cardiol. 2006. 98. 50i-60i)
§ Four RCTs have shown a reduced rate of sudden death without a consistent change in risk of MI (Lancet. 1989. 2. 757-761; Lancet. 1994. 343. 1454-1459; Cardiovasc Drugs Ther. 1997. 11. 485-491; Circulation. 2002. 105. 1897-1903).
§ Atrial fibrillation – human data, which includes “epidemiologic, observational, and randomized studies on incident, paroxysmal, and postoperative atrial fibrillation with acute or chronic fish oil exposure have been contradictory” (Am J Cardiol. 2011. 108. 531-535 - this statement in the text includes 8 references).
§ A RCT in 160 patients who received fish oil 2 grams/day for 5 days pre-CABG showed that the incidence of atrial fibrillation in the treatment group was 15.2% compared with 33% in the control group [p=0.013](J Am Coll Cardiol. 2005. 45. 1723-1728).
§
NEGATIVE STUDY – a 24 week multicenter trial in
663
§ Mechanistic study - 36 patients with paroxysmal atrial fibrillation who were randomized to a control group versus a treatment group of 6 grams of fish oil per day for a mean of 40 days prior to an EP study showed that those “chronically supplemented with fish oils exhibit distinctive electrophysiologic properties including prolonged pulmonary venous and left atrial ERPs and decreased susceptibility to initiation AF from within PVs. These changes may in part explain the antifibrillatory effects of chronic omega-3 … supplementation in patients with AF” (Am J Cardiol. 2011. 108. 531-535).
§ In patients with an implantable cardioverter-defribrillator (ICD), results are mixed.
§ Positive trial – a RCT in 402 patients showed that at 12 months of follow up, those receiving 4 gm/day of fish oil had a 28% event rate, compared with a 39% event rate in the control group (Eur J Clin Nutr. 2003. 57. 1323-1330).
§ Negative trial – those treated with 1.8 grams per day of fish oil in ethyl ester form and concentrated such that the supplements contained 42% EPA and 30% DHA showed that at a median follow up of 718 days there was NOT a reduced risk of VT/VF and in fact a trend toward proarrhythmia, with a 59% event rate in the control group and a 65% event rate in the fish oil group. These were individuals who had not had a recent MI and had the device implanted for arrhythmia not directly temporally associated with arrhythmia, so the authors conclude that the negative results of this trial suggest that the antiarrhythmic effect of fish oil manifests only in the presence of myocardial ischemia. There is some data that the mechanism of arrhythmia is different acute ischemia versus VT/VF in those with coronary artery disease but no acute ischemia (JAMA. 2005 293. 2884-2891).
§ Positive trial – a RCT in 500 patients showed that at 12 months of follow up, those receiving 2 gm/day of fish oil had a 30% event rate, compared with a 33% event rate in the control group (Circulation. 2007. 116. e320-e335).
§ Meta-analysis of 3 trials (n=1148) suggested that patients with coronary artery disease might benefit whereas patients with heart failure might not. Arrhythmias in those with CAD are often due to ectopic beats and prolonged action potentials whereas arrhythmias in those with CHF are often caused by reentry (Eur Heart J. 2009. 30. 820-826).
o Asthma – strong theoretic rationale (i.e. Singular is a leukotriene antagonist), with mixed clinical trial results; Cochrane review concludes there is little evidence to support supplementation (Cochrane Database Syst Rev. 2002. CD001283).
§ In a one year RCT in 12 asthmatics, those who were given fish oil (3 grams per day) showed a 23% improvement in FEV-1, but not until after 9 months of treatment (Int Arch Allergy Appl lmmunol. 1991; 95:156-157).
§ Dramatic benefit in terms of lower airway hyper-responsiveness in 50% of 26 asthmatics who followed a strictly defined omega-3 containing diet for one month (Am J Clin Nutr. 1997. 65. 1011-1017).
§ A crossover RCT of EFA supplementation in 16 patients with exercise-induced asthma found that PFTs improved in the treatment group, bronchodilator use decreased, and there was a reduced concentration of inflammatory mediators in the sputum (Chest. 2006. 129. 39-49).
§ An intriguing RCT in 553 pregnant women administered either omega 3 fatty acids 2.7 grams per day or olive oil (placebo) from week 30 of pregnancy until delivery showed a statistically significant 63% reduction (p=0.03) in asthma in their offspring at 16 years of age (Am J Clin Nutr. 2008; 88: 167-175).
§ In a RCT in 60 children with moderate persistent asthma, 1 gm/day omega 3 fatty acids for 6 weeks associated with significant improvement in childhood asthma control test, PFTs, and sputum inflammatory markers. Additional benefit in this trial when combined with zinc 15 mg/day and vitamin C 200 mg/day (Acta Paediatr. 2009. 98. 737-742).
o Back pain – in a study in which 250 patients seen by a neurosurgeon and diagnosed with nonsurgical neck and back pain were asked to initiate fish oil at a dose of 1.2 g/day EPA + DHA, and then mailed a questionnaire 1 month later, 125 of the 250 returned the questionnaire, at an average of 75 days on the fish oil. 78% were taking 1200 mg and 22% were taking 2400 mg of EFAs. 59% discontinued their prescription NSAID medications for pain. 60% stated that their overall pain was improved, and 60% stated that their joint pain had improved. 80% stated they were satisfied with their improvement, and 88% stated they would continue to take the fish oil (Surgical Neurology. 2006. 65. 326-330).
o Bipolar disease – see manic depression below.
o Borderline personality disorder – in an 8 week RCT in 30 women meeting DSM-IV criteria, those who consumed 1 g/day of ethyl-EPA showed diminished aggression and less severe depressive symptoms (Am J Psychiat. 2003. 160. 167-169).
o CAD – primary and secondary prevention (Return to Home Page and go to “Prevention MI” for details and references).
§ Aggregate data in 2005 from 11 studies and 50,000 subjects shows an average 30% decrease in sudden death. Not all of these studies were randomized, controlled.
§ Along with data that fish oil decreases arrhythmias, also data that it increases vascular compliance and decreases blood pressure.
§ The American Heart Association in 2002 deemed the evidence for the role omega 3 fatty acid intake in primary and secondary prevention of heart disease strong enough to recommend in a position statement (1) two 3 ounce portions per week of fatty fish or 1 fish oil capsule daily for primary prevention and (2) 3 ounces of fatty fish or 1 gram per day of supplemental EPA + DHA for secondary prevention (Circulation. 2002. 106. 2747-2757).
§ HOWEVER, a Cochrane review of 48 RCTs and 41 cohort analyses concludes that there is no clear evidence of a reduced risk of cardiovascular events in persons with or at high risk of cardiovascular disease (Cochrane Database Syst Rev. 2004. CD003177).
o Cancer
§ A systematic review concludes that the published literature does NOT support an association between increased omega 3 fatty acid intake and reduced cancer incidence (JAMA. 2006. 295. 403-415).
§ A Cochrane review concludes that there is insufficient data to support a role for omega 3 fatty acid supplementation in the treatment of cancer cachexia (Cochrane Database Syst Rev. 2007. CD004597).
§ Separate published reviews have examined the data with regard to the role of omega 3 fatty acid intake and risk of colorectal cancer (Cancer Detect Prev. 2003. 27. 55-66), prostate cancer prevention (Cancer Causes Control. 2004. 15. 367-386), and non-melanoma skin cancer (Cancer Detect Prev. 2006. 30. 224-232).
o Cardiac surgery
§ A RCT in 160 patients who received fish oil 2 grams/day for 5 days pre-CABG showed that the incidence of atrial fibrillation in the treatment group was 15.2% compared with 33% in the control group [p=0.013](J Am Coll Cardiol. 2005. 45. 1723-1728).
§ A RCT in 200 patients who received 4.6 grams per day EPA + DHA for 3 weeks prior to CABG or heart valve surgery showed no significant reduction in post-operative atrial fibrillation but a significant decrease in time spent post operatively in the ICU (Am J Cardiol. 2011. 108. 851-856).
o CHF
§ In a RCT (GISSI-HF trial) in 7046 patients with symptomatic heart failure of any cause, omega 3 fatty acids at a dose of 1 gram daily reduced mortality (p=0.04), with a NNT of 56 patients for 3.9 years to save one life (Lancet. 2008. 372. 1223-1230).
§ A prospective cohort study of 2735 US adults in 4 communities (Cardiovascular Health Study) showed that higher plasma omega 3 levels at baseline were associated with a lower incidence of CHF, based on 10 years of follow up (Ann Intern Med. 2011. 155. 160-170).
§ In a 12 month RCT of 133 patients with nonischemic cardiomyopathy in which the treatment group received 5 gm/day (prescription) Omacor for one month, and then 2 gm/day for the remainder of the trial, the active treatment group showed a significant improvement in exercise capacity (p < 0.002) and NYHA functional class (p < 0.001). In addition, the EF increased 10.4% in the active-treatment group as compared with a 5% decline in the placebo group (p < 0.001), and the rate of hospitalization for heart failure was 80.5% lower in the active treatment group (5.9% vs. 30.3%, p < 0.0002) [J Am Coll Cardiol. 2011. 57. 870-879].
o Crohn's disease
§
In a 1 year RCT in 78 patients with Crohn’s
disease in remission, enteric coated fish oil capsules at a daily dose of 2.7
g/day of omega 3 fatty acids reduced the absolute rate of relapse by 33% at one
year. All patients entered in this trial were at high risk of relapse based on
elevated serum concentrations of acute phase reactants at baseline (
§ NEGATIVE TRIAL – a multi-center RCT in 204 patients with Crohn’s disease in remission received 5 grams per day of highly concentrated omega 3 fatty acids (Scand J Gastroenterol. 1996. 31. 778-785).
§ NEGATIVE TRIALS – EPIC-1 included 363 patients with Crohn’s disease in remission and EPIC-2 included 375 patients with Crohn’s disease in remission. The dose of fish oil in each trial was 4 grams per day of omega 3 fatty acids (each 1 gram capsule consisted of 50-60% EPA and 15-25% DHA). The endpoint in each trial was rate of relapse at one year. Capsule counts and the significant decrease in serum triglyceride levels indicate that compliance was good (JAMA. 2008. 299. 1690-1697).
§ A Cochrane review concludes that there is insufficient data to recommend omega 3 fatty acid supplementation for maintenance of remission (Cochrane Database Syst Rev. 2007. CD006320).
o Cystic fibrosis – beneficial, based on a Cochrane analysis (Cochrane Database Syst Rev. 2007. CD002201).
o Dementia – see Alzheimer’s just above.
o Depression:
§ Theoretic rationale based on inverse epidemiologic association between DHA consumption and depression, depletion of DHA in rbc cell membranes in individuals with depression (Biol Psychiat. 1998. 43. 315-319; Psychiat Clin N Amer. 2000. 23. 785-794), and association of higher plasma levels of EPA with less severe depressive symptoms in elderly subjects who participated in the Three-City Study (Am J Clin Nutr. 2008. 87. 1156-1162).
§ A randomized trial in which 70 patients with persistent depression despite "adequate" pharmacotherapy were randomized to placebo or EPA at a dose of 1,2, or 4 grams per day for 12 weeks showed a 50% reduction in HAM-D scores in 69% of the ethyl-EPA 1 gram group compared to 25% of the placebo group. For unexplained reasons, the outcomes in those randomized to 2 and 4 grams per day of ethyl-EPA were comparable to those in the placebo group (Arch Gen Psych. 2002. 59. 913-919).
§ A 4 week RCT in which 20 patients with major depression were treated with adjunctive therapy with ethyl EPA 1 gram twice a day or placebo showed significant benefit in the EPA group at week 3 (Am J Psychiat. 2002. 159. 477-479).
§ A RCT in 28 patients showed benefit with 440 mg EPA + 220 mg DHA (Eur Neuropsychopharmacol. 2003. 13. 267-271).
§ A pilot RCT (N=20) in children ages 6-12 showed EPA 400 mg+ DHA 200 mg effective as monotherapy in childhood unipolar depression (Am J Psychiatry. 2006. 163. 1098-1100).
§ A meta-analysis of 10 RCT’s of at least 4 weeks duration identified a significant antidepressant effect, but the quality of the individual studies was variable, and the size often small (J Clin Psychiatry. 2007. 68. 1056-1061).
§ An 8 week RCT in 60 subjects comparing 1 gm EPA with 20 mg fluoxetine (Prozac) with both together showed that EPA and fluoxetine had equal therapeutic effects and the combination was superior to either alone (Aust N Z J Psychiatry. 2008. 42. 192-198).
§ An 8 week RCT of 46 depressed elderly women living in a nursing home showed that the group who received 1.67 g EPA + 0.83 g DHA/day showed a significantly greater response rate on the Geriatric Depression Scale (p=0.004). The remission rate showed a trend toward a higher rate in the treatment group (p=0.07) [J Am Coll Nutr. 2010. 29. 55-64].
§ A 6 month, 3 arm RCT in 50 individuals over age 65 and with mild cognitive impairment, comparing a supplement rich in EPA (1.67 g EPA+0.16 g DHA/day), a supplement rich in DHA (1.55 g DHA+0.40 g EPA/day) and a safflower oil control group found that the high DHA group, and to a lesser extent, the high EPA group, showed less depressive symptoms, based on scores on the Geriatric Depression Scale (Sinn N et al. Br J Nutr. Epub 9/20/11).
o Developmental coordination disorder – in a 3 month RCT in 117 children, fish oil (588 mg EPA + 174 mg DHA) with evening primrose oil did NOT affect coordination, but significant benefits on cognition and behavior were noted (Pediatrics. 2005. 115. 1360-1366).
o Diabetes Type I – a longitudinal, observational study in 1770 children at increased risk for type I diabetes showed that dietary intake of omega 3 fatty acids is associated with a reduced risk (JAMA. 2007. 298. 1420-1428).
o Diabetes Type II
§ Experimental data shows that consumption increases membrane fluidity, improves insulin sensitivity in skeletal muscle, and improves triglyceride values.
§ A meta-analysis of 26 trials showed no significant changes in HbA1c (Diabetes Care. 1998. 21. 494-500).
§ A Cochrane review concludes that there is no effect on glycemic control or fasting insulin (Cochrane Database Syst Rev. 2008. CD003205).
o Dysmenorrhea – in a 2 month RCT in 42 adolescent girls, those who received 1080 mg/day EPA + 720 mg/day showed a marked reduction in the Cox Menstrual Symptom Scale from a baseline mean value of 69.9 to 44.0 (p < 0.0004) [Am J Obstet Gynecol. 1996. 174. 1335-1338].
o Hypertension – a meta-analysis of 36 trials found that average BP reduction is 2.1 mm Hg systolic and 1.6 mm Hg diastolic (J Hypertens. 2002. 20. 1493-1499).
o Hypertriglyceridemia (Alt Med Alert. 2005. 8. 78-82):
§ Mechanism of action – inhibit hepatic triglyceride synthesis.
§ A review identified 36 crossover and 29 parallel design studies using omega 3 supplements, and found that on average 3 grams per day of EPA + DHA decreases triglycerides by 25-30% (Eur J Nutr. 2004. 43. 6S-11S).
§ A meta-analysis of 25 RCTs concluded that each 1 gram increase dose in fish oil per day lowered the triglyceride level by about 8 mg/dl. The higher the baseline, the greater the magnitude of the reduction of triglycerides (Atherosclerosis. 2006. 189. 19-30).
§ Fish oil is complementary to prescription statin treatment for high triglycerides
§ In a RCT in 52 obese men, those receiving a combination of Lipitor 40 mg/day and EPA + DHA 4 grams per day showed a 40% decrease in triglycerides at week 6, compared to a 26% decrease with Lipitor alone and 25% decrease with EPA + DHA alone (Eur J Clin Invest. 2002. 32. 429-436).
§ In a RCT in 18,645 Japanese men and women who received either a statin alone or a statin plus 1800 mg/day of EPA, the incidence of a major coronary event at 5 years of follow up was 19% lower in the combined treatment group [p=0.011](Lancet. 2007. 369. 1090-1098).
o IgA nephropathy – in a 2 year multicenter RCT in 101 patients, fish oil 12 grams per day slowed the rate of loss of renal function (N Engl J Med. 1994. 331. 1195-1199).
o Infertility - omega 3 fatty acid intake correlated with increased female fertility (Obstet Gynecol. 2007. 110. 1050-1058).
o Kidney transplant recipients - a Cochrane review concludes that there is insufficient evidence of benefit (Cochrane Database Syst Rev. 2007. CD005282).
o Lupus – a 24 week RCT in 52 patients showed that those who received Max-EPA 3 grams per day had a significant reduction in disease activity score (SLAM-R) compared to placebo. This was a four-arm trial which also examined copper 3 mg per day and found no benefit compared to placebo (J Rheumatol. 2004. 31. 1551-1556).
o Manic depression
§ In a 4 month RCT with 30 patients with refractory disease, including rapid cyclers, those who received a fish oil DHA/EPA combination, 15 grams per day, had a significantly longer period of remission than did the placebo group [p = 0.002] (Arch Gen Psychiat. 1999. 56. 407-412).
§ In a 12 week RCT in 75 patients randomized into 3 groups, those who received either 1 gram per day ethyl-EPA or 2 grams per day of ethyl-EPA showed significant improvements in depression as measured by the Hamilton Rating Scale and the Clinical Global Impression Scale (Br J Psychiatry. 2006. 188. 46-50).
o Menopause - beneficial in reducing the frequency of hot flashes in an 8 week RCT in 120 women, but did not alter the severity of hot flashes or quality of life scores. The treatment group received one capsule three times a day, with each capsule containing 350 mg of EPA and 50 mg of DHA. The baseline hot flash frequency of 2.8 per day decreased by 58% in the treatment group, compared with 25% in the placebo group (Menopause. 2009. 16. 357-366).
o Migraines - theoretical rationale and anecdotes.
o Obesity – there is data in children that fish oil supplements facilitate weight loss (The Anti-Inflammation Zone. 2005. Pg 236).
o Osteoarthritis - theoretical rationale and anecdotes, and in a 30 day RCT in 90 patients with either OA or RA or CAD, 300 mg/day of Krill oil found to significantly decrease elevated CRP, and reduce functional impairment, as measured by WOMAC score (J Am Coll Nutr. 2007. 26.39).
o Peripheral vascular disease – no evidence of consistent improved clinical outcomes with regard to the symptom of intermittent claudication (Cochrane Database Syst Rev. 2007. CD003833).
o Premenstrual syndrome – Krill fish oil shown in a 30 day RCT in 70 patients to perform better than ‘ordinary’ fish oil - there was statistically significantly greater improvement in the 2 gram/day Krill oil group, compared to the 2 gram /day of fish oil (Alternative Medicine Review. 2003. 8. 171-176).
o Pregnancy
§ DHA stimulates the production of brain-derived neurotrophic factor (BDNF), which is fundamentally important in the formation of neurons (brain cells) and neural connections.
§ Despite preliminary data that omega 3 fatty acid supplementation is beneficial with regard to cognitive development in infants and children (Prostaglandins Leukot Essent Fatty Acids. 2007. 76. 189-203), the DOMInO trial failed to show a difference in postpartum depression or improved language and cognitive development in the offspring during early childhood. This was a RCT in which 2399 women who were less than 21 weeks’ gestation were randomized to receive DHA-rich fish oil capsules (providing 800 mg/day DHA and 100 mg/day EPA) or matched vegetable oil capsules from study entry to birth. Postpartum depression was assessed at 6 weeks and 6 months; language and cognitive development in the offspring was assessed at 18 months. 96.7% of the enrolled women completed the trial (JAMA. 2010. 304. 1675-1683). A positive finding in this trial was a lower risk of very preterm (<34 weeks gestation) birth in the fish oil treatment group, with an odds ratio in the treatment group of 0.49 (Editorial. JAMA. 2010. 304. 1717-1718).
o Psoriasis – theoretical rationale and anecdotes.
o Renal failure - see also IgA nephropathy and kidney transplant recipients
§ Slows progression in a RCT with a mean follow up of 6.4 years, based on a trial in 120 patients given 6 grams per day of fish oil or placebo for two years, with all subjects then given fish oil (J Am Soc Nephrol. 1999. 10. 1772-1777).
o Rheumatoid arthritis
§ A 12 week crossover RCT in 16 patients showed that fish oil is effective in suppressing clinical symptoms of rheumatoid arthritis (Ann Rheum Dis. 1990. 49. 76-80).
§ A 14 week crossover nonrandomized, double-blind, placebo-controlled trial in 40 volunteers showed that those administered 2.7 g EPA + 1.8 g DHA daily experienced significant reduction in subjective symptoms, and also and reduction in neutrophil leukotriene B4 production (Ann Intern Med. 1987. 106. 497-503).
§ A pilot 12 week RCT in 17 patients who consumed 1.8 g EPA and 0.9 g DHA reported less morning stiffness in the treatment group (Lancet. 1985. i. 184-187).
o Schizophrenia
§ In a study of 20 chronic schizophrenics, 6 weeks of treatment with 10 grams per day of marine derived EPA led to significant improvements in negative symptoms (Lipids. 1996. 31. S163-S165).
§ Cochrane review concludes that there is no clear evidence of benefit (Cochrane Database Syst Rev. 2006. CD001257).
§ In a one year RCT of 81 adolescents and young adults, ages 13-25, with subthreshold psychotic states, those randomized to receive 1.2 grams per day omega 3 fatty acids for 12 weeks (with ongoing monitoring for an additional 40 weeks) had a 4.9% risk of development of a psychotic disorder, compared to 27.5% in the placebo group (p= 0.007), for a NNT of 4.4. Treatment with omega 3 fatty acids was associated with fewer positive symptoms of psychosis, such as delusions and hallucinations (p=0.01) as well as fewer negative symptoms, such as social withdrawal and flat affect (p=0.02) [Arch Gen Psychiatry. 2010. 67. 146-154].
o Stroke prevention (thromboembolic stroke)
§ Health Professionals Follow-up Study, a prospective cohort study of 43,671 men aged 40-75 who completed a detailed and validated semi-quantitative food frequency questionnaire, with 12 years of follow-up, showed a significantly lower risk of ischemic stroke in men who consumed fish at least once a month. In this study there was not an association between increase fish consumption and an increase risk of hemorrhagic stroke (JAMA. 2002. 288. 3130-3136).
§ JELIS trial of 18,645 Japanese with hypercholesterolemia (TC > 252 mg/dl) - those randomized to1800 mg per day EPA with statins had a significant reduction in the risk of strok, compared to those assigned to statins (Stroke. 2008. 39. 2052-2058).
o Ulcerative colitis
§ In a 4 month crossover RCT in 24 patients with active ulcerative colitis, those who received EPA 3.24 g/day + DHA 2.16 g/day had reductions in rectal dialysate leukotriene B4 levels, improvements in histologic findings, and weight gain (Ann Intern Med. 1992. 116. 609-614).
§ A Cochrane review concludes that there is no evidence to support omega 3 fatty acid supplementation for maintenance of remission (Cochrane Database Syst Rev. 2007. CD006443).
· GLA (gamma-linolenic acid) – anti-inflammatory omega 6 fatty acid
o Asthma - efficacy seen anecdotally after 6-8 weeks, and in a placebo controlled trial of a medical food containing 750-1130 mg GLA and 500-750 mg EPA (Curr Med Res Opin. 2009. 25. 2865-2875).
o Atopic dermatitis (eczema) – likely ineffective, based on a systematic review of 11 RCTs (Health Technol Assess. 2000. 4. 1-191). However there are published positive trials (Drugs Exp Clin Res. 1988. 14. 285-290 and 291-297).
o Autoimmune conditions - efficacy seen anecdotally after 6-8 weeks.
o Cyclic mastalgia – likely ineffective, based on a systematic review identified which only 3 RCTs of evening primrose oil and a high quality multicenter trial of GLA, and found no significant effect (Breast. 2007. 16. 503-512).
o Diabetic neuropathy – possibly effective, based on results of several small studies (Diabet Med. 1990. 7. 319-323; Diabetes Care. 1993. 16. 8-15; J Am Board Fam Pract. 2003. 16. 47-57).
o Eczema – see atopic dermatitis just above
o Fetal alcohol syndrome – 900 mg/day may be effective
o Menopause – lack of efficacy, based on a 6 month RCT in 56 women with a dose of evening primrose oil of 4 gm twice a day (BMJ. 1994. 308. 501-503).
o Premenstrual syndrome – likely ineffective, based on a systematic review of 4 small trials of evening primrose oil at doses of 3-6 gm/day (Am J Obstet Gynecol. 2001. 185. 227-235).
o Raynaud’s – may be effective, based on results of one double blind trial (Thromb Haemost. 1985. 54. 490-494).
o Rheumatoid arthritis – a Cochrane review found insufficient evidence to make a reliable assessment (Cochrane Database Syst Rev. 2001. CD002948). However, the author of a subsequent review article concluded “Strong support exists for GLA for pain of rheumatoid arthritis” (Clin J Pain. 2004. 20. 13-18).
o Sources include evening primrose oil (2% to 16% GLA), black currant seed oil (17% GLA), and borage oil (22% GLA).
o NOTE there is some concern about potential toxicity of borage oil based on pyrrolizidine alkaloid content (J Am Pharm Assoc. 1996. NS36. 29-37). Varro E. Tyler, PhD states in his book Herbs of Choice (1994) “Borage seeds have been shown to contain small amounts of pyrrolizidine alkaloids, including the known hepatotoxin amabiline…This means that in the interest of consumer safety, borage seed oil should be certified free of UPAs (unsaturated pyrrolizidine alkaloids) down to the level of 0.5 to 1 mcg/g” (Page 139). HOWEVER, there is data that the UPAs are water soluble and thus not a concern in the oil.
o
At a mechanistic level, health promoting effects
thought due in part to facilitation of conversion of
o Usual supplemental dose is 1000-1500 mg per day.
Amino acids
· Molecular building blocks of protein.
· Given for precursor value, not to supplement protein intake.
· Best taken on an empty stomach.
· L-arginine (1000-2000 mg twice daily)
o Used in treatment of hypertension, coronary artery disease, congestive heart failure (Circulation. 1996. 93. 2135-2141), peripheral vascular disease, erectile dysfunction.
o Precursor of nitric oxide.
o May be dangerous in those on prescription nitroglycerin preparations.
o Theoretically, may exacerbate outbreaks of herpes. However there is data that L-arginine supplementation does NOT affect lysine levels.
o Supplementation may deplete glycine levels.
· L-carnitine (2000-6000 mg/day)
o Plays an essential role in energy production by transporting fatty acids into the mitochondrial matrix for oxidation.
o May improve recovery and stamina in athletes (Physiologie. 1989. 26. 111-129; Am J Physiol. 2002. 282. E474-482).
o
Requirements for carnitine increase in pregnancy
due to the high carnitine requirements of the fetus, and plasma levels in mothers are often low during
pregnancy (Am J Obstr Gyn. 1981. 140.
412-414).
o Treats angina (Clin Trials J. 1986. 23. 338-344), cancer cachexia, congestive heart failure (Int J Clin Pharmacol Ther Toxicol. 1988. 26. 217-220; JACC. 1995. 26. 380-387; Am Heart J. 2000. 139. S120-S123), COPD (Brazilian 2006 study), diabetes (Eur J Clin Nutr. 2005. 59. 592-596), HIV (Immunopharmacol and Immunotoxicol. 1993. 15. 1-12), hypertension (La Clinica Terapeutica. 1994. 144. 391-395), hyperthyroidism (Ann N Y Acad Sci. 2004. 1033. 158-167), impotence (Urology. 2004. 63. 641-646), infertility [male](Fertility and Sterility. 2005. 84. 662-671), MI (Drugs Exp Clin Res. 1992. 18. 355-365), multiple sclerosis, and peripheral vascular disease
o May increase anticlotting action of coumadin.
o Increases oxidative stress, so if supplementing, consider also supplementing with antioxidants.
o
PRECAUTIONS
§ L-carnitine supplementation should be accompanied by biotin supplementation, as per Robert Crayhon, M.S. 1 mg of biotin (a sulfur containing amino acid) for every 500 mg of L-carnitine, because carnitine may increase gluconeogenesis and thus may increase blood sugar, and biotin may inhibit some of the enzymes responsible for gluconeogenesis.
§
Carnitine at doses greater than 2000 mg/day can
reduce thyroid hormone activity, or lead to the need for a higher dose of
medication in those on medication for hypothyroidism, as per
· L-glutamine (2 - 10 g/day)
o Readily synthesized by cells; most prevalent amino acid in bloodstream.
o During catabolic stress, intracellular levels drop more than 50%; thus categorized as a conditionally essential nutrient.
o Critical nutrient for enterocytes in the small intestine and certain immune cells (macrophages and neutrophils); stored in muscle.
o Used to treat cravings due to low blood sugar, memory impairments, depression, fatigue, diarrhea, wounds, peptic ulcer disease, inflammatory bowel disease.
o Evidence suggests that oral supplementation of 5-10 grams immediately after completing a workout may decrease the incidence of URI's in athletes (Alternative Medicine Alert. 2001. 4. 65-67).
· L-lysine (500-1000 mg twice daily)
o Prevents recurrences of herpes, may enhance effect of L-carnitine.
o More effective if seeds, nuts, peas, and chocolate (dietary sources of arginine) are limited.
o Note that vegetarian diets tend to be relatively lysine deficient.
· L-phenylalanine (500-1000 mg daily or in a.m. and before lunch)
o Metabolic precursor of norepinephrine and dopamine, excitatory neurotransmitters.
o May be useful in the treatment of chronic depression, Parkinson's disease.
o May raise blood pressure.
· D-phenyalanine
o May prevent breakdown of brain's natural narcotics.
o May be useful in the treatment of chronic pain.
· DL-phenylalanine (1000 mg daily in the morning)
o May be effective for treatment of depression without raising blood pressure.
o May help with appetite control via stimulation of release of CCK, an appetite suppressant.
· L-taurine (500-2000 mg twice daily)
o Used in treatment of palpitations, arrhythmias, chronic pain, chronic fatigue syndrome, depression, anxiety, irritability, seizure disorders, heart failure (double blind crossover trial in 14 patients for 4 weeks reported in Clin Cardiol. 1985. 8. 276-282).
· L-theanine (50-200 mg as needed, up to four times a day0
o Found in green tea, this is an amino acid derivative.
o Promotes relaxation by increasing alpha brain waves (Trends in Food & Science Technology. 1999. 10. 199-204).
· L-tryptophan (1-3 grams at bedtime)
o Metabolic precursor of serotonin, a neurotransmitter with sedative effects.
o Used as a natural sedative.
o Relatively contra-indicated in autoimmune and inflammatory states.
o Banned in 1989 as a dietary supplement based on association of this supplement with eosinophilia-myalgia syndrome (38 deaths and 1500 total cases). This syndrome was subsequently shown to be due to a contaminant traced to a single Japanese manufacturer, Showa Denko, and not the amino acid itself, but OTC status for the supplement has not been reinstated. May be available by prescription through a compounding pharmacy.
· L-tyrosine (500-1500 mg twice a day)
o Also a metabolic precursor of norepinephrine and dopamine, excitatory neurotransmitters.
o May also raise blood pressure.
Alpha lipoic acid
(
· Antioxidant which is both fat and water soluble, initially thought to be a vitamin, but then found that it is synthesized in the body in very small amounts.
· Sulphur containing substance which functions as a coenzyme in mitochondrial electron transport.
· Converted in the body to DMPS, which binds arsenic and mercury.
· Bioavailability is good.
· Production decreases with age.
· Food sources include liver, yeast, organ meats, broccoli, red meat, and red potatoes.
· Helps to regenerate glutathione.
· Dosage is 40-50 mg per day for health maintenance, 200-300 mg per day for diabetics.
· Safety
o High doses may deplete the body of thiamine, riboflavin, and niacin, so best to take a B complex vitamin with alpha lipoic acid.
o Decreases conversion of T4 to T3 by 56% (Arzneimittelforschung. 1991. 41. 1294).
·
Synthetic
· Poly-MVA is a proprietary product in which lipoic acid is bound to the trace mineral palladium. The binding of lipoic acid to an electrically charged metal substrate increases the absorption of the lipoic acid at a cellular level. There are many anecdotes of subjective improvement in individuals with cancer who take this supplement. More information available at www.polymva.com.
· Uses:
o Diabetic neuropathy - used by European practitioners for this indication for 20 years. A randomized trial in 120 diabetics with symptomatic polyneuropathy in which the treatment group received intravenous infusions of 600 mg of alpha lipoic acid per day for 14 daily doses showed significant symptom improvement in the treatment group (Diabetes Care. 2003. 26. 770-776).
o Diabetes - shown to decrease insulin resistance and lower blood sugar (Arzneim Forsch. 1995. 45. 872-874; Diabetes. 1996. 45. 1798).
o HIV - inhibits replication of the virus.
o Liver disease - complementary to silymarin (milk thistle).
o Memory loss - animal studies show that supplementation improves memory of aged white mice, but not younger mice.
o Neurodegenerative diseases - theoretical benefit, based on test tube data showing that alpha lipoic acid inhibits peroxynitrite-mediated strand damage and hydroxyl radical formation.
Co-enzyme Q 10
(Ubiquinone) [Pizzorno JE and
· Naturally occurring compound with the following functions
o Essential to mitochondrial oxidative phosphorylation (i.e. cofactor in energy production via the electron-transport chain).
o Antioxidant – protects the mitochondria, protects LDL cholesterol from oxidation, and (in conjunction with vitamin C) protects vitamin E from oxidation.
o Reduces CRP levels (in a study in baboons, in conjunction with vitamin E).
o Reduces Lp (a) levels at a dose of 120 mg of Q gel per day in a trial in 25 patients with coronary artery disease (Int J Cardiol. 1999. 68. 23-29).
· Concentrations are highest in tissues with high energy needs (i.e. heart, kidney, muscle).
· Serum levels can be measured, and a ‘normal’ Co Q10 level is 0.7 - 1 mcg/ml (Aim for a level of 2.5 – 3.5 mcg/ml in CHF, as per Ann Intern Med. 2000. 133. 745-746).
·
First identified in 1957 at the
· This is a fat-soluble vitamin-like quinine, similar in structure to vitamin K.
· Naturally present in certain animal foods (beef heart, beef and fish muscle, and eggs) – most humans consume 3-5 mg/day from dietary sources.
· In addition to obtaining CoQ 10 from our diet, humans can synthesize it – synthesis requires at least 8 vitamins and minerals as co-factors.
· Factors which affect CoQ 10 levels in humans
o Age - levels of CoQ 10 in the organs decrease with age (Biochim Biophys Acta. 1995. 1271. 195). Levels in a 70 year old are approximately 50% of the levels in a 20 year old.
o CHF - there is some data that CoQ 10 levels in heart muscle are low.
o Medications
§ Tricyclic antidepressants - shown in some instances to inhibit CoQ 10 dependent enzymes.
§ Phenothiazines (for schizophrenia) - shown in some instances to inhibit CoQ 10 dependent enzymes.
§ Antihypertensives – HCTZ, Clonidine, beta-blockers (may decrease CoQ 10 dependent enzymes).
§ HMG CoA reductase inhibitors (statins) for high cholesterol - decrease CoQ 10 levels by inhibiting CoQ 10 production (JAMA. 2002. 287. 598-605; Biofactors. 2003. 18. 101-111; Arch Neurol. 2004. 61. 889-892; AtherosclerThromb. 2005. 12. 111-119). Note that some or possibly even all of the decrease in serum CoQ 10 levels may be a function of the decrease in LDL cholesterol induced by the statin drug.
§ Diabetes medications - second generation sulfonylureas and biguanide drug therapies for diabetes may decrease CoQ 10 levels.
§ Oral contraceptive use is associated with lower Co Q 10 levels.
· Supplement forms of Co Q 10 (Note absorption of CoQ 10 in supplement form is problematic because CoQ10 is lipophilic; taking with a fatty meal may enhance absorption).
o Softgels which contain solubilized formulations of soy bean oil or emulsifying agents are more absorbable than powder-based capsules or tablets (Nutr Res. 2002. 22. 919-929; Int J Vitam Nutr Res. 1998. 68. 109-113).
o Q-Gel is a patented soft gel in which the particle size is reduced from 25-50 microns in most softgels to 0.4 microns, so it is highly absorbable, as demonstrated by a pharmacokinetic study which showed that the area under the curve was more than twice as high for Q-Gel, as compared with softgel capsules with an oil suspension, powder filled hard-shell capsules, or regular tablets (Int J Vitam Nutr Res. 1998. 68. 109-113).
o All-Q is a solubilized tablet form of C0 Q 10 with better bioavailability than Q-SorB (Nature’s Bounty) and bioequivalence with Q gel (J Med Food. 2005. 8. 397-399).
o CoQsource is the commercial brand of Co Q 10 manufactured using a patented technology, VESIsorb, which creates a colloidal delivery system. A study in 20 healthy men and women showed that the area under the curve with this preparation was greater than that for 3 other oil-based preparations (brand names not specified) [Alt Ther Health Med. 2009. 15(2). 42-46].
o The natural form of Co Q 10 synthesized by biological fermentation/extraction from yeast may be superior to the synthetic form which is chemically synthesized.
o Ubiquinol versus ubiquinone
§ Ubiquinone is the oxidized form
§ Ubiquinol is the reduced form, which is the active form in the body. This became available in supplement form in 2006.
§ Not all patients are able to convert ubiquinone in supplements to ubiquinol. Genetics and age play an important role in this process.
§ In a small trial in 7 patients with symptomatic CHF despite an average of 450 mg/day of ubiquinone, the patients were switched to ubiquinol, average dose 580 mg/day, and plasma total Co Q 10 levels increased from 1.6 mcg/ml to 6.5 mcg/ml, EF increased from 22% to 39%, and symptoms improved (Biofactors. 2008. 52. 435-441).
· Dosage and plasma levels
o Dosage is variable; with doses as high as 1200 mg/day used in clinical trials.
o Splitting the daily dose produces more sustained blood levels than taking the full dose all at once (Biol Pharm Bull. 2003. 26. 52-55).
o Total plasma Co Q 10 levels can be measured; a therapeutic level is considered to be 2.0 - 2.5 mcg/ml, an optimal level 3.5 mcg/ml.
o For most people, the plasma total CoQ10 measurement is approximately 80% ubiquinol and 20% ubiquinone (Biofactors. 1999. 9. 225-229).
· Safety:
o May decrease effectiveness of coumadin. However, in a 4 week prospective placebo-controlled trial (published in Danish) in 24 stable patients taking warfarin, 100 mg Co Q 10 did not affect the INR (Ugeskr Laeger. 2003. 165. 1868-1871).
o Case reports of hypoglycemia and hypotension.
o Some brands contain the additive propylene glycol – this may be an issue if high doses are used, such as for Parkinson’s disease.
o Primarily eliminated via the biliary tract, so it can accumulate in patients with hepatic impairment or biliary obstruction.
· Adverse reactions are rare – mild GI discomfort reported in less than 1% of patients in RCTs (US Pharmacist. 2000. 28-41).
· Cost: varies with brand, on average $30 for 100 mg/day.
·
Uses:
Estimated $200 million in sales in 2002 in the
o Adriamycin
(doxorubicin) administration for lung cancer – 60-200 mg/day of CoQ 10 may be
beneficial (Integr Cancer Ther. 2005.
4. 110). May be best to initiate Co Q 10 3-5 days before initiating
adriamycin. In one study cited by
o AIDS - markedly depleted serum levels. In one open trial (no placebo group), 6 AIDS patients took 200 mg CoQ 10 for 7 months, and helper T cell counts went up in 3 of the 6. Five of the 6 reported symptomatic improvement, and no opportunistic infections were observed in the treatment group (Biochem Biophys Res Commun. 1988. 153. 888-896 and Biochem Biophys Res Commun. 1991. 176. 786-791).
o ALS – a dose escalation trial showed that doses as high as 3000 mg/day for 8 months are safe (Neurology. 2005. 65. 1834-1836), and a RCT is underway in 2006.
o Angina - 4 week, double-blind, placebo-controlled, randomized, cross over protocol using 12 patients and 50 mg CoQ 10 three times a day - exercise time increased (p <0.05) and time until 1 mm depression increased (p <0.01) [Am J Cardiol. 1985. 56. 247-251].
o Asthma – 120 mg per day of Q gel along with 400 mg of alpha tocopherol (vitamin E) and 250 mg of vitamin C reduced the amount of steroid medications required to keep asthma under control in a study in 41 patients (Biofactors. 2005. 25. 235-240).
o Breast cancer
§ 32 women with high-risk breast cancer based on spread of the cancer to the axillary lymph nodes received 90 mg CoQ 10 along with vitamin C, vitamin E, beta carotene and essential fatty acids in an open-label trial and tumor size regressed in 6 of the women (Molec Aspects Med. 1994. 15. S231-240).
§ 2 women with metastatic breast cancer treated with 390 mg/day CoQ 10 showed dramatic regression of cancer (Biochem Biophys Res Commun. 1995. 212. 172-177).
o CAD – see ‘Angina’ just above and ‘MI” just below.
o CHF:
§ Conclude that large, well-designed studies on this topic are lacking. The limited data from well-designed trials indicate there may be some minor benefits with CoQ10 therapy with regard to ejection fraction and end diastolic volume (Ann Pharmacother. 2005. 39. 1522-1526; J Cardiol Fail. 2006. 12. 464-472).
§ A well designed study requires measuring levels and achieving a plasma Co Q 10 level of at least 2.5 mcg/ml, preferably 3.5 mcg/ml (Ann Intern Med. 2000. 133. 745-746).
§ The clinical trial data –mixed (negative studies might be due to lack of achievement of a therapeutic plasma Co Q 10 level):
1. Positive study – marked improvement in CHF Class in 7 of 11 heart transplant candidates treated with CoQ 10 (Biochem Biophys Res Commun. 1992. 182. 247).
2. Negative study – 100 mg per day of Co Q 10 ineffective; plasma levels of Co Q 10 not monitored (Eur Heart J. 1992. 13. 1528-1533).
3. Positive study – 1 year, multi-center, double-blind Italian study with 322 patients getting placebo and 319 patients getting 2 mg/kg/day of CoQ 10. The number of patients requiring hospitalization was smaller (p <0.001) and the episodes of pulmonary edema were reduced (p <0.001). There was no difference in mortality between the two groups. All patients were already on conventional treatment, and were NYHA class III and IV. The authors extrapolated that treating 1000 CHF patients for one year would prevent 200 hospitalizations (Clin Investig. 1993. 71. S134-S136; Integrative Med. 1998. 1. 79-80).
4. Borderline positive study - randomized, double-blind, controlled crossover trial with 79 patients found a nonsignificant increase in ejection fraction, a slight increase in exercise tolerance, and a slight increase in subjective quality of life (J Card Fail. 1995. 1. 101-107).
5. Negative study - 12 week randomized, double blind, controlled trial with 22 patients with ejection fraction less than 45% who received placebo or CoQ 10 100 mg bid, with all baseline drugs continued. Stroke index at rest improved significantly {p<0.005}, but ejection fraction remained unchanged (Biofactors. 1999. 9. 285-289).
6. Negative study - 3 month randomized, double-blind, controlled crossover trial with 30 patients taking 33 mg CoQ 10 three times a day or placebo found no increase in resting systolic function (J Am Coll Cardiol. 1999. 33. 1549-1552).
7. Negative study - 6 month randomized, double blind, controlled trial of 55 patients with Class III or IV CHF and ejection fraction less than 40% receiving 200 mg/day of CoQ 10 or placebo. There was no effect on ejection fraction, peak oxygen consumption, or exercise duration above and beyond that of the standard medical therapy. Mean treatment plasma Co Q 10 level was only 2.2 mcg/ml (Ann Intern Med. 2000. 132. 636-640). Dr Alan Gaby postulates that this study conducted at an inner city hospital and a VA hospital may have been negative because the study population had multiple nutrient deficiencies which were not corrected and thus negated a possible beneficial effect of CoQ 10 (IMCJ. 2006).
8. Negative study – mean plasma Co Q 10 level was only 1.7 mcg/ml (Med J Aust. 2001. 175. 447).
9. Positive study – a RCT in 32 patients awaiting heart transplant showed symptomatic improvement with 60 mg/day (Clin Cardiol. 2004. 27. 295-299).
10. Negative study – no significant improvements in symptoms or cardiac function seen in a group of 15 pediatric patients with dilated cardiomyopathy (Pediatr Cardiol. 2005. 26. 361).
11. Positive study - symptomatic benefit reported in an open-label trial with over 2000 patients (Ann Pharmacol. 2005. 39. 1522).
12. Positive study – significant improvement in ejection fraction, brachial artery endothelial-dependent relaxation, and VO2 peak in a double-blind, placebo-controlled crossover trial in 23 patients with ischemic CHF (Eur Heart J. 2006. Aug 1 Epub).
13. Positive study - in 7 patients with symptomatic CHF despite an average of 450 mg/day of ubiquinone, the patients were switched to ubiquinol, average dose 580 mg/day, and plasma total Co Q 10 levels increased from 1.6 mcg/ml to 6.5 mcg/ml, EF increased from 22% to 39%, and symptoms improved (Biofactors. 2008. 52. 435-441).
o CKD – a 12 week RCT in 97 patients showed that 180 mg/day of Q gel produced a significant reduction in serum creatinine and BUN, and a reduced need for dialysis (J Nutr Environ Med. 2000. 10. 221-228).
o Diabetes – a 12 week RCT in 74 diabetics found that Co Q 10 200 mg daily was associated with modest improvements in HbA1c in type II diabetics, although not statistically significant (p = 0.32) [Eur J Clin Nutr. 2002. 56. 1137-1142]. A trial of Q gel 120 mg per day in 30 hypertensive patients with coronary artery disease showed improvement in insulin metabolism at 8 weeks (J Human Hypertension. 1999. 13. 203-208). Other studies failed to show benefit.
o Ergogenic aid to increase exercise capacity in healthy athletes - several good quality studies show lack of efficacy, and a theoretic concern is that CoQ 10 may act as a pro-oxidant under acidic conditions (Alternative Medicine Alert. 1/02. 5[1]. 5-80).
o Gastric ulcer – benefit for healing documented in mice.
o Gingivitis - biopsies show lower gum tissue CoQ 10 levels in patients with periodontal disease compared with healthy controls. Significant benefit seen in a 3 week double-blind trial using 50 mg daily (Res Commun Chem Pathol Pharmacol. 1975. 12. 111-123 and 1976. 14. 715-719).
o Huntington's chorea - a randomized 30 month study in 347 patients given a 300 mg chewable wafer of CoQ 10 failed to show significant benefit (Neurology. 2001. 57. 397-404), but studies using 600-1200 mg a day showed a 15% slowing in decline in function and a 35% reduction in cerebral cortex lactate concentrations (Mov Disord. 1996. 11. 321-323; Ann Neurol. 1997. 41. 160-165)
o Hypertension (mechanism of action uncertain; hypothesized to be a reduction in peripheral resistance due to preservation of nitric oxide)
§ A meta-analysis found that while Co Q 10 was well tolerated in small, short term RCTs, evidence for efficacy was mixed (J Hum Hypertens. 2007. 21. 297-306).
§ A systematic review of 8 trials of variable quality, and using Co Q 10 at variable doses, 100-225 mg daily, found a mean decrease in systolic blood pressure of 16 mm Hg and a mean decrease in diastolic blood pressure of 10 mm Hg. (Biofactors. 2003. 18. 91-100).
§ Citations for individual published studies include: (Curr Ther Res. 1990. 47. 841-845. Mol Aspects Med. 1994. 15. S257-S263; Mol Aspects Med. 1994. 15. S265-272; J Hum Hypertens. 1999. 13. 203-208; South Med J. 2001. 94. 1112-1117; Eur J Clinical Nutr. 2002. 56. 1137-1142).
§ There is data that serum levels above 2 mcg/ml are associated with significant reductions in blood pressure (J Hum Hypertens. 2007. 21. 297-306).
o Infertility – benefit seen with 100 mg twice a day for 6 months in a pilot study in 22 infertile men, with increased sperm counts and motility (Fertil Steril. 2004. 81. 93-98).
o Lipoprotein (a) elevation – 120 mg of Q gel per day decreased values in a trial in 25 patients with coronary artery disease (Int J Cardiol. 1999. 68. 23-29).
o Migraine prevention
§ In a 3 month open-label with 26 women and 6 men with a history of episodic migraine (31 of the 32 finished the study), 150 mg per day was associated with a greater than 50% reduction in the number of days with migraine headache in 61% of the participants. No adverse events were seen. No significant difference in response in those with and without aura. Average number of days with headache decreased significantly from 7.34 per month to 2.95 per month, and attack frequency decreased significantly from 4.85 per month to 2.81 per month (Cephalagia. 2002. 22. 137-141).
§ In a RCT in 42 individuals with migraine with aura, attack frequency was reduced by 27% following 3 months of treatment with 100 mg tid of a new water soluble, non-commercially available form of Co Q 10 (Neurology. 2004. 62. A356-A357).
§ In a 3 month RCT in 42 individuals, 100 mg three times a day was associated with a 27% reduction in headache frequency. Number of attacks per month in both placebo and treatment groups was 4.4 (Neurology. 2005. 64. 713-715).
o Mitochondrial encephalomyopathies – UbiQGel brand. Benefits seen in several small trials with 8-44 patients, starting at a dose of 150 mg/day and titrating as high as 3000 mg/day (J Neurol. 1998. 245. 681-685; Eur Neurol. 1997. 37. 212-218; J Neurol Sci. 1990. 100. 70-78).
o Muscular dystrophy – 50% of patients on CoQ 10 100 mg daily experienced improvement in physical symptoms (Biophys Acta. 1995. 1271. 281-286). Benefit also shown in a 3 month double-blind trial in 12 patients administered CoQ 10 100 mg daily (Proc Natl Acad Sci. 1985. 82. 4513-4516).
o Muscle pain associated with statin treatment – in a 30 day pilot RCT in 32 patients, Q Sorb 100 mg/day significantly decreased muscle pain severity from baseline (p<0.001) and pain interference with daily activities from baseline (p<0.02), whereas vitamin E 400 IU/day was ineffective (Am J Cardiol. 2007. 99. 1409-1412).
o Myocardial infarction - a RCT with 144 participants enrolled within 72 hours of experiencing an acute MI showed that those taking 60 mg CoQ 10 twice a day had fewer total cardiac events, 24.6% in the treatment group versus 45.0% in the placebo group. Limitations of this study include small size, questionable true blinding since placebo capsules were not identical to CoQ 10 capsules, average age of participants in both groups less than 48 years, more smokers in the CoQ 10 group despite randomization, and only 20% of participants received beta blockers (Mol Cell Biochem. 2003. 246. 75-82).
o Obesity – poor study design in a single trial.
o Parkinson's disease – Vitaline brand. 16 month RCT in 80 patients who took placebo, CoQ10 300 mg daily, CoQ10 600 mg daily, or CoQ10 1200 mg daily. The 1200 mg dose helped slow the progression of Parkinson's by 44 % compared to placebo (p=0.04). No statistically significant benefits were seen with 300 or 600 mg daily (Arch Neurol. 2002. 59. 1541-1550). BE AWARE OF PRODUCTS CONTAINING PROPYLENE GLYCOL. BE AWARE THAT THE MORE EXPENSIVE TRANS ISOMER WAS USED IN THIS STUDY.
o Periodontal disease – see gingivitis above
o Photoaging of skin – topical application of 0.3% for 6 months reduced photo-aging in human skin (Biofactors. 1999. 9. 371).
o Statins – 200 mg a day raised blood CoQ 10 levels to pre-statin drug administration levels (Proc Natl Acad Sci. 1990. 87. 8931-8934). One small RCT (32 patients) shows benefit of supplementation in reducing statin associated myalgias (Am J Cardiol. 2007. 99. 1409-1412).
o Tinnitus – pilot trial positive (Otolaryngol Head Neck Surg. 2007. 136. 72-77).
· Idebenone is a synthetic analog of Co Q 10 shown to be both a powerful antioxidant and to increase levels of nerve growth factor.
Glucosamine (also see ‘chondroitin’ immediately below in this outline)
· Glucosamine, an amino sugar, is a combination of glucose and glutamine
o This compound is synthesized endogenously in human chondrocytes from glucose, and it is required for the synthesis of glycosaminoglycans which are found in synovial fluid, ligaments, and other joint structures.
o The dietary supplement is generally synthesized from chitin in shellfish exoskeletons (Reganasure is a brand name glucosamine product manufactured from corn instead of shellfish).
o Note that the chitin is a highly purified polysaccharide which does not contain protein impurities that may give rise to allergic reactions – shellfish allergies are thought to arise from the ‘meat’ in the shellfish, and not from the shell itself.
· Mechanism of action (presumed) - rebuilds damaged cartilage, by stimulating the synthesis and inhibiting the degradation of glycosaminoglycans and proteoglycans (www.naturaldatabase.com).
· Chemical forms of glucosamine
o Glucosamine sulfate – most clinical studies have been done with this form.
o Glucosamine hydrochloride - Dr. Theodosakis, author of The Arthritis Cure states that glucosamine hydrochloride is also effective.
o N-acetyl glucosamine hydrochloride – Michael Murray, ND states that this form is not absorbed.
· Dose - the usual dose of glucosamine is 1500 mg daily of glucosamine sulfate or glucosamine hydrochloride. Most recent data suggests that once daily dosing is superior to twice or three times a day dosing.
· Safety
o Overall safety - a Cochrane review of 20 RCTs in 2570 patients found the safety profile of glucosamine equivalent to that of placebo (Cochrane Database Syst Rev. 2005. CD002946).
o Diabetes – a 90 day RCT using glucosamine 1500 mg and chondroitin 1200 mg daily (Cosamin DS manufactured by Nutramax Laboratories) found no significant changes in HbA1c levels, leading to the conclusion that oral glucosamine does not result in clinically significant alterations in glucose metabolism in type II diabetics (Arch Intern Med. 2003. 163. 1587-1590). A second trial, conducted in 7 lean and 7 obese individuals, found no change in the area under the 4 hour plasma glucose curve or the area under the 4 hour plasma insulin curve, after 4 weeks of treatment with glucosamine sulfate (Diabetes Care. 2003. 26. 1941-1942).
o Shellfish allergy – this is considered a relative contra-indication to glucosamine; there are not any published reports of reactions to glucosamine in those with shellfish allergy (J Allergy Clin Immunol. 2004. 114. 459-460). Reganasure is a brand name glucosamine product manufactured from corn instead of shellfish.
o Warfarin – while there are case reports of bleeding or bruising in patients on warfarin who take glucosamine, most individuals in the case reports were taking much higher doses than the recommended dose of 1500 mg/day. There is not a defined biochemical mechanism and thus the case reports may represent coincidence rather than cause and effect.
· Adverse effects (uncommon) - include sleepiness, intestinal gas, and stomach upset.
· Efficacy
o Symptom relief knee osteoarthritis – benefit generally noticed within 2 weeks of initiation, maximum at 12 weeks, and persists for at least 8 weeks after discontinuation.
§ A meta-analysis of 15 randomized, controlled trials of glucosamine sulfate (5 trials), glucosamine hydrochloride (1 trial) and chondroitin sulfate (9 trials) in the treatment of knee osteoarthritis concluded that these compounds offer significant benefit. Limitations of the trials analyzed include relatively small sample size (17 - 329 patients), relatively short duration (generally 4-12 weeks), relatively low quality scores (12.3% - 55.4%), and manufacturer support for 14 of the 15 trials (JAMA. 2000. 283. 1469-1475).
§ A 3 year study in 212 Belgian subjects with osteoarthritis of the knee who received 1500 mg daily of glucosamine sulfate (Rotta Pharmaceuticals preparation) showed an average 11.7% reduction in WOMAC score in the treatment group compared with an average 9.8% worsening in the WOMAC score in the placebo group, statistically significant (Lancet. 2001. 357. 251-256).
§ A 3 year study in 202 Czech subjects with osteoarthritis of the knee who received 1500 mg daily of glucosamine sulfate (Rotta Pharmaceuticals preparation) showed a mean reduction of 26% in WOMAC scores, compared to a mean reduction of 16% in WOMAC scores in the placebo group, statistically significant (Arch Intern Med. 2002. 162. 2113-2123).
§ A comprehensive meta-analysis of 15 studies in 1775 patients (1020 glucosamine patients and 755 chondroitin patients) reported benefit (Arch Intern Med. 2003. 163. 1514-1522).
§ A systematic review reported benefit – this review included only studies that met the following criteria: (1) oral glucosamine monotherapy, (2) at least a year in duration, (3) knee osteoarthritis, and (4) reporting as outcome measures the symptom severity and disease progression as assessed by joint space narrowing. Only two studies (n=414) met these criteria; NNT was 9 for benefit (Ann Pharmacother. 2005. 39. 1080-1087).
§ GUIDE Trial – this was a 6 month trial in 318 patients with moderately severe knee OA, comparing oral glucosamine sulfate 1,500 mg once daily (n = 106), acetaminophen 3 gm/day (n = 108), or placebo (n = 104). Glucosamine sulfate was more effective than placebo in treating knee OA symptoms. Although acetaminophen also had a higher responder rate compared with placebo, it failed to show significant effects on the algofunctional indexes (Lequesne index and WOMAC index) [Arthritis Rheum. 2007; 56(2):555-567].
§ A Cochrane analysis of 20 RCTs in 2570 subjects found that (1) glucosamine outperformed placebo with a 28% improvement in pain and a 21% improvement in function using the Lequesne Index, but did not outperform placebo when WOMAC scales for pain, function, and stiffness were used (2) RCTs with the Rotta brand (10 of the 20 trials) when analyzed separately showed greater benefit than RCTs in aggregate using other brands, and (3) in a separate subanalysis of the 8 studies with the highest-quality design, there was not evidence of improvement in pain or function (Cochrane Database Syst Rev. 2005:CD002946). An update in 2009 includes 25 studies with 4963 patients, and reaches the same conclusion as the 2005 review: “Pooled results from studies using a non-Rotta preparation or adequate allocation concealment failed to show benefit in pain and WOMAC function while those studies evaluating the Rotta preparation showed that glucosamine was superior to placebo in the treatment of pain and functional impairment resulting from symptomatic OA.”
o Symptom relief spine osteoarthritis
§ A small 6 week RCT in 160 patients with a clinical diagnosis of osteoarthritis of the spine found a 53% response rate with glucosamine compared with a 33% response rate with placebo (Arthritis Rheum. 2000. 43[suppl]. 1613).
§ A 6 month RCT in 250 patients older than age 25 with chronic low back pain (> 6 months) and MRI findings indicating degenerative lumbar osteoarthritis was negative – 1500 mg per day of glucosamine sulfate (participants had a choice in the trial of taking 500 mg three times a day or all 3 capsules at once) did not reduce pain related disability at 6 months or 1 year of follow up (JAMA. 2010. 304. 45-52 and editorial 93-94).
o Symptom
relief hand osteoarthritis – a 6
month RCT of 162
symptomatic patients with radiographic hand OA found that those randomized to
800 mg/day chondroitin sulfate (highly purified chondroitin of fish origin,
marketed as Chondrosulf in
o Hip osteoarthritis – glucosamine sulfate 1500 mg once a day was no better than placebo in reducing symptoms or radiographic progression in the GOAL trial, a 2 year RCT in 222 patients (Ann Intern Med. 2008. 148. 268-277). The editorialist hypothesizes that inflammation (i.e. synovitis) is more common in osteoarthritis of the knee than of the hip, and this might account for the negative findings in this trial (Ann Intern Med. 2008. 148. 315-317).
o Disease progression – NOTE that determination of radiographic progression by X ray, as done in these studies, is imprecise, as the positioning of the patient as well as the positioning of the X ray beam can have substantial effects on the appearance of the joint space (Arthritis Rheum. 2001. 44. 1786-1794; Arthritis Rheum. 2002. 46. 1223-1227).
§ A 3 year study in 212 patients with osteoarthritis of the knee (see details just above) showed less radiographic progression in those who received glucosamine sulfate 1500 mg once a day (Lancet. 2001. 357. 251-256).
§ Another 3 year RCT in 202 patients with mild to moderate osteoarthritis of the knee (see details just above) showed less radiographic progression in those who received glucosamine sulfate 1500 mg once a day (Arch Intern Med. 2002. 162. 2113-2123; Ann Rheum Dis. 2001. 60[suppl 1]. 57).
§ GAIT trial – at the end of the 6 month trial (see just below), patients were offered the opportunity to continue their original study treatment for an additional 18 months, for a total of 2 years. At the end of the ancillary study, x-ray data was available on 581 knees. Those subjects taking glucosamine and chondroitin sulfate, together or alone, appeared to fare no better than placebo with regard to loss of cartilage. Interpreting the study results was complicated, however, because participants taking placebo had a smaller loss of cartilage, or joint space width, than predicted. (Arthritis Rheum. 2008. 58. 3183-3191).
o GAIT Trial – two part study. Six month trial examining differences in pain and function in 1583 patients suffering from osteoarthritis of the knee (N Engl J Med. 2006. 354. 795-808), and a 2 year trial in half the initial population evaluating for structure-modifying properties of glucosamine and chondroitin (Arthritis Rheum. 2008. 58. 3183-3191).
§ The arms of the 6 month trial included glucosamine HCL 500 mg three times a day (manufactured by Ferro-Pfanisteihl in Germany), chondroitin sulfate 400 mg tid (manufactured by Bioberica in Spain), glucosamine HCL 500 mg three times a day plus chondroitin sulfate 400 mg three times a day, celecoxib (Celebrex) 200 mg daily, and placebo.
§ Subjects (mean age of 59) were stratified at baseline based on symptom severity.
§ Acetaminophen (Tylenol) 500 mg in doses up to 4 grams/24 hours was available to all groups as rescue medicine for pain.
§ The primary outcome measure was a 20% reduction in WOMAC score between baseline and week 24 – the only group in which the primary outcome measure was statistically different from placebo was the celecoxib group (70.1% versus 60.1% in the placebo arm). The response rate was 64% in the glucosamine arm, 65.4% in the chondroitin arm, and 66.6% in the glucosamine plus chondroitin arm, all statistically comparable to placebo.
§ HOWEVER, in the 348 patients with high WOMAC scores at baseline, the response to glucosamine plus chondroitin was statistically better than placebo whereas the response to celecoxib did not differ from placebo. In this subgroup, patients on average used 650 mg less acetaminophen per patient per day.
§ NOTE the placebo response rate was 60%, very high – possible explanations for this include (1) subjects knew they had an 80% chance of receiving active treatment, (2) each subject took 7 capsules per day, and (3) research staff called all patients frequently to help maintain adherence to the medication regimen.
§ Critique of the GAIT trial (editorial pp 858-860 and separate article by Dr. Theodosakis)
o Permitted enrollment of patients who had previously taken glucosamine and chondroitin, and we don’t know how long the washout period is for these substances.
o Enrolled only patients with primary osteoarthritis, and anecdotally patients with secondary osteoarthritis may respond better to glucosamine and chondroitin.
o Most patients had relatively mild pain at the onset of the trial.
o Attrition rate of at least 20% in placebo arm and dietary supplement arms.
o Pharmacokinetics data available subsequent to the initiation of this trial suggests that once daily dosing is preferable to three times a day dosing.
o Standard celecoxib capsules were used with a fitted outer capsule – if individuals opened the outer capsule this would compromise the blinding.
o The 2 year extension examining structure modifying properties is highly likely to be negative, as the natural progression of joint space narrowing is about 0.1 mm per year, and the design of this study is such that a difference of greater than 0.2 mm per year is required for the difference to reach statistical significance.
Chondroitin
· Chondroitin is an endogenous glycosaminoglycan.
o It is a building block for the formation of the joint matrix structure.
o The dietary supplement is chondroitin sulfate, and is generally derived from bovine cartilage (the cartilage is not associated with bovine encephalopathy, but there is a theoretical concern that lax manufacturing practices could allow for cross-contamination of the bovine cartilage with bovine tissue known to cause bovine encephalopathy).
· Mechanism of action is uncertain (www.naturaldatabase.com).
o The available data would suggest that glycosaminoglycans in the joint are not synthesized from intact chondroitin molecules.
o Animal studies suggest that chondroitin functions as an anti-inflammatory (Osteoarthritis Cartilage. 1998. 6[Suppl A]. 14-21).
· Dose - the usual dose of chondroitin is 400 mg 3 times a day of chondroitin sulfate, but a single daily does of 1200 mg appears as effective as split dosing (Osteoarthritis Cartilage. 1998. 6. S25-S30).
· Absorption
o Chondroitin sulfate molecules are 50-300 times larger than glucosamine sulfate molecules, and absorption is estimated at 12-13%, compared with 90-98% for glucosamine sulfate (Rheumatol Int. 1992. 12. 81-88).
o Chondroitin
contains a mixture of glycosaminoglycans with molecular weights ranging from
14,000 to 30,000
o Dr. Theodosakis, author of The Arthritis Cure states that chondroitin molecules are known to be absorbed in fragments.
· Adverse effects (uncommon) - include indigestion, nausea, headache, rash, and hives.
· Efficacy
o The meta-analysis described above for glucosamine (JAMA. 2000. 283. 1469-1475) included 9 RCTs in which chondroitin sulfate was used. In aggregate these studies showed that chondroitin was more efficacious than placebo. Note though that when the magnitude of efficacy of chondroitin was examined as a function of individual trial quality, the efficacy was less dramatic in the higher-quality studies.
o A meta-analysis of 7 RCT's, all conducted in Europe, including a total of 703 patients with osteoarthritis of the hip or knee, mostly 3-6 months in duration, showed a drop in pain scores by about 20% with placebo and about 60% with chondroitin sulfate, a statistically significant difference. Global assessments by physicians and patients also consistently favored chondroitin over placebo (J Rheumatol. 2000. 27. 205-211).
o However, a more recent meta-analysis which examined 20 trials (N=3846) concluded that there were only 3 trials which were large and methodologically rigorous (N=300 + 631 + 622), and that analysis of these 3 trials failed to show significant symptomatic benefit associated with the use of supplemental chondroitin sulfate (Ann Intern Med. 2007. 146. 580-590 and editorial 611-612). Scrutiny of this paper reveals that 1 of the 3 studies combined in this analysis was not yet published, and that 2 of the 3 studies used 800 mg of chondroitin daily instead of 1200 mg (the GAIT trial used 1200 mg daily).
§ One of the 3 studies was 2 year RCT with 300 participants - chondroitin sulfate 800 mg daily had no effect on pain, using an intention to treat analysis. Only 73% of participants completed the two year study (Arthritis Rheum. 2005. 52. 779-786).
§ The second of the 3 studies was the GAIT trial (see above for glucosamine), which showed that chondroitin was no more effective than placebo.
· Disease progression
o An abstract of a 3 year RCT in 119 subjects with osteoarthritis of the hand treated with 1200 mg daily of chondroitin sulfate found fewer erosions in the treatment group (Osteoarthritis Cartilage. 1998. 6 [Supppl A]. 37-38). The full results of this trial have not been published.
o However, in a smaller 2 year RCT in 24 subjects with erosive osteoarthritis of the hand, both the placebo and treatment group showed worsening with regard to erosions (Drugs Exp Clin Res. 2004. 30. 11-16).
o A 1 year pilot study in 42 patients showed slowing of radiographic progression of knee osteoarthritis (Osteoarthritis Cartilage. 1998. 6 [Supppl A]. 39-46).
o A 1 year RCT in 120 subjects in which chondroitin sulfate was administered for two 3 month periods during the year showed slowing of radiographic progression of knee osteoarthritis in the treatment group (Osteoarthritis Cartilage. 2004. 12. 269-276).
o A 2 year RCT in 300 participants which failed to show benefit with regard to pain did show a slowing of radiographic progression of knee osteoarthritis (Arthritis Rheum. 2005. 52. 779-786).
S-adenosylmethionine (SAMe)
·
This is a naturally occurring compound which was
discovered in 1952 and has been used intravenously to treat medical conditions
in
o More stable enteric forms were developed during the 1990's.
o SAMe
became available in the
· Quality – unstable compound and therefore unclear how much active ingredient remains after product sits on store shelf for weeks-months.
· Chemical forms of SAMe
o There is a 1,4 butanedisolfonate form (controlled studies done mostly with this form, and bioavailability is higher) and a tosylate (toluenesulfonate) form which is not well studied.
o The SS isomer is the active form of SAMe and the RS isomer is inactive – it is suggested that 70% of the product consist of the active SS isomer.
· Bioavailability studies show it is best absorbed on an empty stomach, taken 30-60 minutes before meals.
· Usual starting dose is 200 mg before breakfast and before lunch (taken on an empty stomach), increasing the dose by 200-400 mg every 3-7 days. This seems to minimize side effects such as heartburn, jitteriness, loose bowels, and headaches. Doses as high as 3000 mg per day seem to be very safe.
· Expense (~$50/month) is a significant drawback.
· TMG (trimethylglycine) is a precursor to SAMe which is less expensive – it is available as betaine hydrochloride or glycine betaine and suggested dose is 250-500 mg daily.
· May raise homocysteine levels.
· May cause nausea at higher doses.
· Contra-indicated in bipolar disorder.
· Uses:
o Depression
· Benefit based on data from16 open, uncontrolled trials with a total of 660 patients (significant antidepressant effect in all trials despite low doses in many of the studies), 13 placebo-controlled RCTs with 537 patients (superior to placebo in 12 of 13 trials), and 19 controlled trials with 1134 patients comparing SAMe to other antidepressants (as effective as imipramine, chlorimipramine, amitriptyline, nomifensisne, and minaprine, but with fewer side effects). The above data is summarized in the International Journal of Integrative Medicine, Vol, 3, No. 4, December 2001/January 2002, pages 6-14.
· A meta-analysis found it more efficacious than placebo and equally efficacious to tricyclics, with a lower incidence of side effects (Bressa GM. Acta Neurol Scand Suppl. 1994. 154. 7-14).
· A more recent meta-analysis in 2002, done by Hardy, commissioned by the Agency for Health Care Research and Quality (AHRQ), came to similar conclusions as the 1994 meta-analysis. Rapid onset of action (5-10 days) noted in several studies. Overall 60-70% of patients with depression show significant improvement with SAMe.
· Benefit in a 6 week trial of 73 patients when used at 800 mg twice a day as an add-on to SSRI in treatment resistant depression (Am J Psychiatry. 2010. 167. 942-948). Prior to this, benefit reported in an open label trial (J Clin Psychopharmacol. 2004. 24. 661-664).
o Fibromyalgia – benefit based on data from 6 clinical trials, with references cited in the International Journal of Integrative Medicine, Vol, 3, No. 4, December 2001/January 2002, pages 6-14.
o Liver disease -in one study, 123 patients with cirrhosis [84% biopsy proven] were randomized to receive placebo or SAMe 400 mg tid for 2 years in a double blind fashion. Overall mortality/liver transplantation at 2 years was 30% in the placebo group and 16% in the treatment group, missing statistical significance, but if only patients with Child classes A and B were included in an analysis, mortality rates were 29% for placebo and 12% with treatment {p=0.025} (J Hepatol. 1999. 30. 1081-1089). In 17 clinical studies summarized by Osman, SAMe reduced symptoms such as pruritis and fatigue and improved biochemical markers such as bilirubin and others in patients with a variety of liver diseases, including cirrhosis, alcoholic and nonalcoholic hepatitis, and cholestasis (Aliment Pharmacol Ther. 1993. 7. 21-28).
o Osteoarthritis – appears to increase chondrocytes and cartilage thickness and may also have an anti-inflammatory effect, decreasing cytokine-induced cartilage damage.
· Benefit based on data from 9 clinical trials with a total of more than 22,000 participants, with data summarized in a symposium published in the American Journal of Medicine.1987. 83(5A). 1-110.
· A 2002 review and meta-analysis conducted by the Agency for Healthcare Research and Quality concluded that SAMe is more effective than placebo (http://www.ahrq.gov/clinic/tp/sametp.htm).
· A review of 11 studies reported that “SAMe appears to be as effective as NSAIDs in reducing pain and improving limitations in patients with OA, without the adverse effects often associated with NSAIDs” (J Fam Practice. 2002. 51. 425-430).
· Benefit of 1200 mg SAMe equivalent to that of Celebrex 200 mg after 2 months, in a 16 week crossover RCT in 61 adults with osteoarthritis of the knee (BMC Musculoskel Disorder. 2004. 5. 6).
Other dietary
supplements
·
Acai fruit (See also Mona Vie) – grows in the
Amazon in
· Agnus castus fruit extract is an effective and well tolerated treatment for PMS, based on a RCT in 170 women in 6 primary care clinics who fulfilled DSM III-R criteria for PMS, and who rated the severity of 6 PMS symptoms on a visual analog scale from 0 to 10 in a self assessment questionnaire (BMJ. 2001. 322. 134-137).
· Black currant anthocyanosides in a dose of 50 mg improve dark adaptation and help prevent eye fatigue in users of video display terminals, based on the results of 3 RCT's including a total of 33 subjects (Altern Med Rev. 2000. 5. 553-562).
· Choline - deficiency can cause fatty liver or elevations of CPK. Important in fetal development. Precursor for phospholipids in cell membranes. Men need more than women. RDA of 550 mg/day in men probably low and RDA of 450 mg/day in postmenopausal women probably high. Good dietary sources include liver, eggs, wheat germ.
· DIM – this is the form to which I3C (see below) is converted in the body, with the extent of conversion dependent upon the extent of chewing and the amount of stomach acid. The pure crystalline form is not well absorbed though.
· Gogi juice – available only through MLM (multi-level marketing). “Goji juice is hyped as the cure-all remedy for 34 different ailments… Earl Mendel, the well-respected author of the Vitamin Bible, is the face of Himalayan Goji, and he’s making some pretty hefty claims about the berry… The issue is that he’s talking about the berry, not necessarily the juice!” Lab analysis of the juice would suggest that the benefits associated with the berry are not associated with the juice. This information is derived from www.mercola.com, accessed 6/19/07, and is in response to an ‘expose’ on CBC News Marketplace January 24, 2007.
· Glutathione
o Tripeptide composed of cysteine, glutamate and glycine – cysteine has the lowest intracellular concentration (Biol Chem. 2003. 384. 527-537), and cysteine supplementation (i.e. NAC) has been shown to increase levels of glutathione (Eur Respir J. 2004. 23. 629-636).
o Functions as an antioxidant, and also plays an important role in detoxification.
o
Novel formulation, S acetylglutathione, has been
shown to have good oral absorption/bioavailability (Cacciatore I et al. Prodrug Approach for Increasing
Cellular Glutathione Levels. Molecule.
3 March 2010. PMID: 20335977).
o Intravenous increases pain free walking distance in those with peripheral vascular disease, based on a RCT with 40 patients (Mayo Clin Proc. 2002. 77. 754-759).
· Indole-3-carbinol (I3C) in a dose of 200 mg or 400 mg daily for 12 weeks results in complete regression of cervical intraepithelial neoplasia (CIN) in approximately half of patients treated, based on an open trial in 30 women who were randomized to receive either placebo, 200 mg I-3-C, or 400 mg I-3-C (Gynecol Oncol. 2000. 78. 123-129). This compound is found in high amounts in cruciferous vegetables such as cabbage, broccoli, bok choy, and cauliflower.
· Inositol – natural isomers of glucose. There are 9 isomers and myo-inositol is the most abundant isomer in the brain. Small studies show benefit in treatment of depression (Am J Psychiatry. 1995. 152. 792-794), panic disorder (Am J Psychiatry. 1995. 152. 1084-1086; J Clin Psychopharmacol. 2001. 21.335-339), and OCD (Am J Psychiatry. 1996. 153. 1219-1221) at a dose of 12-18 gm daily. Mechanism of action – second messenger system.
· Lecithin - 1200 mg twice a day with niacin may decrease the risk of elevated liver function tests from niacin.
· Lumbrokinase – this anticoagulant enzyme works outside the blood vessels whereas nattokinase works only inside the blood vessels, as per Garry Gordon, MD.
·
Mangosteen juice – fruit is native to
· Mona Vie – blend of 19 fruits, including acai, available as a beverage, with suggested intake of 4 ounces per day.
· MSM – this is the oxidized form of DMSO, and while a popular remedy for osteoarthritis, there is a paucity of human data.
o MSM is a methyl donor, and many of the anecdotal benefits may derive from this fact.
o Safety is good in clinical trials, but these have all lasted less than 12 weeks.
o A 12 week RCT in 118 patients with mild to moderate knee osteoarthritis by both clinical and radiographic criteria in which the subjects were randomized into 4 groups (glucosamine 500 mg + placebo MSM tid, placebo glucosamine + MSM 500 mg tid, glucosamine 500 mg + MSM 500 mg tid, and placebo glucosamine + placebo MSM tid) found that all 3 active interventions improved symptoms significantly compared with placebo, and combination therapy with MSM and glucosamine produced the greatest improvement (Clin Drug Invest. 2004. 24. 353-363).
o A pilot clinical trial showed improvement in pain and clinical function with a dose of 3 grams twice a day in a 12 week RCT in 50 subjects (Osteoarthritis Cartilage. 2006. 14. 286-294).
· NAC (N-acetyl cysteine)
o
Primary conventional uses are treatment of
Tylenol overdose, and prevention of intravenous dye contrast nephropathy
(seminal trial published in
o Theoretically, taking NAC in conjunction with chronic Tylenol use may be beneficial, as chronic Tylenol use might deplete glutathione, and NAC supplementation enhances production of glutathione (Eur Respir J. 2004. 23. 629-636).
o Beneficial in the treatment of COPD, influenza, polycystic ovarian syndrome, and pulmonary fibrosis (idiopathic). May be beneficial in suppression of colon polyps (Cancer Lett. 1999. 147. 109-114), prevention of ototoxicity in patients on hemodialysis receiving gentamycin (Kidney Int. 2007. 72. 359-363), as an adjunct in treatment of Helicobacter pylori (South Med J. 2005. 98. 1095-1097), and in treatment of multiple chemical sensitivities (theoretically enhances sulfation pathway of phase II detoxification) and osteoarthritis (theoretical benefit).
o Mechanism of action includes (1) antioxidant, as a precursor to glutathione, and (2) vasodilator via facilitating the production of nitric oxide.
o Usual supplemental dose is 600 mg bid.
o Long term use should be accompanied by copper supplementation (i.e. 1-2 mg/day of copper amino acid chelate).
o Very few side effects when dosed at 600 mg twice or three times a day.
·
Nattokinase – anticoagulant enzyme which has its
effect inside only inside the blood vessel, as per Garry
· Noni juice – in 2007, biggest selling botanical product in the world (Alternative Medicine. Pg 33. Internal Medicine News. May 1, 2007). Interest originated with the publication of a report which identified an alkaloid named ‘xeronine’ as the pharmacologically active component in noni (Pacific Tropical Botanical Garden Bulletin. 1985. 15. 10-14). No chemical structure for xeronine is given in this report though, and none has subsequently been published either. There are no published clinical outcomes studies. There are case reports of hepatotoxicity (Eur J Gastroenterol Hepatol. 2005. 17. 445-447), but these may not be causally related to the noni juice (World J Gastroenterol. 2006. 12. 3616-3619).
· PQQ – vitamin-like cofactor shown in 1994 to be an essential nutrient in human nutrition. Physiologic functions – induces mitochondrial biogenesis (formation of new mitochondria in aging cells; synergistic with Co Q 10), neuroprotective, some data on memory preservation in humans.
· Pycnogenol-nattokinase (Flite Tabs - Aidan Products) - prevents DVT and leg edema during prolonged flight. Pycnogonel is an anticoagulant derived from pine and nattokinase is an enzyme derived from fermented soybeans. In a RCT of 204 patients at high risk for DVT (including serious athletes with low resting heart rates and individuals with chronic fatigue syndrome) and about to take a 7-8 hour flight, two 150 mg Flite Tabs two hours before flight time and two more six hours later, there were 5 DVTs and 2 cases of superficial phlebitis in the control group, no episodes of either in the treatment group, based on venous dopplers. Furthermore, the post flight edema score was increased by 12% for controls, decreased by 15% in the treatment group (Angiology. 2003. 54. 531-539).
· Spirulina – see ‘Algae’ below.
· 5-HTP (5-hydroxytryptophan)
o 50-100 mg three times a day may be effective for depression and insomnia, but the evidence is "of insufficient quality to be conclusive" since only two trials involving a total of 64 patients were of sufficient quality to meet inclusion criteria for a Cochrane Review (Cochrane Database Syst Rev. 2002. CD003198). For anxiety, there are no published positive RCT’s, but one negative trial (Phytother Res. 2002. 16. 650-654).
o Take with carbohydrate rich food since carbohydrates may increase the amount of 5-HTP which crosses the blood-brain barrier.
o As compared with tryptophan, 5-HTP is not broken down by tryptophan pyrrolase and does not compete with other amino acids for transport across the blood-brain barrier.
o Derived from the West African plant Grifonia simplicifolia, whereas tryptophan is synthesized via bacterial fermentation (and thus theoretical increased risk of contamination of tryptophan).
o BEWARE, analysis of several different products discovered the same contaminant as the one in L-tryptophan which in 1989 was associated with eosinophilia-myalgia syndrome, a muscle disease diagnosed in at least 1500 individuals and responsible for at least 38 deaths. The contaminant can be identified by gas chromatography and is called "peak X." Consumers should use only products from companies which confirm the absence of peak X by chromatography; look for "Peak X Free" on the label. This contaminant is addressed in a "talk paper" issued in 1998 by the FDA, which states that "vigilance is warranted."
Hormones available
OTC as dietary supplements
· Androstenedione - another hormone legally classified as a dietary supplement, touted to improve athletic performance.
o
Banned in 3/04 by the FDA based on lack of
safety data and lack of marketing in the
o Scientific study fails to document improved athletic performance, but does document an associated increase in estradiol levels in men and testosterone levels in women.
o Potential risks include interference with normal fetal and adolescent development, virilization in healthy women with prolonged use, and promotion of sex hormone dependent cancers (ovarian and prostate cancer).
· DHEA - legally classified as a dietary supplement, but really a hormone with unknown long term adverse effects.
o DHEA and its metabolite DHEA-S are the most prevalent circulating hormones in the body.
o Synthesized primarily in the adrenal gland, but also produced in the gonads, the GI tract, and the brain.
o Converted into as many as 150 active metabolites, including estrogen and testosterone
· Obesity might increase the conversion of DHEA into estrogens.
· 7-keto-DHEA, a metabolite which may help boost immune function and reduce body fat does not convert to estrogen and testosterone.
o After age 20-30, levels decline by about 10% per decade, such that a 70 year old on average has levels only 10-20% of the levels of a 20 year old (J Clin Endocrinol Metab. 1984. 59. 551-555).
o At Heartmath Institute, 28 subjects who practiced a mental technique called "Cut-Thru" (recognize insecurity, then mentally choose a more hopeful outlook) were found to have an increase of 100% in DHEA levels at the end of one month of practice.
o Safety – might increase the risk of ovarian, prostate, breast, and uterine cancer.
o Adverse effects – acne, hirsutism, possible unfavorable effects on lipid profile.
o According to the Nutrition Business Journal, sales in 2002 were $47 million.
o Uses:
· Studies in mice suggest an anti-aging role.
· May be useful in treatment of Addison’s disease, AIDS, Alzheimer’s, chronic fatigue syndrome, depression, diabetes, endothelial dysfunction, hypercholesterolemia, low libido in women, lupus, metabolic syndrome, obesity, osteoporosis, and wound healing
· A RCT in those with Addison’s disease found improvements in mood and fatigue with DHEA replacement (J Clin Endocrinol Metab. 2000. 85. 4650-4656).
· A 6 month RCT in 56 elderly men and women, mean age 71, found that DHEA 50 mg reduced abdominal fat and insulin resistance, suggesting a role in prevention and treatment of metabolic syndrome (JAMA. 2004. 292. 2243-2248).
· Controlled clinical trials have shown that taking oral DHEA-S increases bone mineral density in elderly women with low pre-treatment levels (Joint Bone Spine. 2001. 68. 588-594).
· There are published phase I, II, and III trials of DHEA in lupus, and these suggest the possibility of benefit from 200 mg DHEA a day in this condition. However risks of this dose in this condition are not yet well-defined.
· Melatonin - legally classified as a dietary supplement, but really a hormone, with unknown long term adverse effects in humans.
o First isolated from bovine pineal gland in 1958.
o This molecule is found in all bacteria, plants, and animals; the molecule is estimated to be 3-4 billion years old.
o This molecule has a hydrophobic and hydrophilic end and passes through all morphophysiological barriers.
o The enterochromaffin cells of the GI tract secrete 400 times as much melatonin as the pineal gland
o Many functions in the body, including regulation of the sleep/wake cycle, body temperature, and immune activity. Melatonin inhibits aromatase, an enzyme which converts testosterone to estrogen.
o Zinc is a cofactor in the synthesis of melatonin from serotonin.
o
Bioavailability of microgram amounts of oral
melatonin varies widely (
o Lifestyle measures can increase melatonin levels.
· Exercise boosts melatonin production.
· Meditation can raise melatonin levels.
· Music therapy for 30-40 minute morning sessions 5 times per week for 4 weeks in 20 male inpatients at a VA hospital with Alzheimer's was associated with a significant increase in melatonin level (Altern Ther Health Med. 1999. 5. 49-57).
o Drugs can lower melatonin levels – beta blockers and alcohol.
o Uses
· Cancer (melanoma and solid tumors = lung, brain, skin, kidney, breast) - there are approximately 50 small clinical trials of melatonin in humans with cancer (Alt Med Alert. 2005. 8. 109-113), and a meta-analysis of 10 European trials in 643 patients, using doses of melatonin of 10-40 mg, found a 34% reduction in risk of death at one year (J Pineal Research. 2005. 39. 360-366).
· Cluster headaches (Cephalagia. 2005. 403-411).
· Dementia – improvement in behavioral symptoms (Cochrane Database. 2006).
· GERD – 6 mg beneficial in a case study (Alt Ther Health Med. 2008. 14. 54-58).
· Hypertension (essential) - in a crossover RCT in 16 men with untreated essential hypertension, 2.5 mg of melatonin 1 hour before sleep for 3 weeks significantly reduced nocturnal blood pressure (6 mm Hg drop in systolic BP and a 4 mm Hg drop in diastolic BP) and also improved sleep. Improvements in blood pressure and sleep were statistically unrelated (Hypertension. 2004. 43. 192-197).
· IBS - in a RCT in 40 IBS patients, administration of melatonin 3 mg at bedtime for two weeks significantly attenuated abdominal pain and reduced rectal pain sensitivity without improvements in sleep disturbance or psychological distress. The findings suggest that the beneficial effects of melatonin on abdominal pain in IBS patients with sleep disturbances are independent of its action on sleep disturbances or psychological profiles (Gut. 2005. 54. 1402-1407). Benefit also seen with 3 mg hs in an open label study in 17 females (Aliment Pharmacol Ther. 2005. 22. 927-934).
· Insomnia - 0.1- 0.3 mg 30-60 minutes before bedtime. Ineffective if exposed to light after taking melatonin. Data is mixed.
§ A meta-analysis of 14 trials of melatonin for primary sleep disorders found no difference between melatonin and placebo for any efficacy outcome except sleep-onset latency, which was reduced with melatonin by 11.7 minutes, and good evidence of safety in 10 trials (J Gen Intern Med. 2005. 20. 1151-1158).
§ A meta-analysis of 6 trials of melatonin for secondary sleep disorders (n=97) and 9 trials of melatonin for sleep disorders due to sleep restriction (n=437) found good evidence of safety, but no evidence of effectiveness (BMJ. 2006. 332. 385-393).
§ A 2004 AHRQ review found no effect of melatonin supplements on sleep efficacy in persons with primary or secondary insomnia.
§ A rigorous 4 week study in 36 volunteers kept in a soundproof room with no windows and dim lighting and kept on a strict 20 hour cycle of sleep and wakefulness found that melatonin 0.3 mg was beneficial only when administered during daylight hours outside the room (i.e. during the biological day) [Sleep. 2006. 29. 609-618].
§ Useful at doses of 0.3 mg and 3 mg in patients with delayed sleep phase syndrome, based on a trial in 13 patients (Sleep. 2005. 28. 1271-1278).
§ Melatonin in patients with reduced REM sleep results in increased REM percentage, compared to placebo (J Clin Endocrinol Metab. 2004. 89. 128-134).
§ Expert opinion is that melatonin is effective for circadian sleep disorders (i.e. shift work, jet lag) but not primary insomnia.
· Jet lag - 9 of 10 trials subjected to a Cochrane review found that melatonin, taken close to the target bedtime at the destination (i.e. 10 p.m.) decreased jet lag resulting from flights crossing 5 or more time zones. People fall asleep faster and sleep better after 5 mg than after 0.5 mg. The duration of therapy should be 3-6 days. Short acting melatonin works better than a slow-release product. The number needed to treat for benefit is 2 - benefit is likely to be greater if more time zones are crossed and less for westward flights (Cochrane Database Syst Rev. 2002. 2. CD001520). HOWEVER, a 2004 AHRRQ review found minimal benefit for melatonin in the treatment of jet lag.
· Migraine headaches – in a 4 month open label trial in 34 patients who experienced between two and eight migraine attacks per month, there was a significant decrease in headache frequency, severity and duration in the melatonin group (Neurology. 2004. 63. 757).
· Sarcoidosis – in a 2 year open label trial in 18 patients with chronic sarcoidosis, significant response was seen with melatonin 20 mg/day for the first year and 10 mg/day for the second year (J Pineal Res. 2006. 41. 95-100).
· Tinnitus (Otolaryngol Head Neck. 2006. 210-213).
o Safety – doses above 8 mg are associated with decreased sperm motility. May interact with warfarin, may cause fatigue or dizziness.
o Quality is a problem - mass spectrometry identified 7 contaminants in 3 different commercial preparations including some contaminants found in L-tryptophan and associated with an epidemic of eosinophilia-myalgia syndrome in the US in 1989 (Chem Res Toxicol. 1998. 11. 234).
Algae available as dietary supplements
·
Algae
are single cell organisms which are whole food sources of vitamins and
minerals, as well as digestive enzymes.
·
Chlorella
o
Chlorella is a green algae cultivated under conditions that should guarantee the
absence of environmental toxins.
o
Chlorella
has very high amounts of chlorophyll – chlorophyll is nearly identical to
hemoglobin, but has a magnesium atom at its center.
o
Chlorella
is 60% protein by volume, and also contains many vitamins and minerals, but
these cannot be assimilated by humans unless the cell wall is broken, and
verification of this claim requires analysis of a product with a scanning
electron microscope.
o
The cell
wall of chlorella may bind heavy metals and environmental toxins, and thus may
aid in detoxification of the body.
·
Brown
algae
o
Ecklonia cava extract (ECE) is a standardized extract of a
specific species of brown algae, and represents a unique category of
polyphenols, as it has up to 8 interconnected rings, compared with 3 rings in
most polyphenols, and 4 rings in EGCG. This structure allows for 40% fat
solubility and thus a long half life, and also very potent antioxidant
activity.
·
Blue-green
algae
o
AFA is a blue-green algae anecdotally effective in some cases of addictions,
alcoholism, ADHD, autism, and depression. While there are published reports of
neurotoxins and hepatotoxins in some strains of AFA, there is data that oral
intake of blue-green algae harvested from
o Spirulina is a blue-green algae cultivated under conditions that should guarantee the absence of environmental toxins. It may have antiviral, antineoplastic, and anti-inflammatory effects, but current evidence overall is very weak (Alternative Medicine Alert. 2001. 4. 67-70).
o
NOTE wild strains of blue-green algae sometimes thrive in waters that are
often polluted, and thus might be contaminated by toxins.
Probiotics
· Defined in 2001by the WHO as “live organisms which, when administered in adequate amounts, confer a health benefit on the host.”
· Mechanism of action – antibacterial and antiviral effects, anti-inflammatory effects at mucosal surfaces, aide digestion (via production of lactic acid and lactase), modify immune function, synthesis of vitamin K and B vitamins.
· Probiotics include various Lactobacillus species, Bifidobacterium species (bacteria), and Saccharomyces boulardii (yeast).
· Issues pertinent to probiotics in supplement form:
o The organisms in the supplements must survive the manufacturing process to be beneficial.
o Proper packaging and storage is essential so that the organisms stay alive – shipped in dry ice, stored in the refrigerator or freezer.
o The organisms in the supplements must survive stomach acid in order to initiate beneficial effects in the intestines. Theoretically, taking supplements with a meal minimizes inactivation in the stomach by hydrochloric acid, because even though more acid is produced in response to a meal, the food buffers the acid and the pH of the stomach goes up in association with a meal.
o With regard to the above 3 issues, note that there is actually some data to suggest that dead probiotics may be beneficial - a review article entitled “Probiotics in inflammatory bowel disease: possible mechanisms of action” states in the abstract, “Unexpectedly, the beneficial effects described were achieved not only by live bacteria but also by irradiated nonviable bacteria, bacterial DNA components and probiotic-cultured media” (Curr Opin Gastroenterol. 2005. 21. 426-430).
o Quantity of organisms must be sufficient – at least 1-10 billion microorganisms per day for bacteria, 0.5-1 gram for yeast.
o It may be important for supplements to colonize the intestines – data is mixed in this regard.
o It is unclear whether it is important for supplements to contain species of organisms naturally found in the intestines.
o The GOLD STANDARD for any brand name is that it has been documented effective in a randomized clinical trial
o Supplements usually recommended three times a day for treatment, once a day for health maintenance.
o Go to www.consumerlab.com for information on quality brands.
· Contra-indications (Consumer Reports. 7/05. Pgs. 34-35).
o
Children with short-bowel syndrome as per a
spokesman for the
o Individuals with suppressed immunity. Bacteremia (Lactobacillus acidophilus) and fungemia (Saccharomyces boulardii) have been reported (Enache-Angoulvant A, Hennequin C. Invasive Saccharomyces infection: a comprehensive review. Clin Infect Dis. 2005. 41. 1559-1568).
o Pregnancy or lactation – probably not a problem but safety unknown
·
Safety
o
A
study of 12 refrigerated and 8 non-refrigerated Lactobacillus products from
commercial sites in
o
A
systematic review of the safety of L
rhamnosus GG and Bifidobacterium
sp found no reported cases of sepsis in any clinical trial (BMJ. 2006. 333. 1006-1008).
o
Unsafe in predicted severe acute pancreatitis –
prophylaxis with a mixture of probiotics was associated with an increased
mortality in a multicenter RCT in 298 adults (Lancet. 2008. 371. 651-659).
· Uses:
o Asthma – yogurt containing Lactobacillus acidophilus generated a trend toward an increase in interferon gamma and a decrease in eosinophilia, but there was no significant change in clinical parameters, based on data from a crossover RCT in 15 adults with moderate asthma (Ann Allergy Asthma Immunol. 1997. 79. 229-233).
o Atopic disease – prevention. Clinical results have been mixed. NOTE it is believed that administration of probiotics to nursing mothers provides the same benefits to infants as does giving probiotics directly.
§ Lactobacillus GG reduced occurrence of atopic disease in offspring when given to expectant mothers who had atopic disease or a partner with atopic disease or at least one first degree relative with atopic disease. This was a randomized, blinded, controlled trial with 77 subjects who received Lactobacillus GG in a dose of 1 x 1010 (10 billion cfu/day) for 2-4 weeks before expected delivery, and 82 subjects who received placebo. The capsules were also taken postnatally for 6 months. At 2 years of follow up, the relative risk of atopic disease in the active treatment group was 0.51 (p=0.008). 83% of women and children completed follow-up (Lancet. 2001. 357. 1076-1079 and editorial 1057-1059). Limitations of the study included lack of specification of the method of concealing allocation, lack of an intention-to-treat analysis, and a nonspecific definition of atopic eczema (ACP Journal Club. Nov/Dec 2001. 106). At 4 years of follow up (107 subjects available for analysis), the benefit persisted in the treatment group, with a RR of atopic eczema of 0.57 (Lancet. 2003. 361. 1869-1871).
§ A RCT in 1223 pregnant women in which the treatment group received a 4-strain probiotic combination supplement (5 billion cfu each of Lactobacillus GG, L rhamnosis LC705, B breve Bb99, and Propionibacterium freudenreichii species Shermani JS) daily for 4 weeks prior to delivery, continued for 6 months after delivery, found no reduction at age 2 in the primary endpoint of allergic diseases (food allergy + eczema + allergic rhinitis + IgE sensitization), but found a 36% in atopic eczema, for NNT of 16 (J Allergy Clin Immunol. 2007. 119. 192-198). At age 5, the subgroup of children which benefited in terms of less IgE sensitization and less IgE-associated disease was the subgroup born by C-section (J Allergy Clin Immunol. 2009. 123. 335-341).
§ A RCT in pregnant women administered probiotic milk from 36 weeks of pregnancy to 3 months postpartum during breastfeeding showed a significant reduction in eczema at age 2 in children of mothers who consumed the probiotic milk. The milk contained Lactobacillus GG, Lactobacillus acidophilus La-5, and Bifidobacterium animalis Bb-12 (Br J Dermatol. 2010. 163. 616-623).
§ NEGATIVE TRIAL - 105 German women with a family history of atopic disease were randomized to placebo vs.5 billion cfu/day Lactobacillus GG for 4-6 weeks prior to expected delivery and for six months after delivery. There was no difference in atopic dermatitis in the children at 2 years of age (Pediatrics. 2008. 121. e850-e856).
o Atopic disease – treatment of children with established atopic dermatitis
§ Meta-analysis of 10 RCTs found that probiotics effectively treat atopic dermatitis in children (Ann Allergy Asthma Immunol. 2008. 101. 508-516).
§ Cochrane review identified 12 trials and 781 children, with variable results, possibly related to different strains and doses in the individual trials (Cochrane Database Syst Rev. 2008. CD006135). References for positive trials (Japan J Allergol. 2003. 52. 20-30; Arch Dis Child. 2005. 90. 892-897; Allergy. 2005. 60. 494-500; Allergy. 2006. 61. 431-437. Clin Exp Allergy. 2006. 36. 629-633).
§ A small, open trial in which 14 children were treated for at least 6 months with 30-500 mg/day standardized Lactobacillus rhamnosus lysate – treatment associated with substantial improvement in quality of life and skin symptoms (Inflamm Allergy Drug Targets. 2010; 9(3):192-196).
§ An 8 week RCT in 90 children with moderate to severe atopic dermatitis showed that a prebiotic/probiotic combination containing Lactobacillus acidophilus DDS-1, Bifidobacterium lactis UABLA-12, and FOS, providing 5 billion cfu of viable bacteria twice a day, was associated with a mean improvement in SCORAD score of 33.7% vs. 19.4% (p=0.0010 [Am J Clin Dermatol. 2010. 11. 351-361].
o Colic
§ Lactobacillus reuteri 100 million cfu/day more effective than simethicone 60 mg/day, based on a 4 week trial in 90 breast fed infants (Pediatrics. 2007. 119. e124-e130).
§ Lactobacillus reuteri DSM 17 938 100 million cfu per day more effective than placebo in a 3 week RCT in 50 breast fed infants (Pediatrics. 2010. 126. e526-e533).
o
o Cystic fibrosis - a group of children with cystic fibrosis treated with Lactobacillus GG had a reduced incidence of severe respiratory infections when matched with a comparable group of placebo-treated controls (Gastroenterol Int. 1998. 11. 91).
o
Diarrhea
– prevention of antibiotic-associated diarrhea. Note antibiotic-associated
diarrhea occurs in up to 30% of patients receiving antibiotics (Am J Gastroenterol. 1995. 90. 439-448).
§
Saccharomyces boulardii lyophilized (Florastor,
manufactured by Biocodex, www.florastor.com)
is effective (p=0.038) based on a
meta-analysis of 5 RCTs with 1076 patients. (Aliment Pharmacol Ther. 2005. 22. 365-372).
1.
Based
on this meta-analysis, the number of patients needed to treat with Saccharomyces to prevent one case of
antibiotic-associated diarrhea was 10 (ACP
Journal Club. 2006. 144. 45).
2.
In
one of the RCTs, conducted in in 180 hospitalized patients, Saccharomyces boulardii lyophilized was
administered at a dose of 1 gram per day during the course of antibiotics and for
up to 2 weeks after discontinuation of antibiotic. Diarrhea occurred in 21.8%
of the placebo group versus 9.5% of the treatment group, for a p=0.038 (Gastroenterology. 1989. 96. 981-988).
3.
In
a second RCT, conducted in 193 hospitalized patients receiving a beta-lactam
antibiotic, Saccharomyces boulardii
lyophilized was administered at a dose of 1 gram per day during the course of
antibiotics and for 3 days after discontinuation of antibiotic. Diarrhea
occurred in 14.6% of the placebo group versus 7.2% of the treatment group, for
a p=0.03 (Am J Gastroenterology.
1995. 90. 439-448).
§
Lactbacillus rhamnosis GG 10 billion cfu in children less than
12 kg and 20 billion cfu in children more than 12 kg is effective – administration was associated with slightly
shorter mean duration of diarrhea (4.7 vs 5.9 days, P = 0.05), a lower
stool frequency (mean number of stools per day, 1.4 vs 2.0; P<0.02).
By day 7, fewer children who received Lactobacillus GG had a stool
consistency score of less than 4 than did patients who received placebo (P<0.001)
based on results of a 10 day RCT in 202 children for whom a 10 day course of
antibiotic was prescribed (J Pediatr. 1999. 135. 564-568).
§
Lactobacillus sporogens with FOS for a 10 day course is effective, based on a multi-center RCT in 120 children in
§
A meta-analysis of 25 RCTs (n=2810) in which antibiotics were used
to prevent or treat antibiotic-associated diarrhea, 16 in adults and 9 in
children, found a 57% reduction in the risk of antibiotic-associated diarrhea
within 2 months of antibiotic exposure, with the strongest evidence available
for Saccharomyces boulardii, Lactobacillus
rhamnosis GG, and
multispecies probiotic combinations. The relative risk of developing diarrhea
with probiotic was 0.43 (p < 0.001).
The mean daily dosage of probiotic in these studies was 3 billion cfu’s,
but the studies using more than 10 billion cfu’s per day showed the greatest
magnitude of benefit (Am J Gastroenterol. 2006. 101. 812-822).
§
A
second meta-analysis of 19 RCTs also
showed that probiotics reduced the risk of developing antibiotic-associated
diarrhea by 52% (p < 0.001).The benefit was greatest when probiotic was
started within 72 hours onset of antibiotic treatment. The probiotics that were
evaluated included strains of L rhamnosus,
L acidophilus, and S boulardii, with magnitude of effect
similar for the various probiotics (Lancet
Infect Dis. 2006. 6. 374-282).
§
A
meta-analysis that focused on
preventing antibiotic-associated diarrhea in children analyzed 6 RCTs (n=766)
and found a reduction in the risk of diarrhea from 28.5% to 11.9%, a relative
risk reduction of 0.44 (J Pediatr.
2006. 149. 367-372). A subsequent
Cochrane review of 10 RCTs in children reported that whereas a per-protocol
analysis showed benefit, an intention to treat analysis failed to show benefit
of probiotics. However, there was evidence of effectiveness in studies using
doses of more than 5 billion cfu/day (Cochrane
Database Syst Rev. 2007. CD004827).
§
A
97 ml fermented milk drink containing Lactobacillus
casei DN-114 001 at a concentration of 100 million cfu/ml, Lactobacillus bulgaricus at a
concentration of 10 million cfu/ml, and Streptococcus
thermophilus at a concentration of 100 million cfu/ml, consumed twice a
day, reduced the risk of antibiotic associated diarrhea in a RCT in 135 elderly
hospitalized patients receiving antibiotics. Diarrhea developed in 12% of the
probiotic group compared with 34% of the placebo group (BMJ. 2007. 335. 80).
§
Lactobacilli
fermented milk with 50 billion cfu of a combination of Lactobacillus acidophilus CL 1285 and Lactobacillus casei is effective, based on results of a RCT
in 89 hospitalized patients (Can J
Gastroenterol. 2007. 21. 732-736).
o
Diarrhea
– prevention of antibiotic-associated C
difficile diarrhea. Note C difficile
diarrhea estimated in one study to add an average of 4000 British pounds to
inpatient cost, based on prolongation of length of stay (J Hosp Infect. 1996. 34. 23-30).
§
A meta-analysis of 23 RCTs found that probiotics reduced the
relative risk of C difficile associated diarrhea by 46% (West Midlands Health
Technology Assessment Collaboration [
§
HLC
Intensive 20 billion dfu/day (a patented probiotic manufactured by Pharmax, www.pharmaxllc.com, containing a combination of Lactobacillus acidophilus CUL60, Lactobacillus
acidophilus CUL21, Bifidobacterium bifidum CUL20, and Bifidobacterium bifidum CUL34 may be effective, based on an
underpowered 20 day RCT in 150 consecutive elderly patients receiving
antibiotic (138 finishing the trial, 69 in the placebo group and 69 in the
probiotic treatment group) in which probiotic or placebo was initiated within
72 hours of initiation of antibiotic. 15 patients in each group developed
diarrhea, but whereas 5 of the 15 patients in the placebo group tested positive
for C difficile toxin, only 2 of the
15 probiotic-treated patients with diarrhea tested positive for C difficile toxin (not statistically
significant). When samples from all patients were tested for C difficile toxin at the end of the
course of antibiotics, 9 placebo patients (13.0% of the group) and 11 probiotic
treated patients (15.9% of the group) tested positive for C difficile by culture for the organism. HOWEVER, only 5 of the 11
(46%) actually tested positive for the toxin, and only 2 of those 5 actually
had diarrhea (18% of the 11 who tested positive for the organism). In the
placebo group, 7 of the 9 patients were positive for the C difficile toxin
(78%), and 6 of the 7 actually had diarrhea (67% of the 9 who tested positive
for the organism). The t score for those with diarrhea as a percentage of those
testing positive for the organism (67% versus 18%) was significant (p<0.05).
These data suggest that the mechanism of benefit of probiotic may be via toxin
neutralization (International
Microbiology. 2004. 7. 59-62).
o
Diarrhea
– prevention of continuous enteral feeding associated diarrhea. Saccharomyces boulardii lyophilized
(Florastor) is effective
§
In
a multi-center (11 centers) RCT in 128 critically ill patients, those patients
who received 2 grams/day S boulardii
experienced 14% of days with diarrhea, compared with 19% in the placebo group
[p<0.01] (Intensive Care Medicine.
1997. 23. 517-523).
§
In
another study in 40 patients, 500 mg S
boulardii/liter of enteral feeds was associated with a reduction in the
number of days with diarrhea from 16.9% to 8.7% [p<0.001] (Sem Hop Paris. 1983. 59. 1409-1412).
§
In
a study in 20 patients in a burn unit, S
boulardii 2 grams/day was associated with a reduction in the number of days
with diarrhea from 9.1% to 1.5% [p<0.001](Nutrition Clinique Metabolisme. 1987. 1. 31-34).
o
Diarrhea
– prevention of formula-associated diarrhea in infants – benefit seen in a
3-arm, 12 week RCT in 201 infants ages 4-10 months at 14 child care centers.
Less diarrhea in the group in which L reuteri SD2112 was added to the formula,
as well as the group in which B lactis
Bb-12 was added to the formula, compared with the group with ‘straight’ formula
(Pediatrics. 2005. 115. 5-9).
o
Diarrhea
– prevention of radiation-induced diarrhea - VSL #3 is effective (American Journal of Gastroenterology.
2002. 97. 2150-2152).
o
Diarrhea
- prevention of traveler’s diarrhea
§
Lactobacillus GG may be effective (J Pediatr.
1999. 134. 1-2; J Travel Med. 1997.
4. 41-43).
§
Negative study: Nonviable Lactobacillus acidophilus administered from 1 day before to 3 days
after travel to high-risk areas ineffective in a RCT in 348 individuals (Clin Infect Dis. 2006. 43. 1170).
§
Meta-analysis
of 12 RCTs (n=4709) found
that Saccharomyces boulardii and a
mixture of Lactobacillus acidophilus and Bifidobacteria bifidum were effective
in prevention of traveler’s diarrhea, with a RR of 0.85 in patients taking
probiotic (Travel Med Infect Dis.
2007. 5. 97-105).
§
Saccharomyces boulardii lyophilized (Florastor) may be effective at a dose of 250-1000
mg/day
1.
A
RCT in 1231 people traveling to several destinations showed that the incidence
of traveler’s diarrhea was 42.6% in the placebo group, 33.6% in the 250 mg/day
group, and 31.8% in the 500 mg/day group [p<0.002] (Travel Med Int. 1989. 9-17).
2.
Retrospective
data in 1016 individuals indicates that 250-1000 mg/day starting 5 days before
travel and continuing throughout travel is effective (Fortschr Med. 1993. 111. 152-156).
o
Diarrhea
– treatment of AIDS associated diarrhea. Saccharomyces
boulardii lyophilized (Florastor) is
effective.
§
In
a RCT in 35 patients, after 1 week of treatment (dose not specified in review
article, but presumed to be 3 grams/day), diarrhea was controlled in after 1
week in 61% of treatment patients compared with 12% of the placebo group
[p<0.002](Sem Hop Paris. 1995. 71.
735-741).
§
In
an open trial in 17 patients, 3 grams/day was associated with a reduction in
stool output 9.0 stools per day to 2.1 stools per day at the end of 15 days (Annales de Medicine Interne. 1991. 142.
64-65).
o
Diarrhea
- treatment of antibiotic-associated diarrhea. Probiotics are effective based on a meta-analysis of 9 RCT's of
probiotics in 1214 subjects. Four of the
nine trials used Lactobacillus; two
used Lactinex, one used Lactobacillus GG
with 1010 colonies per capsule for 10 days (93 treated patients and
74 controls) and one used fermented milk with cultures (BMJ. 2002. 324. 1361-1364).
o
Diarrhea
– treatment of Clostridium difficile
diarrhea in infants and children. Saccharomyces
boulardii lyophilized (Florastor) may
be effective at a dose of 500-1000 mg/day for 15 days, based on an open
trial in 19 infants and children (J
Pediatr Gastroenterol Nutr. 1993. 16. 1497-1504).