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 - defined as ‘a food or part of a food that has medical or health benefits, including the prevention and treatment of disease’ (AAPS PharmSci. 2003. 5(3). E25).
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, $32 billion in 2012 (J Nutr. 2014. 144. 414-418), and $50 billion in 2018 (NCHS Brief. National Center for Health Statistics. 2021).
In the late 1980's, 36% of men and 48% of women used dietary supplements (Briefel RR and Johnson CL. Secular trends in dietary intake in the United States. Annu Rev Nutr. 2004. 24. 401-431).
NHANES data between 1999-2012 (n=37,958 adults, 74% response rate) shows that use of any dietary supplement within the preceding 30 days was stable between 1999-2000 and 2011-2012 at 52% (p for the trend =0.19) [JAMA. 2016. 316. 1464-1474].
Dietary supplement use in the US population remains stable at 52%, based on data from NHANES 2011-2014 (Nutrients. 2018. 10. 1114) and data from 2017-2018 (NCHS Brief. National Center for Health Statistics. 2021).
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.
ALA (flax oil)
This is derived entirely from plants, but is not efficiently converted into EPA and DHA in the human body.
Only about 15% of ALA is converted to EPA and only about 5% to DHA, and there are a number of identifiable factors which can inhibit this conversion even further (Am J Clin Nutr. 1999. 70. 560S-569S; Curr Opin Clin Nutr. 2004. 7. 137).
Conversion of ALA to EPA requires the action of D6D (rate limiting step) and D5D enzymes, amongst others.
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 ALA via the D6D enzyme.
PCBs damage the D5D and D6D enzymes.
Benefits
Seed husks are a good source of fiber, and will be beneficial in those with constipation.
According to Barry Sears, PhD, ALA inhibits the enzyme responsible for the synthesis of precursors to pro-inflammatory eicosanoids (but this same enzyme is also responsible for synthesis of precursors to anti-inflammatory eicosanoids).
Dietary ALA shown to decrease CRP and IL-6 in dyslipidemic patients (Atherosclerosis. 2003. 167. 237-242). Mode of action is thought to be down regulation of NF-KB.
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).
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).
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 ALA
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 ALA intake had a RR of 0.94, compared to men in the lowest quintile of intake. PLCO trial is ongoing, with plans for a minimum of 13 years of follow up.
Authors identified 6 additional studies that could not be included in the meta-analysis; 5 of these 6 showed no association between ALA intake and prostate cancer risk.
Nine cohort and case control studies show an association between either ALA intake or ALA content of blood and prostate cancer (J Nutr. 2004. 134. 919), with mechanism not understood. Jeff Bland, PhD hypothesizes that the increased risk might be due to abnormal metabolism of ALA to EPA and DHA in a subset of individuals (Functional Medicine Update. 7/04).
In vitro data shows that ALA promotes prostate cancer (Anticancer Res. 1996. 16. 815-820).
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
May promote lean body mass and may support healthy glucose metabolism through a PPAR agonist effect.
Exists in supplement form in either a free fatty acid form or as a stabilized form which is resistant to oxidation.
Fish oil – contains EPA (eicosapentanoic acid) and DHA (docosahexanoic acid), which are anti-inflammatory omega 3 fatty acids.
For information on dietary sources and mechanism of action, return to Home Page and click on “Nutrition” and scroll to polyunsaturated fats.
Excellent review article: J Am Board Fam Pract. 2005. 18. 28-36.
Popularity - NHANES data between 1999-2012 (n=37,958 adults, 74% response rate) shows that use of fish oil within the preceding 30 days increased from 1.3% in 1999-2000 to 11% 2011-2012 (p for the trend <0.001) [JAMA. 2016. 316. 1464-1474].
Safety:
Atrial fibrillation - in 4 RCT in which atrial fibrillation was a secondary endpoint, there is a dose-related increase in risk, such that at 4 grams/day EPA + DHA the risk is statistically significant and nearly double, at 1.8 grams/day the risk is 84% increased, of borderline statistical significance (p=0.06), and at 840 mg/day there is a nonsiginficant increased risk of 9% (Editorial. JAMA. 2021. 325. 1073).
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 in those taking fish oil supplements (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).
In a RCT of 1516 patients undergoing cardiac surgery at one of 28 centers in the United States, Italy, or Argentina and not using fish oil supplements regularly, those randomized to a preoperative dose of fish oil of 10 grams over 3-5 days or 8 grams over 2 days, and a postoperative dose of 2 grams per day until hospital discharge or postoperative day 10 (each one gram capsule contained 465 mg EPA and 375 mg EPA) showed a nonsignificantly lower risk of major bleeding as compared with those who received olive oil as a placebo (Circ Cardiovasc Qual Outcomes. 2018. 11. e004584).
However, there was a trend toward increased bleeding risk in the REDUCE-IT trial (for details of this trial, navigate to the https://www.drlevyhealthinfo.com/prevention-of-myocardial-infarction page of this website, secondary prevention section, and scroll down to the sub-section on omega-3 fatty acids) [N Engl J Med. 2019. 380. 11-22].
Glucose elevation - conflicting reports regarding effect on glucose levels in diabetics
A Cochrane review (Cochrane Database Syst Rev. 2001. CD003205) reported no beneficial or adverse effects on glucose control in diabetics.
However, a more recent RCT showed a slight increase in fasting glucose but no increase in glycosylated hemoglobin (Am J Clin Nutr. 2002. 76. 1007-1015).
LDL cholesterol – fish oil supplementation does raise LDL; 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.
Uses
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).
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).
NEGATIVE TRIAL - 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).
NEGATIVE TRIAL - in a RCT of 2157 adults aged 70 years or older, fish oil at a dose of 330 mg EPA + 660 mg DHA per day did not modify cognitive function, as measured by the Montréal Cognitive Assessment, at 3 years of follow-up (JAMA. 2020. 324. 1855-1868).
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).
A 12 week RCT of 68 medical students showed that those who received 2085 mg EPA + 348 mg DHA daily had a 20 % reduction in anxiety symptoms (and a 14% decrease in IL-6, a marker of inflammation) [Kiecolt-Glaser et al. Brain Behav Immun. Epub 7/19/11].
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 US outpatients, 542 with confirmed paroxysmal symptomatic atrial fibrillation and 121 with persistent atrial fibrillation. Those treated with 8 gm Lovaza® for 1 week, followed by 4 gm Lovaza through week 24 had the same rate of recurrent symptomatic atrial fibrillation as the placebo group (JAMA. 2010. 304. 2363-2372). Note 4 gm Lovaza contains 3.24 mg EPA + DHA.
NEGATIVE STUDY – in OPERA, a multicenter RCT of 1516 patients scheduled for cardiac surgery at 28 centers in the US, perioperative supplementation with omega 3 fatty acids did not reduce the risk of postoperative atrial fibrillation. Patients received a loading dose of 10 grams fish oil over 3-5 days, or 8 grams over 2 days, and continued on fish oil 2 grams per day until hospital discharge or day 10, whichever came first. Each gram of fish oil (Lovaza®) contained at least 840 mg of EPA + DHA in ethyl ester form (JAMA. 2012. 308. 2001-2011).
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).
A RCT of 187 patients with persistent atrial fibrillation for more than one month in which the treatment group was randomized to 6 grams per day of fish oil for at least one month prior to cardioversion, with continuation post cardioversion for a maximum of one year or until atrial fibrillation returned – 90 days post cardioversion, the atrial fibrillation recurrence rate was significantly lower in the fish oil group than in the control group [38.5% vs. 77.5%, p<0.001] (Heart Rhythm. 2012. 9. 483-491).
NEGATIVE STUDY - a 6 month RCT of 190 patients with paroxysmal or chronic atrial fibrillation, in which treatment patients received 4 grams per day of omega 3 (containing 3.2 gm/day EPA + DHA) showed no reduction in the rate of recurrent a fib, and no changes in biomarkers of inflammation or oxidative stress (Am J Cardiol. 2015. 115. 196-201).
INCREASD RISK of atrial fibrillation reported in the REDUCE-IT trial (for details of this trial, navigate to the https://www.drlevyhealthinfo.com/prevention-of-myocardial-infarction page of this website, secondary prevention section, and scroll down to the sub-section on omega-3 fatty acids) [N Engl J Med. 2019. 380. 11-22].
INCREASED RISK of atrial fibrillation were observed in the treatment group in the STRENGH Trial (2.2% versus 1.3%; P < 0.001). For details of this trial, navigate to the https://www.drlevyhealthinfo.com/prevention-of-myocardial-infarction page of this website, primary prevention section, and scroll down to the sub-section on omega-3 fatty acids [JAMA. 2020. 324. 2268-2280 and editorial 2262-2264].
NEGATIVE STUDY - in the 2 x 2 VITAL Rhythm study of EPA 460 mg/day plus 380 mg/day (and also vitamin D 2000 IU daily) in 25,119 participants aged 50 and older, at a median follow up of 5.3 years, atrial fibrillation occurred in 3.7% of the EPA + DHA group versus 3.4% of the placebo group (P = 0.19) [JAMA. 2021. 325. 1061-1073].
BEWARE in 4 RCT in which atrial fibrillation was a secondary endpoint, there is a dose-related increase in risk, such that at 4 grams/day EPA + DHA the risk is statistically significant and nearly double, at 1.8 grams/day the risk is 84% increased, of borderline statistical significance (p=0.06), and at 840 mg/day there is a nonsiginficant increased risk of 9% (Editorial. JAMA. 2021. 325. 1073).
In patients with an implantable cardioverter-defibrillator (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).
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).
Autoimmune disease prevention - in the VITAL trial, a RCT of 25,871 older participants (median age 67 years), with a two-by-two factorial design of vitamin D3 2000 IU daily and fish oil 1 gram daily, containing 460 mg EPA + 380 mg DHA, there was a trend toward lower incidence of autoimmune disease, wit ha 15% reduction in relative risk (p=0.19) [Hahn J et al. BMJ. 2022].
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).
Bipolar disorder – see manic depression below.
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).
CAD – primary and secondary prevention (Return to Home Page and go to “Prevention MI” for details and references –see both primary prevention and secondary prevention sections of this web page).
Cancer cachexia treatment - 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).
Cancer prevention
Breast cancer - in a meta-analysis (n = 20,905), marine omega-3 intake was associated with a 14% reduction in risk of breast cancer (95% CI 0.78 – 0.94), regardless if measured by dietary reporting or serum markers (BMJ. 2013. 346; J Nutr. 2003. 133. 1409-1414).
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).
In the VITAL trial, a RCT of 25,871 older participants (median age 67 years), with a two-by-two factorial design of vitamin D3 2000 IU daily and fish oil 1 gram daily, containing 460 mg EPA + 380 mg DHA, “Supplementation with n-3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo” (N Engl J Med. 2019. 380. 23-32 and editorial 89-91).
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).
A meta-analysis found that omega 3 supplementation was associated with a 34% decreased odds of atrial fibrillation post open heart surgery (Can J Cardiol. 2013. 29. 196-203).
There is some data that fish oil supplementation reduces distal occlusion in coronary vein grafts (J Am Coll Cardiol. 2011. 58. 2047-2067).
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 inthe 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].
In an ancillary study to the VITAL trial (25,871 US adults randomized to receive 2000 IU daily vitamin D3, 1000 mg daily of omega-3 fatty acids, placebo, or both supplements, for a median of 5.3 years), there was a significant lead decreased risk of hospitalization for heart failure in those randomized to omega-3 fatty acids (HR = 0.69). The effect was more pronounced in those with diabetes (HR = 0.53); in a secondary analysis the effect was more pronounced in A black participants (JACC Heart Fail. 2022. 10. 227-234).
CKD - see 'renal failure' just below
Colic – in a 3 month prospective multicenter RCT of 589 healthy Italian newborns less than one week old, those administered L reuteri DSM 17938 showed a significantly lower mean duration of crying time (p<0.01), and a significantly lower mean number of regurgitations per day (p<0.10). The authors calculated that administration of probiotic was associated with a cost savings per patient of $118.71 for the family and $140.30 for the community (JAMA Pediatrics. 2014. 168. 228-233).
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 (N Engl J Med. 1996. 334. 1557-1560).
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).
Cystic fibrosis – beneficial, based on a Cochrane analysis (Cochrane Database Syst Rev. 2007. CD002201).
Dementia – see Alzheimer’s just above.
Depression Prevention - ineffective (at a dose of 465 mg EPA + 375 mg DHA/day) in a RCT of 18,353 adults in the VITAL-DEP ancillary study, at a median of 5.3 years of follow-up (JAMA. 2022. 326. 2385-2394).
Depression Treatment:
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 systematic review of small trials with variable doses of EPA + DHA reported benefit (Am J Clin Nutr. 2006. 84. 1308-1316).
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).
An 8 week RCT of 432 Canadian adults suffering from a major depressive episode lasting at least 4 weeks showed a lack of statistically significant improvement in the group treated with 1050 mg EPQA + 150 mg DHA daily (p=0.088). However, in a preplanned subgroup analysis for patients without comorbid anxiety disorder (n=204), active treatment was superior to placebo on both scales (p<0.01). This study suggests that omega 3 fatty acids are beneficial for depressed patients only if they do not also suffer from anxiety (J Clin Psychiatry. 2011. 72. 1054-1062).
An 8 week trial of 42 patients with major depressive disorder showed that those randomized to 1.8 gm/day EPA + 0.4 gm/day DHA in conjunction with citalopram were more likely to experience full remission [44% vs. 18%] (J Clin Psychopharmacol. 2012. 32. 61-64).
A meta-analysis of RCTs reported benefit, and that formulations with mostly EPA were more effective than formulations with mostly DHA (PLOS One. 2014. 9. E96905).
Benefit reported in a 12 week RCT of 400 participants ages 15-25 with major depression, at a dose of 1.4 grams per day omega 3 fatty acids in conjunction with cognitive behavioral therapy (Rice S et al. Early Interven Psychiatry. Epub 8/13/14).
A meta-analysis of 8 RCTs (n=448) of 3-52 weeks’ duration, in which fish oil was an adjunct to prescription antidepressant treatment showed a significant antidepressant effect for fish oil augmentation (Am J Psychiatry. 2016. 173. 575-587 as cited in ACP Journal Club. 2016. 165. JC28).
A meta-analysis of 26 RCTs (n=6292) showed that formulations with mostly EPA were more effective than formulations with mostly DHA (Hallahan B, et al. Br J Psychiatry. 2016. E-publication 4/21/16 as cited in ACP Journal Club. 2016. 165. JC29).
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).
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).
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).
A RCT of 12,536 patients with elevated fasting glucose, reduced glucose tolerance, or diabetes found no difference in rates of cardiovascular death, major cardiovascular events, total mortality, or death from arrhythmia between the treatment group (1 gram omega 3) and the placebo group, at a median of 6.2 years of follow up (N Engl J Med. 2012. 367. 309).
In the VITAL-DKD study, a prespecified ancillary study to the VITAL study, with a 2 x 2 design of 1312 adults with type 2 diabetes, neither fish oil at a dose of EPA + DHA 1 gram per day nor vitamin D3 2000 IU daily for 5 years resulted in significant difference in change in estimated GFR at five years as compared with placebo (JAMA. 2019. 322. 1899-1909 and editorial 1866-1868).
Dry eyes
Beneficial in contact lens users with dry eyes, at a dose of 720 mg EPA + 480 mg DHA daily, based on data from a 6 month RCT of 496 contact lens wearers.
Beneficial in a meta-analysis of 7 RCTs (n=790) with most studies using fish oil at doses of 2 grams per day or more for 1-6 months (Med Sci Monitor. 2014. 20. 1583-1589).
However, in a 12 month RCT of 349 patients assigned to 3 grams per day EPA + DHA, outcomes were similar in the active treatment group and the placebo group (olive oil placebo) [N Engl J Med. 2018. 378. 1681-1690].
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].
Epilepsy
Low dose (1080 mg EPA + DHA daily) effective atreducing seizure frequency (33.6%, p=0.02) in a 10 week crossover RCT of 24 patients with drug resistant epilepsy, but high dose fish oil (2160 mg EPA + DHA daily) was ineffective (J Neurol Neurosurg Psychiatry. 2015. 86. 65-70).
In two additional trials, high dose fish oil ineffective (Epilepsy Behav. 2005. 7. 253-258; Epilepsy Behav. 2008. 12. 187-190).
In a 3 month RCT of 70 children with epilepsy resistant to anticonvulsant medication, those randomized to 360 mg EPA + 240 mg DHA daily, 57% of the fish oil group was seizure free at 3 months, compared with 3% in the placebo group (N Am J Med Sci. 2015. 7. 317-321).
Heart transplant recipients – treatment with 3.4 grams per day EPA + DHA associated with better long term control of BP post heart transplant (Eur Heart J. 2002. 22. 428-436).
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).
HOWEVER, in a RCT of 2157 adults aged 70 years or older, fish oil at a dose of 330 mg EPA + 660 mg DHA per day did not affect systolic or diastolic blood pressure at 3 years of follow-up (JAMA. 2020. 324. 1855-1868).
Hypertriglyceridemia (Alt Med Alert. 2005. 8. 78-82):
Mechanism of action – inhibit hepatic triglyceride synthesis.
A Cochrane review (Cochrane Database Syst Rev. 2001. CD003205) reported that fish oil reduced triglycerides in diabetics.
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).
REDUCE-IT trial reported improved outcomes in those already receiving statin therapy, with the addition of 4 g/day of icosapent ethyl [IPE] (for details of this trial, navigate to the https://www.drlevyhealthinfo.com/prevention-of-myocardial-infarction page of this website, secondary prevention section, and scroll down to the sub-section on omega-3 fatty acids) [N Engl J Med. 2019. 380. 11-22].
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).
Infantile colic – see Colic just above
Infertility - omega 3 fatty acid intake correlated with increased female fertility (Obstet Gynecol. 2007. 110. 1050-1058).
Kidney transplant recipients - a Cochrane review concludes that there is insufficient evidence of benefit (Cochrane Database Syst Rev. 2007. CD005282).
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).
A 6 month trial of 50 patients (32 completed the trial) in which active treatment patients took 6 capsules daily of a (Metagenics) fish oil supplement containing a total of 2.25 mg EPA + 2.25 mg DHA or 6 capsules daily of an identically-appearing olive oil capsule showed a trend toward improvement on the Energy=Fatigue subscale of the Rand SF-36 (Arriens C et al. Nutr J. 2015. 14[82]).
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).
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).
Migraines - theoretical rationale and anecdotes.
Multiple sclerosis – data is mixed
A two year RCT in 316 patients showed a trend toward improved status (p=0.07) in the group supplemented with 1.71 gm EPA + 1.14 gm DHA daily (Br Med J. 1978. 2. 1390-1391).
An open-label trial in 20 M.S. patients showed significant decreases in serum levels of several different inflammatory mediators (J Neuroimmunol. 1995. 56. 143-153).
Negative RCT – in a 6 month RCT of 92 patients with active relapsing-remitting multiple sclerosis, the investigators found no beneficial effects on disease activity when they compared the group receiving 350 mg of eicosapentaenoic acid and 850 mg of docosahexaenoic acid daily with the group receiving placebo (Arch Neurol. 2012. 69. 1044-1051).
Myocardial infarction - in a 6 month RCT of 360 patients who survived a MI and were receiving current guideline-based background CHD therapies, those randomized to 3.6 grams per day EPA + DHA within 30 days following the MI showed better remodeling, as measured by statistically significant reductions in left ventricular end-systolic volume index and fibrosis (Circulation. 2016. 134. 378-391).
Obesity – there is data in children that fish oil supplements facilitate weight loss (The Anti-Inflammation Zone. 2005. Pg 236).
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).
Osteoporosis - HOWEVER, in a RCT of 2157 adults aged 70 years or older, fish oil at a dose of 330 mg EPA + 660 mg DHA per day did not affect the incidence of nonvertebral fractures at 3 years of follow-up (JAMA. 2020. 324. 1855-1868).
Peripheral vascular disease – no evidence of consistent improved clinical outcomes with regard to the symptom of intermittent claudication (Cochrane Database Syst Rev. 2007. CD003833).
Polycystic ovary syndrome (PCOS) - in a randomized crossover trial in 22 women with PCOS, 4 grams per day of omega 3 supplementation (containing 1.9 grams per day EPA + DHA) was associated with a 25% reduction in the serum concentration of bioavailable testosterone (p<0.05) [Am J Clin Nutr. 2011. 93. 652-662].
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.
Preterm delivery (defined as delivery prior to 37 weeks of gestation) - reduced in the FOTIP study of 232 women with a history of preterm delivery who were randomized to 2.7 grams of fish oil supplement or olive oil placebo from week 20 of their pregnancy until delivery. The risk of preterm delivery was 33.3% in the placebo group, 21.3% in the fish oil group (BJOG. 2000. 107. 382-395).
HOWEVER, early preterm delivery (defined as delivery prior to 34 weeks of gestation) NOT reduced in the ORIP trial of 5517 women and 5544 pregnancies. The treatment group received three 500 mg capsules per day providing approximately 800 mg DHA daily and 100 mg EPA daily from < 20 weeks of gestation to 34 weeks of gestation (discontinued at 34 weeks of gestation based on data in the DOMInO trial (see just below) which showed a higher incidence of post-term delivery [ > 41 weeks of gestation] with fish oil supplementation). Early preterm deliveries in 2.2% of women in the omega 3 group and 2.0% of women in the control group (N Engl J Med. 2019. 381. 1035-1045).
Postpartum depression and cognitive development in infants and children NOT reduced in the DOMInO trial. 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).
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).
Psoriasis – theoretical rationale and anecdotes.
Psoriatic arthritis - 3 gm/day EPA + DHA – benefit reported in a 24 week RCT of 145 patients (Scand J Rheumatol. 2018. 47. 27-36).
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).
AV graft thrombosis
In a small 1 year RCT of 24 patients, using a dose of 4 grams per day of fish oil, decreased the AV graft thrombosis rate from 75.6% to 14.9% (J Am Soc Nephrol. 2002. 13. 184-190).
In a 1 year multicenter RCT (FISH study) of 201 adults at 15 hemodialysis centers, there was a trend toward a decrease in the percentage of grafts with loss of native patency (48% versus 62%, p=0.06) in the group treated with 4 grams of fish oil (1600 mg EPA + 800 mg DHA) per day, and a number of predefined secondary outcomes of the study did reach statistical significance. In addition, there was a statistically significant reduction in systolic and diastolic blood pressure (JAMA. 2012. 307. 1809-1816 and editorial 1859-1860).
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).
Studied in 13 RCTs, and improvements seen in at least two outcome measures in 12 of the 13 trials (Internal Medicine News. 10/1/04. 19).
High doses beneficial when added to DMARD treatment of early rheumatoid arthritis, based on data from a 1 year RCT of 140 adults, at a dose of 5.5 grams per day EPA + DHA. The primary outcome was failure of triple DMARD therapy, and this occurred in 10% of the high dose fish oil group, 32% of the control group, for a RRR of 667%, and a NNT = 5 (Ann Rheum Dis. 2015. 74. 89-95).
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].
Sickle cell disease
In a trial with 16 patients, omega 3 supplementation at 15 mg EPA per kg body weight reduced the median number of crises during the 6 month treatment period, as compared with the 6 months prior to treatment (p<0.001) [APMIS. 2011. 119. 442-448].
In a 1 year RCT of 140 patients in Sudan, those randomized to fish oil (278 mg of DHA + 29 mg EPA per capsule), those in the fish oil group had a significantly lower number of vaso-occlusive events per year (p<0.0001), a significantly lower incidence of severe anemia (p<0.05), a decreased need for blood transfusion (p<0.05). In addition, fewer in the treatment group who were unable to attend school at least once during the trial because of illness (p<0.05). The number of fish oil capsules administered in this trial was a function of the age of each patient at study entry (Am J Clin Nutr. 2013. 97. 37-44).
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 increased 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 stroke, compared to those assigned to statins (Stroke. 2008. 39. 2052-2058).
Tourette’s Syndrome – a RCT of 33 children and adolescents showed that those randomized to receive fish oil (EPA:DHA 2:1, initial dose of 500 mg, titrated to 6 gm/day maximum according to clinical response and tolerance) has a significantly higher response rates on the YGTSS-Global Measure and the YGTSS-Impairment Measure (Pediatrics. 2012. 129. e1493-e1500).
Triglycerides – see ‘Hypertriglyceridemia’ just above.
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
At a mechanistic level, health promoting effects thought due in part to facilitation of conversion of ALA to EPA and in part to activation of PPAR-gamma, inhibition of NF-KB, and impairment of estrogen receptor function (Int J Cancer. 2004. 109. 949-954). There is also some evidence that reduces platelet aggregation.
Sources include the following
Ahiflower oil - clean, nutty taste; in addition to GLA, contains a significant quantity of omega 3 fatty acid (in the form of stearidonic acid) and an optimal ratio of omega 3:6 of 4:1; available for purchase since 2015. Human clinical trials show safety at doses as high as 9 grams per day, and ability of ahiflower to raise both EPA and DGLA levels.
Black currant seed oil (17% GLA)
Borage oil (22% GLA). 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.
Echium oil - GLA content is similar to that of evening primrose oil, but the plant from which the oil is derived is toxic to foraging animals, and this raises potential concerns pertaining to safety in humans
Evening primrose oil (EPO) - 2% to 16% GLA. Potential safety concerns related to the quality of the solvent extraction process, and that in 2021 most EPO comes from China, and supply chain traceability to the source farms is lost.
Usual supplemental dose is 1000-1500 mg per day.
Uses
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).
Atopic dermatitis (eczema)
A systematic review of 11 RCTs found no benefit (Health Technol Assess. 2000. 4. 1-191).
However there are published positive trials (Drugs Exp Clin Res. 1988. 14. 285-290 and 291-297).
Alan Gaby, MD reports that for reasons uncertain, even though more GLA in borage oil studies as compared with evening primrose (EPO) studies, the EPO seems more effective than borage oil.
Autoimmune conditions - efficacy seen anecdotally after 6-8 weeks.
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).
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).
Eczema – see atopic dermatitis just above
Fetal alcohol syndrome – 900 mg/day may be effective
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).
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).
Raynaud’s – may be effective, based on results of one double blind trial (Thromb Haemost. 1985. 54. 490-494).
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).
Amino acids
Molecular building blocks of protein.
Given for precursor value, not to supplement protein intake.
Best taken on an empty stomach.
L-alanine
Stabilizes blood sugar (may be beneficial for those with hypoglycemia)
Reduces elevated triglycerides
May prevent seizures
L-arginine (1000-2000 mg twice daily)
Used in treatment of congestive heart failure (Circulation. 1996. 93. 2135-2141), coronary artery disease, erectile dysfunction, hypertension, infertility, and peripheral vascular disease.
Endogenous levels of ADMA (asymmetric dimethylarginine) may determine an individual’s response to L-arginine supplementation
Specialty labs offer measurements of ADMA
ADMA is a competitive inhibitor of L-arginine metabolism by nitric oxide synthase
L-arginine appears to normalize endothelial function in those with high levels of ADMA; appears to have no effect in those with low levels of ADMA
Precursor of nitric oxide (NO) – NO acts as a neurotransmitter in the brain, a mediator of host defense in the immune system, and as an vasodilator and antiatherogenic molecule in the cardiovascular system
Supplementation may increase Growth Hormone levels
May be dangerous in those on prescription nitroglycerin preparations
Theoretically, may exacerbate outbreaks of herpes. However there is data that L-arginine supplementation does NOT affect lysine levels
Supplementation may deplete glycine levels
Doses of 3-8 grams per day appear to be safe
L-asparagine (aspartic acid)
Protects the liver; facilitates detoxification of ammonia
Promotes uptake of trace minerals in the GI tract
L-carnitine (2000-6000 mg/day) acetyl-L-carnitine and propionyl-L-carnitine are derivatives
Carnitine is a dipeptide composed of methionine and lysine.
Plays an essential role in energy production by transporting fatty acids into the mitochondrial matrix for oxidation.
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).
Increases oxidative stress, so if supplementing, consider also supplementing with antioxidants, such as alpha lipoic acid.
Uses
May improve recovery and stamina in athletes (Physiologie. 1989. 26. 111-129; Am J Physiol. 2002. 282. E474-482).
Treats angina (Jpn Heart J. 1984. 25. 587-597; Int J Clin Pharm Ther Toxicol. 1985. 23. 569-572; Clin Trials J. 1986. 23. 338-344; Drugs Exp Clin Res. 1991. 17. 225-235), cancer cachexia, cognitive decline (Int Clin Psychopharmacol. 2003. 18. 61-71), congestive heart failure (Int J Clin Pharmacol Ther Toxicol. 1988. 26. 217-220; Drugs Exptl Res. 1991. 17. 225-235; Eur Heart J. 1994. 15. 1267-1273; JACC. 1995. 26. 380-387; Cardiovasc Drugs Ther. 1998. 12. 291-299; Am Heart J. 2000. 139. S120-S123), COPD (Brazilian 2006 study), diabetes (Eur J Clin Nutr. 2005. 59. 592-596; Exp Clin Endocrinol Diabetes. 2013. 121. 234-239), fatigue in seniors (Arch Gernotol Geriatr. 208. 46. 181-190; Am J Clin Nutr. 2007. 86. 1738-1744), 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, myocardial infarction (Mayo Clin Proceed. 2013. 88. 544-551). and peripheral vascular disease (J Am Coll Cardiol. 1995. 26. 1411-1416; Am J Med. 2001.110. 616-622).
in a RCT of 107 women with clomiphene-resistant PCOS, the ovulation rate in the treatment group (3 gm carnitine daily) was 64.7%, as compared with 17.6% in the placebo group (p<0.00001) and the pregnancy rate was 49.4%, as compared with 1.1% (p<0.0001) [Eur J Obstet Gynecol Reprod Biol. 2014. 180. 148-152].
CONTROVERSY
An article published in April 2013 reported evidence that ingested L-carnitine can encourage the growth of intestinal bacteria capable of converting carnitine to trimethylamine, which can be oxidized by the liver to TMAO (Nat Med. 2013. 19. 576-585). TMAO can adversely affect vascular health, based on data in mice (Nature. 2011. 472. 57-63). However, it is unclear whether ambient levels of TMAO in humans are mediators of atherosclerosis (Editorial. Mayo Clin Proc. 2013. 88. 786-789).
A meta-analysis of 13 RCTs (n=3629) showed that L-carnitine supplementation in patients with a previous MI was beneficial; associated with decreased mortality and reduced onset of angina and arrhythmias (Mayo Clin Proc. 2013. 88. 544-551).
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 Hyla Cass, MD
May increase anticlotting action of coumadin
L-citrulline
Precursor to the amino acids arginine and ornithine
Stimulates growth hormone
L-cysteine
Sulfur-containing amino acid
Useful in the treatment of asthma and bronchial disease
Converted into NAC, which is incorporated into the antioxidant glutathione
L-glutamine (2 - 10 g/day)
Readily synthesized by cells; most prevalent amino acid in bloodstream.
During catabolic stress, intracellular levels drop more than 50%; thus categorized as a conditionally essential nutrient.
Critical nutrient for enterocytes in the small intestine and certain immune cells (macrophages and neutrophils); stored in muscle.
Used to treat cravings due to low blood sugar, memory impairments, depression, fatigue, diarrhea, wounds, peptic ulcer disease, inflammatory bowel disease.
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-glycine
May decrease uric acid levels
May prevent seizures
May promote sleep
L-histidine
Anti-anxiety effect
Contra-indicated in those with high histamine levels (histadelia)
L-leucine
Stimulates insulin release and inhibits protein breakdown
Beneficial in those with cirrhosis
L-lysine (500-1000 mg twice daily)
Prevents recurrences of herpes, may enhance effect of L-carnitine
More effective if seeds, nuts, peas, and chocolate (dietary sources of arginine) are limited
Note that vegetarian diets tend to be relatively lysine deficient
L-methionine
Sulfur-containing amino acid
Reduces histamine levels
Cofactor in the synthesis of choline
Beware supplementation may increase homocysteine levels (whereas supplementing with SAMe does not)
L-ornithine
Promotes fat metabolism
Stimulates production of growth hormone
Facilitates detoxification of ammonia
L-phenylalanine (500-1000 mg daily or in a.m. and before lunch)
Metabolic precursor of norepinephrine and dopamine, excitatory neurotransmitters
May be useful in the treatment of chronic depression, Parkinson's disease
May raise blood pressure
Contra-indicated in those with PKU (a genetic condition), cirrhosis of the liver, and those taking an MAO inhibitor
D-phenylalanine
May prevent breakdown of brain's natural narcotics
May be useful in the treatment of chronic pain
Contra-indicated in those with PKU (a genetic condition), cirrhosis of the liver, and those taking an MAO inhibitor
DL-phenylalanine (1000 mg daily in the morning)
May be effective for treatment of depression without raising blood pressure
May help with appetite control via stimulation of release of CCK, an appetite suppressant
Contra-indicated in those with PKU (a genetic condition), cirrhosis of the liver, and those taking an MAO inhibitor
L-proline
May lower blood pressure
Promotes wound healing
L-serine
Derivative of glycine
No known therapeutic uses
L-taurine (500-2000 mg twice daily)
Sulfur-containing amino acid (most abundant sulfur-containing amino acid in the human heart)
Mechanism of action - depresses excitability of neurons
Uses: anxiety, arrhythmias, chronic fatigue syndrome, chronic pain, congestive heart failure (double blind crossover trial in 14 patients for 4 weeks reported in Clin Cardiol. 1985. 8. 276-282), depression, irritability, palpitations, seizure disorders, and tics.
L-theanine (50-200 mg as needed, up to four times a day)
Found in green tea, this is an amino acid derivative
Promotes relaxation by increasing alpha brain waves (Trends in Food & Science Technology. 1999. 10. 199-204)
L-tryptophan (1-3 grams at bedtime)
Metabolic precursor of serotonin, a neurotransmitter with sedative effects
Used as a natural sedative
Relatively contra-indicated in autoimmune and inflammatory states
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)
Also a metabolic precursor of norepinephrine and dopamine, excitatory neurotransmitters
May raise blood pressure
L-valine
Promotes muscle coordination
Levels tend to be low in those with anorexia nervosa
Alpha lipoic acid (ALA, thioctic 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, 600 mg per day for diabetics.
Safety
High doses may deplete the body of thiamine, riboflavin, and niacin, so best to take a B complex vitamin with alpha lipoic acid.
High doses may deplete the body of biotin, so consider 2-4 mg/day biotin with alpha lipoic acid.
Intravenous infusions may cause hypoglycemia.
Decreases conversion of T4 to T3 by 56% (Arzneimittelforschung. 1991. 41. 1294).
While side effects are rare, some do experience dermatologic or GI side effects, and in a tiny percentage of individuals, ALA may cause insulin autoimmune syndrome, a potentially serious condition characterized by transient hypoglycemia (Gatti M, et al Assessment of adverse reactions to alpha-lipoic acid containing dietary supplements through spontaneous reporting systems (Clin Nutr. 2021.. 40. 1176-1185)
Synthetic ALA is a racemic mixture of ‘L’ and ‘R’ forms - the ‘R’ form of lipoic acid is the only form which exists in nature, and it has approximately twice the antioxidant effects of regular lipoic acid, and R-dihydro-lipoic acid is believed to be the metabolically active form of R-lipoic acid. ‘R’ form must be refrigerated.
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:
Burning mouth syndrome - 600 mg daily shown beneficial in several published trials.
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).
Diabetes - shown to decrease insulin resistance and lower blood sugar (Arzneim Forsch. 1995. 45. 872-874; Diabetes. 1996. 45. 1798).
HIV - inhibits replication of the virus.
Liver disease - complementary to silymarin (milk thistle).
Memory loss - animal studies show that supplementation improves memory of aged white mice, but not younger mice.
Neurodegenerative diseases - theoretical benefit, based on test tube data showing that alpha lipoic acid inhibits peroxynitrite-mediated strand damage and hydroxyl radical formation.
Carotenoids
This is a family of fat-soluble compounds (more than 1100 known carotenoids), which are yellow, orange, and red plant-derived compounds. Approximately 50 of these have provitamin A activity, and all of them are antioxidants.
Carotenoids include alpha carotene, beta-carotene, astaxanthin, lutein, lycopene, and zeaxanthin
Astaxanthin
Neuroprotection - increases BDNF and protects against aluminum
Uses
Eye fatigue - beneficial at a dose of 6 mg/day for eye fatigue, eye irritation, and blurry vision (J Clin Ther Med. 2005. 21. 637-650; J Clin Ther Med. 2006. 22. 41-54).
Memory loss - beneficial at a dose of 12 mg/day in a RCT of middle aged individuals with complaints of age-related forgetfulness (J Clin Biochem Nutr. 2012. 51. 102-107).
Beta carotene - note that the USPSTF recommends in 2014 and 2022 AGAINST beta carotene supplementation for prevention of cancer or CVD in adults (JAMA. 2022. 327. 2326-2333).
Units of measure and regulatory change
In May 2016, the U.S. Food and Drug Administration (FDA) announced regulations that require amendments to the existing supplement facts label, which uses units and conversions based on the 1968 Recommended Daily Allowances (RDA). The new regulations became mandatory in 2019-2020.
For beta carotene
Historic conversion: 1 IU = 0.6 mcg beta-carotene (i.e. 25,000 IU = 15,000 mcg = 15 mg)
2020 conversion is as follows
1 mcg RAE = 2 mcg supplemental beta-carotene
1 mcg RAE = 12 mcg beta-carotene
Water soluble precursors to Vitamin A; as many as 50% of individuals do not efficiently convert carotenes to vitamin A (FASEB Journal. 2009. 23. 1041-1053). Hypothyroidism interferes with the conversion of beta-carotene to vitamin A.
Beta carotene and lung cancer - data from prospective, observational studies and from randomized, controlled trials is in conflict with the epidemiologic data, for reasons unclear.
The epidemiologic data shows an inverse relationship between beta carotene intake and lung cancer risk. However, the USPSTF (United States Preventive Services Task Force) in 2022 “recommends against the use of beta carotene supplements … for the prevention of cardiovascular disease or cancer” [D recommendation] (JAMA. 2022. 327. 2326-2333).
The Women’s Healthy Eating and Living study showed a 43% reduction in cancer risk in women with the highest versus lowest blood carotenoid levels.
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBCCPS) studied the effect of Vitamin E alone, beta carotene alone, and both together on the incidence of lung cancer in 29,000 male Finnish smokers, age 50-69, for 5-8 years. The investigators actually found an 18% increase in the incidence of lung cancer among the men receiving the beta carotene (New Engl J Med. 1994. 330. 1029-1035).
The Physician Health Study I - in this study, 22,000 male physicians age 40-84 were given either beta carotene supplements or placebo for 12 years. There was no effect on cancer rates from the supplements (New Engl J Med. 1996. 334. 1029-1035).
The Beta-Carotene and Retinol Efficacy Trial (CARET) studied the effect of beta carotene and retinol supplements on 18,000 adult smokers, former smokers, and workers exposed to asbestos, for 4 years. The investigators found a 28% higher incidence of lung cancer and a 17% greater mortality rate among those who received supplements (New Engl J Med. 1996. 334. 1150-1155).
The Women’s' Health Study - in this study, 40,000 women were given either beta carotene or placebo for 2 years. There was no effect on cancer rates from the supplements (J Natl Cancer Inst. 1999. 91. 2102-2106).
Beta carotene and heart disease - the USPSTF (United States Preventive Services Task Force) in 2022 “recommends against the use of beta carotene supplements … for the prevention of cardiovascular disease or cancer” [D recommendation] (JAMA. 2022. 327. 2326-2333).
HPS Study – RCT in 20,536 individuals with coronary artery disease, occlusive arterial disease, or diabetes who received vitamin E 600 mg daily + vitamin C 250 mg daily + beta carotene 20 mg daily or placebo. 83% in each group completed the 5 year follow up. Despite a significant increase in blood levels of the vitamins, there were no differences between the treatment and placebo groups with regard to all cause mortality, nonfatal MI, or heart disease death (Lancet. 2002. 360. 23-33).
Women’s Antioxidant Cardiovascular Study - RCT in 8171 female health care professionals at increased risk of cardiovascular disease (a previous event or 3 or more risk factors). A 2 x 2 x 2 design found no overall effects from vitamin E (d alpha tocopherol acetate 600 IU every other day), vitamin C 500 mg/day or beta carotene 50 mg every other day, alone or in combinations (Arch Intern Med. 2007. 167. 1610-1618).
Coenzyme Q10 (Ubiquinone/Ubiquinol)
[Pizzorno JE and Murray MT. Textbook of Natural Medicine. 2000. Chapter 76; Am Fam Physician. 2005. 72. 1065-1070]
Naturally occurring compound with the following functions
Essential to mitochondrial oxidative phosphorylation (i.e. cofactor in energy production via the electron-transport chain) - the oxidized form, ubiquinone, accepts the electrons, and is converted into ubiquinol, the reduced form
Antioxidant – ubiquinol, the reduced form, protects the mitochondria, protects LDL cholesterol from oxidation, and (in conjunction with vitamin C) protects vitamin E from oxidation.
Enhances immune system function - improves ratio between T4/T8 lymphocytes, increases production of NK cells and stimulates production of antibodies.
Reduces CRP levels (in a study in baboons, in conjunction with vitamin E).
Reduces Lp (a) levels - a meta-analysis of 7 RCTs (n = 409) showed that doses of 100 - 300 mg/day for 4-12 weeks associated with slight but statistically significant decrease in mean Lp (a) levels of 3.54 mg/dl (Pharmacol Res. 2016. 105. 198-209).
First identified in 1957 at the University of Wisconsin.
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 Coenzyme Q10 from our diet, humans can synthesize it – synthesis requires at least 8 vitamins and minerals as co-factors.Concentrations are highest in tissues with high energy needs (i.e. heart, kidney, muscle).
The human body is estimated to contain about 2 grams of Coenzyme Q10 - the estimated daily requirement (from dietary intake, endogenous production, or supplements) is 5 mg for a healthy individual (Antioxidants. 2020. 9. 386).
Factors which lower Coenzyme Q10 levels in humans
Age - levels of Coenzyme Q10 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.
CHF - there is some data that Coenzyme Q10 levels in heart muscle are low.
Medications
Adrenergic stimulants
Antipsychotics
Beta-blockers
Biguanides (metformin)
Diabetes medications - second generation sulfonylureas and biguanide drug therapies for diabetes may decrease Co Q10 levels.
HMG CoA reductase inhibitors (statins) for high cholesterol - decrease CoQ10 levels by inhibiting CoQ10 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 CoQ10 levels may be a function of the decrease in LDL cholesterol induced by the statin drug.
Hormone replacement therapy
Oral contraceptive use is associated with lower CoQ10 levels.
Phenothiazines (for schizophrenia) - shown in some instances to inhibit Co Q10 dependent enzymes.
Statins
Sulfonylureas
Thiazide diuretics
Tricyclic antidepressants - shown in some instances to inhibit Co Q10 dependent enzymes.
Supplement forms of Coenzyme Q10 and bioavailability
Coenzyme Q10 is lipophilic; taking with a fatty meal may enhance absorption.
NOTE absorption of Coenzyme Q10 in supplement form is limited because
Coenzyme Q10 is a very large molecule (ubiquinone is 864 Daltons and ubiquinol is 866 Daltons).
In some formulations which use lipid based softgel technology to enhance bioavailability, the Coenzyme Q10 is partly in crystalline form, and crystals are absorbed much less efficiently than individual molecules of CoQ10.
In dogs and humans, crystal-free formulations are 1500% more bioavailable in lymph and 200-400% more bioavailable in plasma than crystalline ubiquinol formulations (Review Article. Judy WV. Integr Med. 2022. 21[5]. 30-35).
Single Coenzyme Q10 molecules are emulsified into micelles by bile salts in the small intestine - the micelles function as microspheres with the water soluble part of the Co Q 10 molecule on the outer surface of the micelle, and this facilitates absorption
Absorption is a passively facilitated diffusion process, facilitated by a lipid molecule - data in dogs administered a ubiquinol formulation indicates that 92% of ubiquinol is converted into ubiquinone in the acidic environment of the stomach/proximal small intestine prior to absorption and converted back to ubiquinol prior to entering the blood (Integr Med. 2021. 20[4]. 24-28 and 20[5]. 26-30).
Coenzyme Q10 products formulated as monoglycerides (as opposed to tri- or diglycerides) are absorbed more efficiently (Nutrition. 2019. 57. 133-140).
Coenzyme Q10 forms into chylomicrons in the endothelial cells of the intestine (enterocytes); the chylomicrons diffuse into the lymph and the lymph slowly transports Co Q 10 molecules to the blood.
95% of Coenzyme Q10 in the blood is in the reduced (ubiquinol) form
REFERENCE: Review Article. Judy WV. Integr Med. 2022. 21[5]. 30-35.
See just below for data on bioavailability of various formulations of Coenzyme Q10 - note though that as of 2022, the majority of bioavailability studies examine bioavailability in the blood at 2-3 hours post single dose, and there is data that while mean absorption in the lymph peaks at 2 hours, peak absorption in the blood does not peak for 6 hours (Review Article. Judy WV. Integr Med. 2022. 21[5]. 30-35).
REFERENCE: Mantle D et al. Bioavailability of coenzyme Q10. Antioxidants. 2020. 9. 386.
Note that while some products (such as Q-Gel) claim both water- and lipid-solubility (the claim is legitimate based on the USP water-solubility test), the published data fails to support significantly enhanced bioavailability of these products (Review Article. Judy WV. Integr Med. 2022. 21[5]. 30-35).
BEWARE that while one strategy to increase bioavailability of CoQ10 is to combine it with high-dose piperine (such as BioPerine®), high dose bioperine may significantly increase the blood levels of prescription medications, as piperine inhibits P-glycoprotein, which transports drugs absorbed in the intestines back into the gut lumen, and piperine inhibits the cytochrome P450 enzyme CYP3A4, which metabolizes some drugs.
Supplements - ubiquinol versus ubiquinone
Ubiquinol supplements became available in 2006.
Initial data suggested that ubiquinol supplements had greater bioavailability than ubiquinone supplements.
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 CoQ10 levels increased from 1.6 mcg/ml to 6.5 mcg/ml, ejection fraction increased from 22% to 39%, and symptoms improved (Biofactors. 2008. 52. 435-441).
However, an in vitro study of 13 ubiquinol products marketed in the US found that while the supplements are relatively stable at room temperature (only 8% of ubiquinol converted to ubiquinone), the mean percentage of ubiquinol converted to ubiquinone at the 2.2 pH of gastric juice was nearly 54% (Integr Med. 2021. 20[4]. 24-28).
Furthermore, in an in vivo study with 6 large dogs showed that the ingested ubiquinol is largely oxidized to ubiquinone before it reaches the enterocytes, then converted back to ubiquinol as it passes from the enterocytes into the lymph system (Integr Med. 2021. 20[5]. 22-26).
Based on ongoing research, a review article concludes that "A review of the relevant literature leads to the conclusion that (1) both forms of coenzyme Q10 are bioactive, (2) absorption and bioavailability is more dependent upon the formulation of the coenzyme Q10 supplement than on the form of coenzyme Q10…, (3) a well-formulated ubiquinone supplement will significantly increase the concentration of ubiquinol in the plasma and in lipoprotein's, (4) there is no evidence that individuals older than age 40 must take a ubiquinol supplement and (5) it is misleading to suggest that ubiquinol is the water-soluble form of coenzyme Q10.” (Judy WV. Integr Med. 2021. 20[6]. 24-28).
Note that ubiquinol by its nature as an electron donor is much less stable than ubiquinone. One study showed that ubiquinol is unstable in the air, water, and in the acidic conditions between the stomach and small intestines (Integr Med. 2021. 20[5]. 26-30).
Dry powder Coenzyme Q10 versus crystalline Coenzyme Q10 versus crystal free (CF) Coenzyme Q10 formulations and single dose absorption and steady state bioavailability - a randomized, double-blind laboratory study which included 3 formulations of CF CoQ10 in lipid based softgels (brand name products Q-Best (renamed Thorne CoQ10), CoQsol-CF, and HiSorb), 3 formulations of crystalline CoQ10 in lipid based softgels (brand name products CoQ-Sol, Q-Gel, and Q-Sorb), and 3 formulations of dry powder CoQ10 in hard gelatin capsules found that single dose absorption was significantly higher for the CF formulations as compared to the crystalline and dry powder formulations (P < 0.001) and that that single dose absorption was significantly higher for the crystalline formulations as compared to the dry powder formulations (P < 0.001).
In terms of percentages/quantity, absorption into the blood of crystal-free formulations is 8.35% of a 100 mg dose, but only 0.75% - 3% for crystalline formulations; the estimated daily requirement (from dietary intake, endogenous production, or supplements) is 5 mg for a healthy individual (Antioxidants. 2020. 9. 386).
The relationship between single dose absorption and steady state bioavailability is described by a linear equation, indicating that studies of single dose absorption provide good estimates of steady state bioavailability (Integr Med. 2022. 21 [1]. 28-34).
Bioavailability of various brand name formulations of Coenzyme Q10
All-Q is a solubilized tablet form of Coenzyme Q10 with better bioavailability than Q-Sorb (Nature’s Bounty) and bioequivalence with Q-Gel (J Med Food. 2005. 8. 397-399).
Bio-Quinone in one study was found to be 3 -10 times better absorbed than the other six brands tested (Nutrition. 2019. 57. 133-140).
CoQsource is the commercial brand of Coenzyme Q10 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].
MitoQ is a patented product which is a combination of ubiquinol with the lipophilic triphenylphosphonium cation and has enhanced ability to enter the mitochondria (Townsend Letter. December 2017. 29-33).
Q-Gel is a patented soft gel (patented Bio Solv® technology) in which the particle size is reduced from 25 - 50 microns in most softgels to 0.4 microns, increasing its surface area and exposure to bile salts for enhanced micellization and absorption. 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).
Dosage and plasma levels
Dosage is variable; with doses as high as 1200 mg/day used in clinical trials. Plasma levels reach a plateau at 2400 mg of C0Q10 per dose.
Divided dosing produces higher blood levels than taking the full dose all at once (Biol Pharm Bull. 2003. 26. 52-55; Free Radic Res. 2006. 40. 445-453; (Antioxidants. 2020. 9. 386).
Total plasma CoQ10 levels can be measured; a a ‘normal’ CoQ10 level is 0.7 - 1 mcg/ml, a therapeutic level is considered to be 2.0 - 2.5 mcg/ml, an optimal level is considered to be 3.5 mcg/ml (strive to achieve a level of 2.5 – 3.5 mcg/ml in CHF, as per Ann Intern Med. 2000. 133. 745-746).
The plasma total CoQ10 measurement reflects approximately 80% ubiquinol and 20% ubiquinone (Biofactors. 1999. 9. 225-229).
Safety:
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 CoQ10 did not affect the INR (Ugeskr Laeger. 2003. 165. 1868-1871).
Case reports of hypoglycemia and hypotension.
Some brands contain the additive propylene glycol – this may be an issue if high doses are used, such as for Parkinson’s disease.
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).
Uses:
Adriamycin (doxorubicin) administration for lung cancer – 60 - 200 mg/day of Coenzyme Q10 may be beneficial (Integr Cancer Ther. 2005. 4. 110). May be best to initiate Coenzyme Q10 3-5 days before initiating adriamycin. In one study cited by Alan Gaby, MD, all 7 control patients developed cardiac toxicity, and none of the 7 experimental patients developed cardiac toxicity.
AIDS - markedly depleted serum levels. In one open trial (no placebo group), 6 AIDS patients took 200 mg Coenzyme Q10 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).
ALS (Lou Gehrig Disease) – a dose escalation trial showed that doses as high as 3000 mg/day for 8 months are safe (Neurology. 2005. 65. 1834-1836).
Angina - 4 week, double-blind, placebo-controlled, randomized, cross over protocol using 12 patients and 50 mg Coenzyme Q10 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].
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).
Breast cancer
32 women with high-risk breast cancer based on spread of the cancer to the axillary lymph nodes received 390 mg Coenzyme Q10 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; Lockwood K et al. Biochem Biophys Res Commun. 1994. 199. 1504-1508).
2 women with metastatic breast cancer treated with 390 mg/day Coenzyme Q10 showed dramatic regression of cancer (Biochem Biophys Res Commun. 1995. 212. 172-177).
CAD – see ‘Angina’ just above and ‘MI” just below.
CHF – supplementation may improve survival (Q-SYMBIO study - details below)
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 Coenzyme Q10 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 Coenzyme Q10 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 Coenzyme Q10 level; might be due to untreated deficiencies of other vitamins and minerals, as one of the negative studies was conducted at an inner city VA hospital):
Positive study – marked improvement in CHF Class in 7 of 11 heart transplant candidates treated with Coenzyme Q10 (Biochem Biophys Res Commun. 1992. 182. 247).
Negative study – 100 mg per day of Coenzyme Q10 ineffective; plasma levels of Coenzyme Q10 not monitored (Eur Heart J. 1992. 13. 1528-1533).
Positive study – very large 1 year, multi-center, double-blind Italian study with 322 patients receiving placebo and 319 patients receiving 2 mg/kg/day of Coenzyme Q10. 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).
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).
Negative study - 12 week randomized, double blind, controlled trial with 22 patients with ejection fraction less than45% who received placebo or CoQ10 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).
Negative study - 3 month randomized, double-blind, controlled crossover trial with 30 patients taking 33 mg CoQ10 three times a day or placebo found no increase in resting systolic function (J Am Coll Cardiol. 1999. 33. 1549-1552).
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 Coenzyme Q10 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 Coenzyme Q10 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 Coenzyme Q10 (IMCJ. 2006).
Negative study – mean plasma Coenzyme Q10 level was only 1.7 mcg/ml (Med J Aust. 2001. 175. 447).
Positive study – a RCT in 32 patients awaiting heart transplant showed symptomatic improvement with 60 mg/day (Clin Cardiol. 2004. 27. 295-299).
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).
Positive study - symptomatic benefit reported in an open-label trial with over 2000 patients (Ann Pharmacol. 2005. 39. 1522).
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).
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 Coenzyme Q10 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).
Positive study – in the Q-SYMBIO study, a 2 year RCT of 420 patients with NYHA class III or IV heart failure, those treated with 100 mg three times a day had lower all-cause mortality (p=0.01), cardiovascular mortality (p=0.02), and hospitalization for heart failure (p=0.05). The primary outcome measure was a composite of major adverse cardiovascular events, and significantly fewer of the treatment patients reached the primary endpoint (p=0.003) [Mortensen SA et al. Eur J Heart Failure. 2013. 15. S20]. A subgroup analysis of Europeans in this study showed improved ejection fraction with Coenzyme Q10 (Cardiology Journal. 2019. 26. 147-156).
Positive study – ubiquinol 600 mg/day beneficial a 12-week trial of 150 patients with heart failure with a preserved ejection fraction. Subjective improvements based on a standardized questionnaire, but no improvement in 6-minute walk test performance (Am J Cardiol.2022. 176. 79-88).
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).
Diabetes
12 week RCT in 74 diabetics found that Coenzyme Q10 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.
Diabetic Polyneuropathy – in a 12-week RCT of 49 patients with type 2 diabetes and diabetic polyneuropathy, those randomized to 400 mg/day of Coenzyme Q10 showed 60% improvement in symptom scores, compared with 0% improvement in symptom scores in the placebo group. 58% in the treatment group showed improvement in polyneuropathy stage, as compared with 8% in the placebo group (p<0.001) [J Diabetes Complications. 2012. 26. 352-358].
Ergogenic aid to increase exercise capacity in healthy athletes - several good quality studies show lack of efficacy, and a theoretic concern is that Coenzyme Q10 may act as a pro-oxidant under acidic conditions (Alternative Medicine Alert. 1/02. 5[1]. 5-80).
Fibromyalgia – in an open label trial of 20 patients with fibromyalgia (mean age 46.6 years), the 10 who received Coenzyme Q10 100 mg 3 times a day for 3 months showed significant improvements in biochemical markers, a 35% decrease in the mean number of tender points (p<0.001), a 39% improvement in the Headache Impact Test-6 score (p<0.001), and a 49% improvement in the Fibromyalgia Impact Questionnaire score (p<0.001) [PLoS One. 2012. 7. e35677].
Gingivitis - biopsies show lower gum tissue Coenzyme Q10 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).
Huntington's chorea - a randomized 30 month study in 347 patients given a 300 mg chewable wafer of Coenzyme Q10 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).
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 Coenzyme Q10 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 Coenzyme Q10 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).
Infertility – benefit seen with 100 mg Coenzyme Q10 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).
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).
Lithotripsy – in a RCT of 100 patients scheduled for lithotripsy, those treated with Coenzyme Q10 200 mg daily for one week prior to and after lithotripsy showed significantly improved measures of renal function at 1 week after lithotripsy (BJU Int. 2014. 113. 942-950).
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 CoQ10 (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).
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).
Muscular dystrophy – 50% of patients on Coenzyme Q10 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 CoQ10 100 mg daily (Proc Natl Acad Sci. 1985. 82. 4513-4516).
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).
Myocardial infarction - a RCT with 144 participants enrolled within 72 hours of experiencing an acute MI showed that those taking 60 mg CoQ10 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 Coenzyme Q10 capsules, average age of participants in both groups less than 48 years, more smokers in the 10 group despite randomization, and only 20% of participants received beta blockers (Mol Cell Biochem. 2003. 246. 75-82).
Obesity – poor study design in a single trial.
Parkinson's disease – Vitaline brand. 16 month RCT in 80 patients who took placebo, Coenzyme Q10 300 mg daily, Coenzyme Q10 600 mg daily, or Coenzyme Q10 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.
Periodontal disease – see gingivitis above
Peripheral neuropathy – see diabetic polyneuropathy just above
Photo-aging of skin – topical application of 0.3% for 6 months reduced photo-aging in human skin (Biofactors. 1999. 9. 371).
Prostate cancer – treatment with high dose Coenzyme Q10 was associated with substantial reductions in PSA and tumor size; no response to treatment though until 90 days into the trial (Judy WV et al. First International Conference of the Intl Coenzyme Q10 Assn. 1998. 143).
Statins – 200 mg a day raised blood Coenzyme Q10 levels to pre-statin drug administration levels (Proc Natl Acad Sci. 1990. 87. 8931-8934).
Statin myalgia treatment
One small RCT (32 patients) shows benefit of supplementation in reducing statin associated myalgias (Am J Cardiol. 2007. 99. 1409-1412).
A 3 month RCT of 76 patients, using a dose of Coenzyme Q10 60 mg twice a day (Miller Pharmacal Group, powder versus softgel versus micronized formulation not specified in Methods section of the paper) failed to show benefit (Am J Cardiol. 2012. 110. 526-529).
A 3 month RCT of 60 subjects (Fedacko J, et al. Can J Physiol Pharmacol. 2013;2:165-70).
In a 30 day trial of 50 subjects, those who received 50 mg Coenzyme Q10 twice a day, CoQ10 supplementation reduced statin-related muscle symptoms in 75% of the subjects, whereas there were no changes in pain scores in the placebo group (Med Sci Monit. 2014. 20. 2183-2188).
NEGATIVE META-ANALYSIS – in a meta-analysis of 6 studies (n=302), 5 studies evaluated the effect of Coenzyme Q10 on CPK levels, and 5 studies assessed the effect of Coenzyme Q10 on muscle pain. The studies were heterogeneous and small. No benefit was identified (Mayo Clin Proc. 2015. 90. 24-34).
Positive meta-analysis (J Am Heart Assoc. 2018. 7. e009835).
Tinnitus – pilot trial positive (Otolaryngol Head Neck Surg. 2007. 136. 72-77).
PRODUCTS
Brand names of formulations of crystal-free Coenzyme Q10 in lipid based softgels - Q-Best (renamed Thorne CoQ10), CoQsol-CF, and HiSorb
Brand names of formulation of crystalline Coenzyme Q10 in lipid based softgels - CoQ-Sol, Q-Gel, and Q-Sorb
Idebenone is a synthetic analog of Coenzyme Q10 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
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.
The dietary supplement is generally synthesized from chitin in shellfish exoskeletons (Reganasure is a brand name glucosamine product manufactured from corn instead of shellfish).
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.
Popularity – Nutrition Business Journal estimated consumer spending in 2012 on $753 million on supplements of glucosamine and chondroitin.
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
Glucosamine sulfate – most clinical studies have been done with this form.
Glucosamine hydrochloride - Dr. Theodosakis, author of The Arthritis Cure states that glucosamine hydrochloride is also effective.
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. Based on pharmacokinetics, once daily dosing may be superior to twice or three times a day dosing.
Safety
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).
As of 2005, no hospitalizations or deaths have ever been attributed to glucosamine, based data from European pharmacovigilance programs.
Hypercholesterolemia - a study failed to show a significant effect of glucosamine on serum cholesterol levels (BMC Pharmacology and Toxicology Online. 10/10/12), but there are anecdotes of individuals (presumably with genetic uniqueness) who experience marked increases in total cholesterol in association with taking glucosamine.
Diabetes - anecdotes of increases in blood sugar, but the published scientific literature indicates no effect on blood sugar from a population perspective
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 supplementation does not result in clinically significant alterations in glucose metabolism in patients with type 2 diabetes mellitus” (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).
A RCT of 407 women showed that a 2.5-year intervention of glucosamine sulfate 1500 mg daily had no effect on mean HbA1c over 6.5 years of follow up (Am J Med. 2017. 130. 731-737).
Data from 404,508 individuals in the UK Biobank prospective cohort study showed a 17% lower risk of diabetes in association with glucosamine use, at a median of 8.1 years of follow up (Diabetes Care. 2020. 43. 719-725).
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). For those who are concerned, and for vegans, there are brands which are totally shellfish free – Google ‘Shellfish-free glucosamine products’ for brand name products.
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.
Increase in intraocular pressure - in a 3 month RCT in 88 patients, those randomized to glucosamine sulfate 750 mg three times a day had an increase of 1.1 mm Hg in intraocular pressure, with no increase in those randomized to placebo (p=0.002). The proportion of patients who had a clinically significant increase in intraocular pressure (defined as > 2 mm Hg) was 34.1% of those in the glucosamine group, as compared with 12.5% in the placebo group (p<0.03) [Eye. 2017. 31. 389-394].
Adverse effects (uncommon) - include sleepiness, intestinal gas, and stomach upset.
Efficacy
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 reported benefit – 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].
Mixed data on efficacy: 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 sub-analysis 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.”
Mixed data on efficacy: A meta-analysis of 19 RCTs (n=3159), 15 of which used glucosamine sulfate, 4 of which used glucosamine hydrochloride, 17 in those with knee OA, 1 in those with hip OA, and 1 in those with knee and hip OA, concluded that neither glucosamine sulfate nor glucosamine hydrochloride reduces pain in knee or hip OA. Data suggest that glucosamine sulfate improves function (Int J Clin Pract. 2013. 67. 585-594, as cited in ACP Journal Club. 2013. 159. JC8).
MOVES trial reported benefit – this was a 6 month RCT of 606 participants with Kellgren and Lawrence grades 2-3 knee OA and moderate to severe pain by WOMAC score. Participants were randomized to celecoxib 200 mg daily versus glucosamine hydrochloride (GH) 500 mg/chondroitin sulfate (CS) 400 mg three times a day. The patients on celecoxib appeared to demonstrate superior results at the predefined assessment at 1, 2, and 4 months, but at 6 months, the treatments were equally effective, with 79.7 % of the glucosamine/chondroitin group designated as responders, and 79.2% of the celecoxib group designated as responders. There was a reduction of > 50% in the presence of joint swelling in both groups. Adverse events were low in both groups. The conclusion of the abstract is “CS+GH has comparable efficacy to celecoxib in reducing pain, stiffness, functional limitation and joint swelling/effusion after 6 months in patients with painful knee osteoarthritis, with a good safety profile” (Hochberg MC et al. Ann Rheum Dis. Epub 2/13/2015).
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).
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).
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).
GAIT Trial – two part study. 6-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 hydrochloride 500 mg three times a day (manufactured by Ferro-Pfanisteihl in Germany), chondroitin sulfate 400 mg three times a day (manufactured by Bioberica in Spain), glucosamine hydrochloride 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%, which is a very high placebo response rate – 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. N Engl J Med. 2006. 354. 858-860; and separate article in a non-peer reviewed publication, by Jason Theodosakis, MD)
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.
Enrolled only patients with primary osteoarthritis, and anecdotally patients with secondary osteoarthritis may respond better to glucosamine and chondroitin.
Most patients had relatively mild pain at the onset of the trial.
Attrition rate of at least 20% in placebo arm and dietary supplement arms.
Pharmacokinetics data available subsequent to the initiation of this trial suggests that once daily dosing is preferable to three times a day dosing.
Standard celecoxib capsules were used with a fitted outer capsule – if individuals opened the outer capsule this would compromise the blinding.
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 which inhibits cartilage degradation, and contributes to the resilience and elasticity of cartilage.
It is a building block for the formation of the joint matrix structure.
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).
The available data would suggest that glycosaminoglycans in the joint are not synthesized from intact chondroitin molecules.
Animal studies suggest that chondroitin functions as an anti-inflammatory (Osteoarthritis Cartilage. 1998. 6[Suppl A]. 14-21).
Popularity – Nutrition Business Journal estimated consumer spending in 2012 on $753 million on supplements of glucosamine and chondroitin.
Dose - the usual dose of chondroitin is 400 mg 3 times a day of chondroitin sulfate, but a single daily dose of 1200 mg appears as effective as split dosing (Osteoarthritis Cartilage. 1998. 6. S25-S30).
Absorption
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).
Chondroitin contains a mixture of glycosaminoglycans with molecular weights ranging from 14,000 to 30,000 Daltons. The source and processing of a preparation thus may significantly effect the amount of absorption, and thus conceivably the therapeutic effect. A marine-sourced low molecular weight (<16,000 Dalton) product may be more efficiently absorbed.
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.
Safety - as of 2005, no hospitalizations or deaths have ever been attributed to chondroitin, based data from European pharmacovigilance programs.
Efficacy
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.
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).
A meta-analysis of 20 trials (n=3842) reported that the higher quality trials failed to show pain reduction with chondroitin in patients with knee or hip OA (Ann Intern Med. 2007. 146. 580-590 and editorial 611-612; and cited in ACP Journal Club. 2007. 147. 44). HOWEVER, scrutiny of this paper reveals that 1 of the 3 high quality studies combined in this analysis was not yet published, 2 of the 3 studies used 800 mg of chondroitin daily instead of 1200 mg, and the third study was the GAIT trial, which used 1200 mg daily, but there was a 60% placebo response rate in the GAIT trial.
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 Europe) showed improvements in hand pain and function. Benefits were not noticeable until after 3 months of treatment (Gabay C. Arth & Rheum. Epub 9/6/11).
In a 2 year trial of 194 patients with OA of the knee with a primary outcome of measurement of disease progression (see abstract in the section just below), both the chondroitin sulfate 1200 mg/day group and the celecoxib group experienced marked improvement in joint swelling and symptoms, with greatest improvement in the celecoxib group (Arthritis Res Ther. 2016. 18. 256).
In the CONCEPT trial, a 6 month RCT of 603 patients randomized either to chondroitin sulfate 800 mg daily, celecoxib 200 mg daily or placebo, at the end of the trial, those in the chondroitin group experienced improvement in function and reduction in pain similar in magnitude to those in the celecoxib group., with benefit in both treatment groups statistically significantly greater than in the placebo group. Whereas the statistical difference between celecoxib and placebo appeared at day 30 and persisted, the statistical difference between chondroitin sulfate and placebo did not appear until day 90. (Ann Rheum Dis. 2017. 76. 1537-1543).
Disease progression
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.
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).
A 1 year pilot study in 42 patients showed slowing of radiographic progression of knee osteoarthritis (Osteoarthritis Cartilage. 1998. 6 [Supppl A]. 39-46).
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).
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).
A 2 year trial of 194 patients with OA of the knee showed that chondroitin sulfate 1200 mg/day slowed disease progression to a greater extent than celecoxib 200 mg/day. Disease progression was measured by loss of cartilage volume, as determined by quantitative MRI (Arthritis Res Ther. 2016. 18. 256).
S-adenosylmethionine (SAMe)
This is a naturally occurring compound, found in all living cells, which was discovered in 1952.
Commercially produced in yeast cultures.
Used intravenously to treat medical conditions in Europe since the 1970's.
More stable enteric forms were developed during the 1990's.
SAMe became available in the U.S. in 1999.
Quality – unstable compound and therefore unclear how much active ingredient remains after product sits on store shelf for weeks-months.
Chemical forms of SAMe
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.
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:
Depression
Anecdotally, 60-70% of patients with depression show significant improvement with SAMe. Some patients respond within 5-10 days.
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).
Benefit based on data from 16 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 in 2002, done by Hardy, commissioned by the Agency for Health Care Research and Quality (AHRQ), identified 28 acceptable studies of SAMe versus antidepressant or placebo, and found that SAMe was superior to placebo and equally effective/possibly superior to prescription antidepressants
Benefit in a 6 week trial of 73 patients when used at 800 mg twice a day as an add-on treatment in SSRI nonresponders, with a NNT of 6 for response and 7 for remission. Adverse effects similar with SAMe to placebo (Am J Psychiatry. 2010. 167. 942-948). Prior to this, benefit reported in an open label trial (J Clin Psychopharmacol. 2004. 24. 661-664).
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.
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).
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 - by the second month of Phase 1, there was no significant difference between both groups (p < 0.01). The endpoints of the study included pain, functional health, mood status, isometric joint function tests, and side effects. (BMC Musculoskeletal Disorders. 2004. 5:6).
A Cochrane review identified 4 trials (n=656) comparing SAMe to placebo or no intervention; the methodologic quality of the quality of reporting were poor, the results inconclusive (Cochrane Database Syst Rev. 2009:CD007321).
Other dietary supplements
Acai fruit (See also Mona Vie) – grows in the Amazon in Brazil, has a very high ORAC value. Freeze-dried product subject to extensive biochemical analysis and lead content is only 22 ppb, as per educational CD by Alex Schauss.
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).
Bromelain - extract of pineapple stem which has anti-inflammatory and fibrinolytic activity
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.
BEWARE that in a small RCT, choline bitartrate supplements significantly raised the levels of the prothrombotic and proatherogenic metabolite trimethylamine-N-oxide (TMAO), whereas in this same RCT, daily ingestion of 4 large eggs (P = .28) or phosphatidylcholine supplements (P = .27) failed to increase plasma TMAO levels (Am J Med. 2021. 134. 1160-1169).
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.
EGCG - green tea catechins. BEWARE, in high doses, associated with elevated LFTs.
In a study cited by Consumer Reports (February 2018), in a study of postmenopausal women, those who took a green tea extract twice a day (containing a total of 1315 mg of catechins) were 7 times more likely to have elevated liver enzymes than those who took placebo (Cancer Prevention Research. August 2017).
Some European regulatory agencies propose that the tolerable upper intake should be 300 mg /day (Regulatory Toxicology and Pharmacology. 2017. 84. 94-101).
Based upon a systematic review, the authors state that a safe level of EGCG is 704 mg/day in beverage form and 338 mg/day in bolus form: 100 g dry weight of green tea contains approximately 7000 mg EGCG (Regulatory Toxicology and Pharmacology. 2018. 95. 412-433).
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
Tripeptide composed of cysteine, glutamate and glycine – rate-limiting biochemical step in the synthesis is incorporation of cysteine into the molecule.
Synthesized (in every cell) in the body; but the body's ability to synthesize glutathione declines with age (Am J Clin Nutr. 2011. 94. 847-853).
Glutathione-dependent enzymes: glutathione peroxidases (antioxidants), glutathione S-transferases (detoxification enzymes) and glutathione reductase (converts inactive glutathione back to active form).
Drugs which depleted glutathione: Acetaminophen (Tylenol®), antacids, antibiotics, anti-viral medications, H2 blockers, oral contraceptives, PPI, tricyclic antidepressants.
Functions
Primary antioxidant in the body (and recycles other antioxidants such as vitamins C and E)
Important role in phase II metabolic detoxification (removal of toxins from the body)
Boosts immune system function - increases natural killer cells and enhances T cell function
Longevity in humans is associated with higher glutathione levels in the body
Limited bioavailability in dietary supplement form
NAC -conflicting published data regarding whether NAC supplementation is effective at raising glutathione levels and reducing oxidative stress.
Lactobacillus fermentum ME-3 (a probiotic, renamed Limosilactobacillus fermentum ME-3 in 2020) shown in human clinical trials to synthesize glutathione.
Oral glutathione is ineffective as an antioxidant in a 4-week RCT of 40 participants who were administered 500 mg twice a day for four weeks - oxidative stress markers were not reduced and there was no increase in total reduced, GSH, oxidized GSSH, or change in ratio of GSH/GSSH (J Altern Complement Med. 2011. 17(9). 827-833).
Novel formulation, S-acetyl glutathione, 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). As per Scott Berliner RPh (personal correspondence), some studies show that glutathione levels achieved with 200 mg twice a day on an empty stomach approach levels achieved with intravenous administration.
Patented forms of oral liposomal glutathione shown in published studies (at doses of 250 - 1000 mg per day) to increase glutathione levels in the body, reduce oxidative stress, and improve immune system function.
Topical or transdermal glutathione is ineffective as an antioxidant, but a modified version of topical glutathione [glutathione–cyclodextrin nanoparticle complex (GSH-CD)] is effective at reducing biomarkers of oxidative stress and increasing glutathione levels (Antioxidants (Basel). 2023. 12(7). 1375).
Intravenous (IV) glutathione (2 grams) does raise glutathione levels, but has a short half life
Intranasal and nebulized glutathione - research is limited
Benefits
Parkinson disease - clinical improvement reported with intravenous glutathione given daily for a month, but return to baseline after approximately two months without glutathione (Prog Neuropsychopharmacol Biol Psychiatry. 1996. 20(7). 1159-70; Mov Disord. 2009. 24(7). 979-83).
Peripheral vascular disease - Intravenous glutathione increases pain free walking distance, based on a RCT with 40 patients (Mayo Clin Proc. 2002. 77. 754-759).
Hyaluronic Acid
Supplements are either high molecular weight (>500,000 daltons) or low molecular weight (<500,000 daltons).
There is some data that low molecular weight hyaluronic acid may be pro-inflammatory rather than anti-inflammatory.
Comprehensive article on low-molecular weight versus high molecular weight hyaluronic acid appeared in Journal of Applied Nutrition. 2004. 54. 10-32. Authors suggest consuming supplements of 800,000 daltons or higher.
Hydrolyzed cartilage (type II cartilage) supplements contain low molecular weight hyaluronic acid.
Lozenge may be ideal method of delivery of a supplement, as oral mucosa is highly vascularized, and swallowing a supplement may inactivate due to acidity of the stomach.
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 Southeast Asia and has high levels of xanthones, which are antioxidants and also anti-inflammatory, reducing the activity of LOX and COX-2 enzymes. No published human studies as of 2007.
Methylene blue
Antioxidant which can be administered in either its oxidized or reduced forms (Thomas Levy, MD presentation at ICIM conference, September 2024).
Facilitates ATP production via effect on cytochrome oxidase (Thomas Levy, MD presentation at ICIM conference, September 2024).
Administration in published studies is reported to successfully treat advanced infections, including advanced septic shock (Thomas Levy, MD presentation at ICIM conference, September 2024).
Usual oral dosage is 20-30 mg daily.
Beware optical purity is important (Dale Guyer, MD presentation at ICIM conference, September 2024).
Quality of brand is important, as some brands are contaminated with heavy metals.
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.
MSM is a methyl donor, and many of the anecdotal benefits may derive from this fact.
Safety is good in clinical trials, but these have all lasted less than 12 weeks.
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).
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)
Primary conventional uses are treatment of Tylenol overdose, and prevention of intravenous dye contrast nephropathy (seminal trial published in N Engl J Med. 2000. 343. 180-184; followed by numerous additional [heterogeneous] trials, and 13 meta-analyses, of which 7 showed benefit, 5 were indeterminate, and 1 showed no benefit)
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).
Beneficial in the treatment of addictions in multiple small RCTs.
Beneficial in the treatment of bipolar disorder (Biol Psychiatry. 2008. 64. 468-75; J Affect Disord. 2011. 129. 317-320).
Beneficial in the treatment of bronchiectasis - NAC 600 mg twice a day reduced the incidence of exacerbations (1.31 vs. 1.98), reduced the volume of sputum, and improved the quality of life in a RCT of 161 patients (Respir Res. 2019. 20. 73).
Beneficial in the treatment of OCD (J Clin Pharm Ther. 2016. 41. 214-219).
Beneficial in the treatment of PTSD (J Clin Psychiatry. 2016. 77. e1439-e1446).
Beneficial in the treatment of COPD, influenza, polycystic ovarian syndrome, pulmonary fibrosis (idiopathic), smoking cessation (Prado E et al. Redox Rep. 2015. 20. 215-222).
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).
Mechanism of action includes (1) antioxidant, as a precursor to glutathione, and (2) glutamate receptor antagonist and (3) vasodilator via facilitating the production of nitric oxide.
Usual supplemental dose is 600 mg bid; some studies use, especially for psychiatric conditions use doses as high as 1000 mg twice a day.
Long term use should be accompanied by copper supplementation (i.e. 1-2 mg/day of copper amino acid chelate).
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 Gordon, MD (see also Lumbrokinase above)
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 - derived from Pine bark and contains a class of polyphenol antioxidants known as proanthocyanidins
Usual dose is 100 - 300 mg daily
Uses include the following
ADHD at 1 mg/kg/day - benefit seen in a 4 week RCT in 61 children, with significant reduction in hyperactivity and significant improvement in attention (Eur Child Adolesc Psychiatry. 2006. 15. 329-335).
Erectile dysfunction - in a 3-month pilot RCT of 21 males suffering from ED, 120 mg of Pycnogenol daily significantly improved the symptoms of impotence (Nutr Res. 2003;23(9):1189- 1198).
Hypertension - some positive and some negative clinical trials.
Menopause at 100 mg twice a day, based on data from a well-conducted 6 month RCT in 230 perimenopausal Taiwanese women, with improvement reported in hot flashes, memory, anxiety, depression, and sleep (Acta Obstet Gynecol Scand. 2007. 86. 978-985).
Varicose veins at 50 mg twice a day
Venous insufficiency at 150-300 mg per day (Phytomedicine. 2000.7. 383-388; Alternative Medicine Alert. 2004. 7. 64-68; Angiology. 2005. 56. 699-705)
Pycnogenol-nattokinase (Flite Tabs - Aidan Products) - prevents DVT and leg edema during prolonged flight. Pycnogenol is derived from pine bark 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).
Quercitin
Stabilizes release of histamine from mast cells, antioxidant, anti-inflammatory, and supports intestinal barrier function, based on animal studies
Present in apples, outer skin of onions, berries, broccoli, capers, kale, and shallots
Bioavailability is limited, estimated at 3-17%; bromelain in combination or a patented process that binds quercitin to phospholipids increases bioavailability
There is data on safety in humans at doses of 500 mg twice a day for up to 12 weeks
Resveratrol – increases mitochondrial ATP production, protects mitochondria from reactive oxygen species, up-regulates sirtuin 1 (Cell. 2006. 127. 1109-1122), and clears beta-amyloid from Alzheimer’s disease cells (J Biol Chem. 2005. 280. 37377-37382). 150 mg daily is an average dose.
Spirulina – see ‘Algae’ below.
Tianeptine - illegally sold as a supplement in the US since 2014; a drug not approved for use in the United States, with potential to cause harm (Consumer Reports. March 2021. 40-45).
Reports of addiction, similar to addiction to opioids
883 reports to poison control centers between 2015 - 2020
Historically developed in France in the 1960’s; approved as a controlled substance medication is some countries
5-HTP (5-hydroxytryptophan)
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).
Take with carbohydrate rich food since carbohydrates may increase the amount of 5-HTP which crosses the blood-brain barrier.
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.
Derived from the West African plant Grifonia simplicifolia, whereas tryptophan is synthesized via bacterial fermentation (and thus theoretical increased risk of contamination of tryptophan).
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 - touted to improve athletic performance.
Banned in 3/04 by the FDA based on lack of safety data and lack of marketing in the U.S. prior to the passage of DSHEA legislation in 1994.
Scientific study fails to document improved athletic performance, but does document an associated increase in estradiol levels in men and testosterone levels in women.
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 - unknown long term adverse effects in humans, based on lack of research
DHEA and its metabolite DHEA-S are the most prevalent circulating hormones in the body.
Synthesized primarily in the adrenal gland, but also produced in the gonads, the GI tract, and the brain.
Converted into as many as 150 active metabolites, including estrogen and testosterone
Obesity might increase the conversion of DHEA into estrogen.
7-keto-DHEA, a metabolite which may help boost immune function and reduce body fat does not convert to estrogen and testosterone.
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).
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.
Safety – might increase the risk of breast, ovarian, prostate and uterine cancer.
Adverse effects – acne, hirsutism, possible unfavorable effects on lipid profile.
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, infertility in women, low libido in women, lupus, metabolic syndrome, obesity, osteoporosis, and to facilitate 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
First isolated from bovine pineal gland in 1958.
This molecule is found in all bacteria, plants, and animals; the molecule is estimated to be 3 - 4 billion years old.
Melatonin is produced in the pineal gland, retina, white blood cells and GI tract (the enterochromaffin cells of the GI tract secrete 400 times as much melatonin as the pineal gland)
Melatonin is synthesized in the body from serotonin (via an enzyme, NAT, which is a vitamin B6 and zinc-dependent enzyme)
Many functions in the body
Neurohormone - regulation of the sleep/wake cycle
Regulation of body temperature
Modulation of immune activity - chemopreventive
Anti-inflammatory
Antioxidant - one of the most potent antioxidants, unique antioxidant in that melatonin is fat and water soluble
Inhibits aromatase, an enzyme which converts testosterone to estrogen
Counteracts lipid peroxidation and DNA damage (J Pineal Res. 2014. 57. 357-366).
Melatonin is present in a wide variety of foods, but in miniscule quantities
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).
Melatonin deficiency can be caused by any of the following
Acetaminophen
Aspirin
Alcohol abuse
Caffeine in excess
Electromagnetic fields (EMF)
High glycemic index foods
Medications - long list
Vitamin B12 deficiency
Sources of melatonin supplements
Historically extracted from pineal glands of animals, but no longer sourced this way due to risk of prions and viral contamination
Synthetic - almost all supplemental melatonin on the market in 2022 is synthetic, and synthesis often involves petrochemicals
Phytomelatonin complex recently marketed (approximately 2020) - comprised of extracts from alfalfa, chlorella, and rice, with preliminary data showing greater anti-inflammatory and greater antioxidant effects than synthetic melatonin (ORAC 300% higher). Brand name Herbatonin
Uses
Atopic dermatitis treatment - in a 4 week RCT of 73 children and adolescents, those who received 3 mg melatonin showed significant improvement in severity of dermatitis (p <0.001 for the change, as compared with placebo) and significant shortening of sleep latency by 21 minutes (p = 0.02) [JAMA Pediatr. 2016. 170. 35-42].
Cancer (melanoma and solid tumors, such as 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 10 mg each evening for 2 weeks (Cephalagia. 2005. 403-411).
Coronary artery disease - mixed clinical data in 2017
Dementia
Numerous studies suggest that supplementation protects against development of 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).
2 mg controlled release in the evening daily for one month reduced nocturnal BP in those with nocturnal hypertension (Am J Med. 2006; 119(10):898-902).
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 reported with 3 mg hs in an open label study in 17 females (Aliment Pharmacol Ther. 2005. 22. 927-934).
In an 8 week placebo controlled trial, those taking melatonin showed 3.5 fold improvement in IBS symptom scores and 3 fold improvement in quality of life (J Clin Gastroenterol. 2007. 41. 29-32).
Insomnia - 0.1 - 0.3 mg 30-60 minutes before bedtime. Ineffective if exposed to light after taking melatonin. Data is mixed.
Melatonin in patients with reduced REM sleep results in increased REM percentage, compared to placebo (J Clin Endocrinol Metab. 2004. 89. 128-134).
A 2004 AHRQ review found no effect of melatonin supplements on sleep efficacy in persons with primary or secondary insomnia.
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).
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).
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 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].
A meta-analysis of 19 studies (N = 1683) concluded that those who took melatonin supplements fell asleep 7 minutes faster and increased overall sleep time by 8 minutes, with much individual variation in the response (PLos One. 2013).
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.
Mild cognitive impairment - 3-24 mg/day for 15 – 60 months beneficial (Am J Neurodegener Dis. 2012; 1(3):280-91; J Pineal Res. 2007; 43(4):404-09).
Migraine headache prevention
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).
In a 12 week RCT of 196 patients randomized to melatonin 3 mg, amitriptyline 25 mg or placebo at bedtime, mean headache frequency reduction was 2.7 migraine headache days in the melatonin group, 2.2 migraine headache days in the amitriptyline group, and 1.1 migraine headache days in the placebo group, with a p < 0.01 when comparing melatonin with placebo (Goncalves A et al. J Neurol Neurosurg Psychiatry. 2016. 87. 1127-1132).
Myocardial infarction - in the MARIA RCT, intravenous melatonin favorably affected biomarkers of inflammation, attenuated reperfusion injury and decreased ventricular arrhythmias after reperfusion (Curr Vasc Pharmacol. 2009; 7(3):367-73).
Parkinson’s disease - may reduce the risk of developing Parkinson’s
Peptic ulcer disease healing – in a small 21 day trial, 14 patients were randomized to placebo, melatonin 5 mg twice a day, or tryptophan 250 mg twice a day. All patients received conventional treatment with omeprazole 20 mg daily; all patients were H pylori positive; 7 had duodenal ulcers and 7 had gastric ulcers. At 21 days, all ulcers had healed by EGD in the melatonin and tryptophan groups, whereas only 3 of the 7 gastric ulcers and 3 of the 7 duodenal ulcers had healed in the placebo group (p < 0.05) [J Physiol Pharmacol. 2011. 62. 521-526].
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 - 3 mg/day (Otolaryngol Head Neck. 2006. 210-213; Ann Otol Rhinol Laryngol. 2011. 120. 433-440).
Traumatic brain injury - beneficial in animal studies
Dosage - 0.3 mg is a physiologic dose (historically, in 1992, a 20 year patent was obtained by Dr. Wurtman and MIT for doses under 1 mg, for induction of sleep, and this might be the historic basis of virtually all supplements containing 1 mg or more of melatonin)
Onset of action
60-90 minutes for immediate release melatonin
45-60 minutes for phytomelatonin, based on preliminary research in 2022
Safety
Doses above 8 mg are associated with decreased sperm motility.
May interact with warfarin
Melatonin supplementation does NOT suppress endogenous synthesis, based on data from multiple studies dating back to the 1980’s (Holistic Primary Care. Winter 2022. Pages 1-2).
Side effects - dizziness, grogginess, headache, vivid dreams - these side effects are often dose-related
Contraindications - should be used with caution in those with autoimmune disease, leukemia, lymphoma, and mental illness’ those who are pregnant or breastfeeding
Quality
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).
Analysis of 31 commercially available supplements showed actual melatonin content ranging from 17% to 478% of label claim, lot to lot variation of content as high as 465%, and adulterated with serotonin in 8 samples (Erland LAE et al. J Clin Sleep Med. 2017).
Summary articles:
Minich D. Holistic Primary Care. Winter 2022. Pages 1-2
Smith, Pamela W. Melatonin: More than just a hormone that regulates sleep. Townsend Letter. February/March 2021. 30-34).
Review article. Nutrients (open access). 2022
Pregnenolone - unknown long term adverse effects in humans, based on lack of research
Adrenal hormone, and synthesis decreases with age; may be beneficial in treatment of fatigue based on anecdotes
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
Chlorella is a green algae cultivated under conditions that should guarantee the absence of environmental toxins. The CK strain of chlorella is the most intensively studied variety (in terms of published studies) – it has a relatively thinner cell wall, and this might facilitate absorption.
Chlorella has very high amounts of chlorophyll – chlorophyll is nearly identical to hemoglobin, but has a magnesium atom at its center.
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.
The cell wall of chlorella may bind heavy metals and environmental toxins, and thus may aid in detoxification of the body.
Usual supplemental dose is 2-3 grams per day, with doses of 4-10 grams per day considered acceptable for those with health concerns.
Brown algae
Fucose-containing, sulfated polysaccharides known collectively as fucoidans have antitumor, immunomodulatory, antiangiogenesis, antioxidant, antiviral, antithrombotic, and anti-inflammatory effects in preclinical studies (Review Article. IMCJ. 2012. 12[5]. 51-55).
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
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 Klamath Lake does NOT have dangerous levels of toxins. This is nicely outlined in an extensively referenced article by Christian Drapeau (Townsend Letter. Dec 2010. 56-59) which refutes a 1996 article by John McPartland which erroneously stated that Klamath Lake AFA contained unacceptable levels of neurotoxins.
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).
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 2001 by the WHO as “live organisms which, when administered in adequate amounts, confer a health benefit on the host.”
Functions of beneficial bacteria in the gut
Essential to the normal anatomical and physiological development of the intestinal mucosa.
Provide non-immunological protection against infection (i.e. antibacterial and antiviral effects)
Prime the immune system from birth to deliver the correct immune response.
Influence brain chemistry and behavior [in mice] independent of the autonomic nervous system, GI-specific neurotransmitters, or inflammation
Facilitate a wide variety of metabolic functions
Probiotics include various Lactobacillus species, Bifidobacterium species (bacteria), and Saccharomyces boulardii (yeast).
Issues pertinent to probiotics in supplement form:
The organisms in the supplements must survive the manufacturing process to be beneficial.
Proper packaging and storage is essential so that the organisms stay alive – shipped in dry ice, long term storage in the refrigerator or freezer.
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.
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).
Quantity of organisms must be sufficient – at least 1-10 billion microorganisms per day for bacteria, 0.5-1 gram per day for yeast.
The GOLD STANDARD for any brand name is that it has been documented effective in a randomized clinical trial
Go to www.consumerlab.com for information on quality brands.
Contra-indications (Consumer Reports. 7/05. Pgs. 34-35).
Children with short-bowel syndrome as per a spokesman for the American Academy of Pediatrics.
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).
Safety
A study of 12 refrigerated and 8 non-refrigerated Lactobacillus products from commercial sites in Seattle found that 30% grew contaminant bacterial species in laboratory culture media (Berman S et al. The Internet Journal of Alternative Medicine. 2003. 1).
A systematic review of the safety of L rhamnosus GG and Bifidobacterium species found no reported cases of sepsis in any clinical trial (BMJ. 2006. 333. 1006-1008).
Pregnancy or lactation – probably not a problem but safety unknown
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).
Therapeutic Uses: many
NOTE: A meta-analysis of 84 clinical trials involving over 10,000 patients showed the probiotics "are generally beneficial in treatment and prevention of gastrointestinal diseases (Ritchie ML, et al. PLoS One. 2012).
Abdominal pain post colonoscopy - Lactobacillus acidophilus NCFM in combination with Bifidobacterium lactis Bi-07 (12.5 billion cfu daily of each for 14 days) beneficial in a RCT of 320 patients post colonoscopy. Those taking the probiotic had an average of 1.99 pain days post procedure, compared with an average of 2.78 pain days post procedure in the placebo group (D’Souza B et al. ANZ J Surg. 2017).
Allergic rhinoconjunctivitis - beneficial in a RCT of 173 healthy individuals with seasonal symptoms, randomly assigned to receive 2 capsules per day of Kyo-Dophilus® during the spring allergy season (Am J Clin Nutr. 2017. 105. 758-767).
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).
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. NOTE Alan R. Gaby, MD hypothesizes that negative studies might be a function of small amounts of cow’s milk proteins in the probiotics used in the negative studies.
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 10(10) (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).
Lactobacillus rhamnosus HN001 × 10(9) cfu/day reduced the cumulative incidence of eczema by 49% (p < 0.05) at 2 years of age in a RCT of 474 pregnant New Zealand women who had, or whose husband/partner had, a history of allergic disease. This was a 3-arm trial of Lactobacillus rhamnosus HN001, Bifidobacterium animalis subsp lactis strain HN019 (9 × 10(9) cfu/day), or placebo, beginning at 35 weeks of gestation until delivery or until the infants were age 6 months (if breast feeding). The infants were randomly assigned to receive the same treatment from birth until 2 years of age. Compared with placebo, the Bifidobacterium animalis subsp lactis strain HN019 nonsignificantly reduced the incidence by 10% (J Allergy Clin Immunol 2008;122:788-794.). At age 11, the benefit of Lactobacillus rhamnosus HN001 persisted with a RR of eczema of 0.46 (p = 0.015) and a RR of hay fever of 0.73 (p < 0.05) [Pediatr Allergy Immunol. 2018. 29. 808-814].
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% reduced risk of 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).
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].
An RCT of 43 children from newborn to age 11 showed that subjects who received Lactobacillus salivarius LS01 twice daily for 8 weeks, then once daily for 8 weeks showed that quality of life (SCORAD Index and itch index) was improved at 20 weeks of follow up (J Clin Gastroenterol. 2014. Suppl 1. S34-36).
A 3 month RCT of 220 children aged 1 - 18 showed benefit with a combination of Lactobacillus paracasei, Lactobacillus fermentum, and Lactobacillus paracasei + fermentum (Wang IJ et al. Clin Exp Allergy. Epub 1/20/15).
A 12 week RCT of 50 children aged 4 - 17 showed benefit with 1 billion cfu daily of a capsule containing a combination of Bifidobacterium lactis CECT 8145, Bifidobacterium longum CECT 7347, and Lactobacillus casei CECT 9104 (Navarro-Lopez, V et al. JAMA Dermatol. Epub 11/8/17).
Lactobacillus fermentum ME-3 is beneficial (renamed Limosilactobacillus fermentum ME-3 in 2020, available for purchase as Reg’Activ®) [Presentation at the fourth Central European Congress on Food, May 15-17, 2008].
Bacterial vaginosis – see ‘vaginitis’ just below
Cavities – see ‘dental caries’ just below
Colic
Lactobacillus reuteri DSM 17938 100 million cfu/day (commercially available as Gerber Soothe Colic drops) 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 17938 100 million cfu per day (commercially available as Gerber Soothe Colic drops) more effective than placebo in a 3 week RCT in 50 breast fed infants (Pediatrics. 2010. 126. e526-e533).
Lactobacillus rhamnosis 5 billion cfu daily (commercially available as Culturelle) beneficial in a 4 week RCT of 45 breastfed infants, with mean of 105 versus 240 minutes of crying (p < 0.001). In addition the concentration of fecal calprotectin decreased significantly in the treatment group (Nutrients. 2020. 12. E1693).
Colon cancer prevention – theoretical benefit.
Probiotics have antimutagenic and anticarcinogenic activities in the colon (Dig Liver Disease. 2006. 38[Suppl 2]. S277-S282).
Animal data is suggestive of a benefit, and a 12 week Phase II RCT in 37 participants with a history of colon cancer and an additional 43 participants who were status post polypectomy, with histologically confirmation of an adenomatous polyp which showed favorable alteration of specific biomarkers of colon cancer (i.e. surrogate endpoints) in the treatment group, who received a symbiotic consisting of oligofructose-enriched inulin with Bifidobacterium lactis Bb12 and Lactobacillus rhamnosus GG (Am J Clin Nutr. 2007. 85. 488-496).
Constipation
Consider a combination of Lactobacillus acidophilus and Bifidobacterium based on open label trials (Can J Gastroenterol. 2003; Nov 17:655-659; Bekkali N et al. Nutr J. 2007).
In an 8 week RCT of 100 million cfu daily of Lactobacillus reuteri DSM 17938 (commercially available as Gerber Soothe Colic drops), the frequency of bowel movements was significantly higher in the treatment group with p < 0.05 at week 2, p < 0.04 at week 4, and p < 0.03 at week 8 (J Pediatr. 2010. 157. 598-602).
A systematic review of RCTs of probiotics found that in adults and children, probiotic supplementation augments the number of stools and reduces the number of hard stools (World J Gastroenterol. 2010. 16. 69–75).
In a 14-day RCT of 100 adults with 1-3 bowel movements at baseline, in those randomized to Bifidobacterium lactis HN019 at a low dose of 1.8 billion cfu/day, there was a reduction in whole gut transit time (WGTT) of 25%; in those randomized to Bifidobacterium lactis HN019 at a high dose of 17.2 billion cfu/day, there was a reduction in whole gut transit time (WGTT) of 33% (Waller PA, et al. Scand J Gastroenterol. 2011).
In a 15 week RCT of 56 adults administered 4 tablets per day of a probiotic with 100 million cfu per tablet of Lactobacillus reuteri DSM 17938 for 15 days, then 2 tablets per day for 90 days (commercially available as Gerber Soothe Colic drops), mean improvement at the end of the trial was 41.5% in the probiotic group compared with 10.2% in the placebo group. The mean severity of constipation was significantly improved at days 60 and 105 of the trial but not at day 15 (Benef Microbes. 2018. 9. 51-60),
Mostly negative study of Bifidobacterium lactis HN019 - in a 28-day RCT of 228 adults with functional constipation, neither low dose nor high dose probiotic decreased whole gut transit time; increased stool frequency was seen only in the subgroup of 65 patients with more severe constipation at baseline (Ibarra A et al. Gut Microbes. 2018).
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).
Ten patients with chronic infections due to Pseudomonas received 2 tablets per day ofL acidophilus, L bulgaricus, B bifidum and Strep thermophiles – each tablet contained 600 million cfu. During the 6 months of treatment, no patient had a pulmonary exacerbation. This was a significant reduction as compared with the 2 years prior to the study; the reduced frequency exacerbations as compared with baseline persisted for 6 months after completion of the trial (Pediatr Pulmonol. 2010. 45. 536-540).
Dandruff - see seborrheic dermatitis
Dental caries prevention
Milk fermented with Lactobacillus rhamnosis beneficial in one 7 month RCT, in which the control group consumed regular milk (Caries Res. 2001. 35. 412-420).
A probiotic chewing gum containing a blend of 3 probiotic organisms reduced the incidence of new caries by 75% (p < 0.05) in a RCT of 138 children ages 2-3 living in a low socioeconomic area in Sweden. The product, EvoraKids, was no longer commercially available in 2017 (BMC Oral Health. 2015. 15. 112).
Reconstituted milk powder containing 10,000,000 cfu Lactobacillus paracasei SD1 reduced the number of new caries by a statistically significant 17% in a 6-month RCT of 487 Thai preschool children. In addition, regression of existing caries was significantly higher by 76% in the treatment group (Caries Res. 2020. 54. 491-501).
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). Benefit is likely strain specific - strains with evidence of efficacy include those listed just below and B. lactis Bl-04, B. lactis Bi-07, and L. acidophilus NCFM.
Lactobacillus 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 Italy with active infections requiring antibiotics. Out of 98 evaluable patients, 71% in the treatment group had no diarrhea versus 38% in the placebo group. The duration of diarrhea was 0.7 days in the treatment group vs 1.6 days in the placebo group (p=0.002) [Minerva Pediatrica. 2003. 55. 447-452].
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).
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).
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).
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).
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).
A systematic review and meta-analysis of 63 RCTs (n = 11,811) showed that administration of probiotics was associated with a RR of 0.58 (0.50-0.68, p<0.001, NNT of 13) for antibiotic-associated diarrhea (JAMA. 2012. 307. 1959-1969).
HOWARU® Restore, a fixed combination of equal amounts of Lactobacillus acidophilus NCFM, Lactobacillus paracasei Lpc-37, Bifidobacterium lactis Bi-07 and Bifidobacterium lactis Bl-04 shown to be beneficial in a trial in China of more than 500 antibiotic-treated patients. The probiotic was administered 2 hours after the morning dose of antibiotic (course of antibiotic ranged from 10-21 days) and continued for 7 days after the last dose of antibiotic. The rate of diarrhea was 24.6% in the placebo group, 19.6% in the low dose group [4.17 billion cfu/day], and 12.5% in the high dose group [17 billion cfu/day]. NNT to obtain a reduction in antibiotic-associated diarrhea was 8.4 (Ouwehand AC et al. Vaccine. 2014).
NEGATIVE trial – PLACIDE trial – largest RCT to date – 8 week RCT of 2981 inpatients > 65 years of age. Active treatment group received 21 days of 60 billion cfu of a microbial preparation containing 2 strains of L acidophilus and 2 strains of Bifidobacterium (Lancet. 2013. 382. 1249-1257 and also Health Technol Assess. 2013. 17. 1-140 as cited in (ACP Journal Club. 2014. 160. JC6).
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).
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).
Saccharomyces boulardii 500 mg twice a day for 4 weeks reduced the probability of recurrence of C diffiile by 57% ( p < 0.05) in a RCT of 124 patients treated with vancomycin or metronidazole (JAMA. 1994. 271. 1913-1918).
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 [UK].DPHE 2006. Report #56). Most consistent evidence is for Saccharomyces boulardii.
A systematic review and meta-analysis of 20 RCTs (n=3818) showed that probiotics reduced the incidence of antibiotic-associated C difficile-associated diarrhea (CDAD) by 66%. In a population with a 5% incidence of antibiotic-associated C difficile diarrhea, probiotic prophylaxis would prevent 33 episodes per 1000 persons. Adverse events occurred in 9.3% of probiotic treated patients and 12.6% of controls. The authors conclude “moderate quality evidence suggests that probiotic prophylaxis results in a large reduction in CDAD without an increase in clinically important adverse events (Bradley CJ et al. Probiotics for the Prevention of Clostridium difficile-Associated Diarrhea. Ann Intern Med. 2012. 157. 878-888).
HOWARU® Restore, a fixed combination of equal amounts of Lactobacillus acidophilus NCFM, Lactobacillus paracasei Lpc-37, Bifidobacterium lactis Bi-07 and Bifidobacterium lactis Bl-04 shown to be beneficial in a trial in China of more than 500 antibiotic-treated patients. The probiotic was administered 2 hours after the morning dose of antibiotic (course of antibiotic ranged from 10-21 days) and continued for 7 days after the last dose of antibiotic. The rate of C. diff diarrhea was 4.8% in the placebo group, 1.8% in the low dose group [4.17 billion cfu/day], and 1.8% in the high dose group [17 billion cfu/day] (Ouwehand AC et al. Vaccine. 2014).
HOWARU® Restore (see just above for composition and dosage) shown to be beneficial in the PICO study, as adjunct to treatment with vancomycin or metronidazole in 33 patients with mild to moderate first-episode antibiotic-associated C difficile diarrhea. The mean number of days with diarrhea was 3.5 days in the antibiotic + probiotic group, compared with 12 days in the antibiotic + placebo group (Barker AK et al. J Antimicrob Chemother. 2017).
A Cochrane review of 31 RCTs (n = 4492) in adults and children concluded that probiotics prevent C difficile-associated diarrhea (Cochrane Database Syst Rev. 2013. CD006095). an updated Cochrane review of 39 RCTs showed a 60% lower incidence of C difficile-associated diarrhea in those receiving probiotics (1.5% vs. 4.0%, p < 0.001) [JAMA. 2018. 320. 499-500].
Diarrhea – prevention of continuous enteral feeding-associated diarrhea. Saccharomyces boulardii lyophilized (Florastor) is effective
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).
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).
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).
Diarrhea – prevention of radiation-induced diarrhea
VSL #3 is effective (American Journal of Gastroenterology. 2002. 97. 2150-2152).
A combination of Lactobacillus acidophilus and Bifidobacteria bifidum product containing 2 billion cfu per capsule, administered twice a day starting 7 days prior to initiation of RT and continuing until completion of the course of RT, is effective based on a RCT in 63 women with cervical cancer (Radiat Oncol. 2010. 5. 31).
Diarrhea – prevention of rotavirus-induced diarrhea. There is data on effectiveness of Lactobacillus rhamnosis, Lactobacillus casei, Streptococcus thermophiles, and Bifidobacteria bifidum (Scand J Nutr. 2001. 45. 8-12).
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/daA 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).
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).
Diarrhea – treatment of AIDS associated diarrhea. Saccharomyces boulardii lyophilized (Florastor) is effective.
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).
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).
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).
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).
Diarrhea - treatment of Clostridium difficile diarrhea – data is mixed, with positive trials more common when the study group has recurrent Clostridium difficile diarrhea (Note: an estimated 20% of patients with Clostridium difficile experience recurrences of diarrhea 3-28 days after antibiotic treatment is discontinued (Am J Med. 1989. 86. 15-19; Gut. 1983. 24. 206-212; Gastroenterology. 1980. 78. 431-434).
Lactobacillus GG (Cuturelle) 10 billion cfu dialy is effective (Lancet. 1987. 2. 1519; J Pediatr Gastroenterol Nutr. 1995. 21. 224-226).
Lactobacillus acidophilus NCFM, Lactobacillus paracasei Lpc-37, Bifidobacterium lactis Bi-07 and Bifidobacterium lactis Bl-04, 17 billion cfu per capsule, one capsule daily is effective in a 28 day RCT of 33 patients with an initial episode of mild to moderate Clostridium difficile. The median number of days of diarrhea was significantly lower in the treatment group (p = 0.005) [J Antimicrob Chemother. 2017. 72. 3177-3180].
Saccharomyces boulardii lyophilized (Florastor) is effective and safe at a dose of 500 mg twice a day, in combination with standard antibiotics (but no more effective than antibiotic alone for initial episode of Clostridium difficile diarrhea, in a post hoc analysis), based on a 4 week multi-center RCT in 124 patients (64 with initial episode and 60 with recurrent episode). Relapse rate was 64.7% in the placebo group and 34.6% in the treatment group [p=0.04] (JAMA. 1994. 271. 1913-1918). Benefit seen with Saccharomyces boulardii lyophilized (Florastor) in combination with high dose vancomycin in a second multi-center RCT in 170 patients presenting with chronic and multi-resistant Clostridium difficile diarrhea (Clin Infect Dis. 2000. 31. 1012-1017).
Positive meta-analysis of 6 RCTs (n = 354) found probiotics effective in treatment of Clostridium difficile diarrhea, based on an endpoint of new episode of Clostridium difficile diarrhea within 1 month of antibiotic exposure, or previous episode of Clostridium difficile diarrhea. The benefit reported in this meta-analysis was predominantly a function of two positive trials, each of which was conducted using Saccharomyces boulardii lyophilized (Am J Gastroenterol. 2006. 101. 812-822). Saccharomyces boulardii has a unique mechanism of action – it produces a protease that can degrade exotoxins produced by Clostridium difficile (Infect Immun. 1999. 67. 302-307).
Review article “The effect of probiotics on Clostridium difficile diarrhea” (Am J Gastroenterol. 2000. 95. 511S-513S).
Negative systematic reviews (CMAJ. 2005. 173. 167-170; Cochrane Database Syst Rev. 2008. CD004611).
Diverticulitis
Prevention of recurrence – in a 12 month RCT, in which 210 patients with uncomplicated diverticular disease in remission were randomized to receive either prescription mesalazine, Lactobacillus casei subspecies DG 24 billion cfu, both, or placebo for 10 days of each month, significantly fewer patients had recurrence of abdominal pain (and significantly fewer patients experienced diverticulitis) in probiotic group. Mesalazine was equally effective to probiotic, and the combination was more effective than either probiotic or mesalazine alone (Aliment Pharmacol Ther. 2013. 38. 741-751).
Treatment (in conjunction with antibiotic) - in a RCT of 88 patients with acute uncomplicated diverticulitis, those who received Lactobacillus reuteri 4659, 500 million cfu twice a day along with ciprofloxacin 400 mg twice a day and metronidazole 500 mg three times a day had decreased abdominal pain, decreased inflammatory markers, and decreased length of hospital stay (Int J Colorectal Dis. 2019. 34. 1087-1094).
Eczema – see atopic disease just above.
Fatty liver
Improvement in fatty liver severity at 4 months, as determined by ultrasound was significantly greater in the treatment group (p < 0.001) in a 4 month RCT of 48 obese children with biopsy-proven moderate to severe NAFLD. Treatment was with VSL #3, one satchet (450 billion cfu) in those aged less than 10 and 2 satchets in those 10 years old or older (Aliment Pharmacol Ther. 2014. 39. 1276-1285).
Food allergies – in a study in 27 infants with atopic eczema and cow's milk allergy, the group of 13 who received an extensively hydrolyzed whey formula with the addition of Lactobacillus GG (5 x 10(8) colony-forming units/gm formula) showed significant improvement in the clinical score of atopic dermatitis, along with a significant decrease in the concentration of alpha 1-antitrypsin and the median concentration of fecal tumor necrosis factor-alpha. The conclusion in the abstract is “These results suggest that probiotic bacteria may promote endogenous barrier mechanisms in patients with atopic dermatitis and food allergy, and by alleviating intestinal inflammation, may act as a useful tool in the treatment of food allergy” (J Allergy Clin Immunol. 1997. 99. 179-185).
Functional abdominal pain in children - Lactobacillus reuteri DSM 17938 at a dose of 100 million cfu daily (commercially available as Gerber Soothe Colic drops) effective in a 12 week trial of 55 children aged 5- 17 with functional abdominal pain or irritable bowel syndrome. The median number of days with pain was 26 in the treatment group versus 65 in the placebo group (p < 0.03). NOTE temperature of storage/shipping should not exceed 77 degrees F (J Pediatr Gastroenterol Nutr. 2017. 64. 925-929).
Gastroenteritis (acute) treatment (with or without oral rehydration therapy).
Saccharomyces boulardii lyophilized (Florastor) is effective.
Benefit seen with a dose of 500 mg/day in a RCT in 38 young children in a study published in French (Ann Pediatr. 1985. 32. 561-563).
Benefit seen after 48 and 96 hours with a dose of 300 mg/day in a RCT in 130 young children (3 months to 3 years old) in another study published in French (Ann Pediatr. 1994. 41. 397-400).
Benefit seen after 48 hours in a RCT in 92 adults, in a study published in German (MMW Munch Med Wochenschr. 1990. 132. 188-192).
A meta-analysis of 4 RCTs (n=619) conducted in infants and children less than 12 years of age showed reduced duration of diarrhea, but the authors commented that the results should be interpreted with caution due to methodological limitations of the included studies (Aliment Pharmacol Ther. 2007. 25. 257-264).
Negative trial - RCT in 571 children with acute diarrhea, in which one of the 5 arms of treatment was with Saccharomyces boulardii (BMJ. 2007. 335.340).
Probiotics may be effective - many initial studies showed benefit but two large studies published in 2018 did not show benefit (Editorial. N Engl J Med. 2018. 379. 2076-2077).
Cochrane review of 23 studies (n=1917) showed a reduction in mean duration of diarrhea of 30 hours, from 72 hours to 42 hours (Cochrane Database Syst Rev. 2004. CD003048).
A RCT in 230 male infants in Bangledesh showed that 10 billion cfu/day of Lactobacillus paracasei was more effective than placebo in the treatment of nonrotavirus acute diarrhea (Pediatrics. 2005. 116. e221-e228).
Meta-analysis of 34 RCTs (n = 4844) of probiotics in the prevention and treatment of acute diarrhea showed benefit (Lancet Infect Dis. 2006. 6. 374-382).
A 5 arm RCT in 571 children, which showed that the groups receiving Lactobacillus rhamnosus GG and those in the group receiving a mixture of four different probiotic strains had significantly shorter duration of diarrhea. In this trial, the children receiving Bacillus clausii and Enterococcus faecium SF68 did not improve more rapidly (BMJ. 2007. 335. 340).
Lactobacillus reuteri DSM 17938 108 cfu daily effective in a RCT of 127 Turkish children hospitalized with acute gastroenteritis (Acta Pediatr. 2014. 103. E300-e305).
Lactobacillus rhamnosus GG (5 day course) ineffective in a RCT of 971 participants ages 3 months to 4 years (N Engl J Med. 2018. 379. 2002-2014).
Combination product containing Lactobacillus rhamnosus R0011 and Lactobacillus helveticus R0052 (5 day course) ineffective in a multicenter RCT in Canada of children ages 3 to 48 months presenting to the emergency department (N Engl J Med. 2018. 379. 2015-2026).
Gluten sensitivity - VSL#3 has the capacity to hydrolyze wheat flour allergens (J Food Prot. 2007 Jan;70:135-44).
Halitosis treatment – in a 4 week trial of individuals with periodontitis-related halitosis, those administered 2 billion cfu daily of Lactobacillus salivarus in a slow-dissolving tablet showed a significant reduction in both oral malodor and degree of bleeding upon probing of gum tissue (Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010. 110. 201-208).
Helicobacter pylori eradication
A lyophilized and inactivated culture of Lactobacillus acidophilus increases Helicobacter pylori eradication rates based on a RCT in 120 patients who received triple therapy. Eradication rate was 72% in the triple therapy group and 88% in the triple therapy plus probiotic group (Aliment Pharmacol Ther. 2000. 14. 1625-9).
Lactobacillus GG supplementation (6 x 109 cfu twice a day for 14 days) reduces H. pylori therapy-related side effects and overall treatment tolerance, based on a RCT in 120 healthy asymptomatic subjects screened positive for H. pylori infection and deciding to receive eradication therapy with 1-week pantoprazole (40 mg b.i.d.), clarithromycin (500 mg b.i.d.), tinidazole (500 mg b.i.d.) [Digestion. 2001. 63. 1-7].
HLC Intensive 25 billion cfu/day (manufactured by Pharmax www.pharmaxllc.com) when co-administered with triple therapy prevents the emergence of antibiotic resistant enterococci, based on a RCT in 162 patients. There was no change in the incidence rate of antibiotic resistance in the treatment group, whereas the number of patients harbouring antibiotic resistant enterococci increased significantly in the group which received only placebo probiotic, even though the number of enterococci were similar in both groups (Int J Antimicrob Agent. 2005. 26. 69-74).
HLC Intensive for 15 days in conjunction with 7 days of eradication therapy modulates the response of the intestinal microflora to the effects of antibiotic therapy (i.e. prevents increases in the facultative anaerobe population) in a pilot RCT in 30 subjects divided into 3 groups (Int Immunopharm. 2005. 5. 1091-1097).
A review of 14 trials (n=1671) and a meta-analysis of 11 RCTs showed higher eradication rates when probiotic supplementation was added to conventional treatment, including in 2 RCT’s (n=208) in patients with previous eradication failure, and the addition of probiotics to conventional treatment was associated with fewer side effects of treatment (Aliment Pharmacol Ther. 2007. 25. 155-168). Of note, 6 of the 14 trials were of poor quality (Jadad < 3) and the larger trials showed less of an effect (ACP Journal Club. 2007. 146. 63).
Saccharomyces boulardii 250 mg twice a day for 4 weeks, in conjunction with 7-10 days of omeprazole, amoxicillin, and clarithromycin increased the eradication rate (but not to a statistically significant degree) in a randomized, unblinded intervention trial in 90 children with symptoms of gastritis (62% tested positive for H. pylori at the onset of the trial). Of those testing positive at onset, 80.9% treated with standard care only tested negative at the end of the trial, compared with 93.3% also given S boulardii (trend not statistically significant). Side effects occurred in 31% of those treated with standard care alone, compared with 8% also given S boulardii (p<0.05)[Acta Paediatrica. 2009. 98. 127-131].
A RCT of 804 patients undergoing triple therapy for H pylori showed that those who also received 1 capsule twice a day of a combination of L rhamnosus GG and Bifidobacterium BB-12 10 billion cfu had a cure rate of 87.4% versus 72.6% in the placebo (with triple therapy group [p < 0.001] (Medicine. 2015. 94. e685).
Benefit reported in a network meta-analysis. (Medicine (Baltimore). 2019. 98(15). e15180).
Hepatic encephalopathy - VSL #3 450 billion cfu (1 satchet) daily was as beneficial as lactulose in a 2 month RCT of 120 patients with cirrhosis and minimal hepatic encephalopathy (Pratap MV et al. Hepatol Res. Epub 9/29/14).
Hypercholesterolemia treatment – clinical trial results are mixed, with benefit reported for L reuteri NCIMB 30242, L acidophilus La5, and B lactis Bb12 (Nutr Rev. 2014. 72. 18-29).
Lactobacillus acidophilus L1 effective in one trial (J Am Coll Nutr. 1999. 18. 43-50).
Bifidobacterium longum effective in one clinical trial (J Dairy Sci. 2003. 86. 2452-2461).
Lactobacillus acidophilus and Bifidobacterium lactis beneficial in a clinical trial in diabetics (J Dairy Sci. 2011. 94. 3288-3294). clinical trial results are mixed, with benefit reported for L reuteri NCIMB 30242, L acidophilus La5, and B lactis Bb12 (Nutr Rev. 2014. 72. 18-29).
Hypertension - a review of 9 clinical trials concluded that chronic intake of high-potency, multi-species probiotic supplements lowered BP in hypertensive individuals (Hypertension. 2014. 64. 897-903).
IBD – data is mixed with a bit more positive data for ulcerative colitis than for Crohn’s. NOTE that 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).
Crohn’s disease
E coli Nissle 1917 (a strain not commercially available in the U.S. but sold in Germany as Mutaflor) at a dose of 1 billion cfu daily, increased to 5 billion cfu daily was more effective than placebo at preventing relapse (33% relapse rate versus 64% relapse rate) in a pilot one year RCT of 28 patients with active colonic Crohn’s, in whom remission was induced with prednisolone. All patients in the probiotic group were able to discontinue prednisolone after 6 months (J Clin Gastroenterol. 1997. 25. 653-658). NOTE sale of E coli containing probiotics now prohibited in many Western countries, including the U.S.
Saccharomyces boulardii lyophilized (Florastor) 1 gram per day with mesalamine 1 gram twice a day was associated with a reduction in relapse rate from 37.5% to 6.25% when compared to mesalamine 1 gram three times a day (p=0.04) in a 6 month RCT of 32 patients (Dig Dis Sci. 2000. 45. 1462-1464).
Lactobacillus GG may be beneficial in children based on an open-label trial in which 3 of 4 children were able to reduce steroid dosage by 50% (J Pediatr Gastroenterol Nutr. 2000. 31. 453 –457).
Lactobacillus GG 6 billion cfu twice a day ineffective in maintenance of remission after surgical resection for Crohn’s disease, based on a 1 year RCT in 45 patients. Clinical recurrence occurred in 17% of the probiotic group and 11% of the placebo group; endoscopic recurrence occurred in 60% of the probiotic group and 35% of the placebo group (Gut. 2002. 51. 405-409).
Lactobacillus GG 2 billion cfu daily ineffective in maintenance of remission in a 6 month RCT of 11 patients (BMC Gastroenterol. 2004. 4. 5).
Lactobacillus GG 1 billion cfu twice a day ineffective in maintenance of remission in a 2 year RCT of 75 patients (Inflamm Bowel Dis. 2005. 11. 833-839).
Probiotic ineffective at reducing the rate of endoscopic or symptomatic recurrence status post-surgical resection for Crohn’s disease, based on 4 separate trials - a one year RCT of 32 patients dosed with Lactobacillus GG 6 billion cfu twice a day (Gut. 2002. 51. 405-409), a 2 year RCT of 9 patients dosed with a combination probiotic (Dig Dis Sci. 2007. 52. 385-389), a 6 month RCT of 78 patients dosed with Lactobacillus johnsonii LA1, 2 billion cfu twice a day (Gut. 2006. 55. 842-847), and a 12 week multicenter RCT of 64 patients dosed with Lactobacillus johnsonii LA1, 1 billion cfu daily (Inflamm Bowel Dis. 2007. 13. 135-142).
Ulcerative colitis
Probiotics to maintain remission
E coli Nissle 1917 (a strain not commercially available in the U.S. but sold in Germany as Mutaflor) at a dose of 100-200 mg/day as effective as mesalamine 500 mg three times a day at preventing relapse in a study of 120 patients with inactive ulcerative colitis (Aliment Pharmacol Ther. 1997. 11. 853-858). NOTE sale of E coli containing probiotics now prohibited in many Western countries, including the U.S.
E coli Nissle 1917 at a dose of 200 mg once a day, based on a 12 month RCT in 327 patients with ulcerative colitis in remission, comparing this treatment to mesalamine 500 mg 3 times daily. The probiotic and mesalamine were equally effective at preventing relapse (Gut. 2004. 53. 1617-1623). NOTE sale of E coli containing probiotics now prohibited in many Western countries, including the U.S
VSL #3 (each dose contains 450 billion viable lyophilized bacteria of 4 strains of Lactobacillus, 3 strains of Bifidobacterium, and 1 strain of Streptococcus salivarus suspension subspecies Thermophilus) at a dose of 1,800 billion live bacteria twice a day induced full remissions in 18 of the 34 and a strong clinical response in another 8 of the 34, in a 6 week open-label trial in 34 patients with mild to moderate ulcerative colitis unresponsive to conventional treatment. 3 patients had no response and 3 patients had worsening. Outcomes were confirmed endoscopically, and DNA sequencing was used to confirm the presence of VSL#3 bacterial species in the mucosal biopsy samples (Am J Gastroenterol. 2005. 100. 1539-1546).
Lactobacillus GG 9 billion cfu twice a day, based on a 1 year RCT in 187 patients with ulcerative colitis in remission, comparing the probiotic with mesalamine 800 mg tid. Remission maintained at 12 months in 85% of the probiotic group and 80% of the mesalamine group (Aliment Pharmacol Ther. 2006. 23. 1567-1574).
Probiotics to induce remission
E coli Nissle 1917 effective in a 1 year RCT of 116 patients with active ulcerative colitis - remission achieved in 68% of the probiotic group and 75% of the mesalamine 800 mg tid group (Lancet. 1999. 354. 635). NOTE sale of E coli containing probiotics now prohibited in many Western countries, including the U.S.
VSL#3 at a dose of 900 billion live bacteria daily was associated with significant improvement in Inflammatory Bowel Disease Questionnaire score, whereas this was not the case with placebo, in a 12 month RCT in 40 patients who underwent ileal pouch-anal anastomosis for ulcerative colitis (Gastroenterology. 2003. 124. 1202-1209).
B longum 200 billion cfu in combination with 6 grams FOS and inulin, each twice a day ineffective in a 4 week trial of 13 patients [p=0.06] (Gut. 2005. 54. 242-249).
Combination ofB breve Yakult, B bifidum Yakult and L acidophilus at a dose of 10 billion cfu daily more effective than placebo in a 12 week RCT of 19 patients who underwent ileal pouch-anal anastomosis (Scand J Gastroenterol. 2005. 40. 43-51).
VSL#3 at a weight based dosage ranging from 450 billion cfu/day to 1.4 trillion cfu/day was effective in a one year RCT of 29 children between the ages of 1-16 newly diagnosed with ulcerative colitis. 93% on probiotics went into remission compared with 36% with placebo (p<0.001) [Am J Gastroenterol. 2009. 104. 437-443].
VSL #3 at a dose of 3600 billion cfu twice a day effective in a 12 week trial of 84 patients (Clin Gastroenterol Hepatol. 2009. 7. 1202.1209).
IBS – many published studies, several review articles (Neurogastroenterol Motil. 2007. 19. 166-172). A combination of lactobacilli and Bifidobacterium appears to be most beneficial in those with IBS (World J Gastroenterol. 2006.12. 853-857).
Activa yogurt, which contains B animalis DN-173 010, improved health-related quality of life scores and bloating (Aliment Pharmacol Ther. 2007. 26. 475-486).
HLC Intensive (Lactobacillus acidophilus CUL60, Lactobacillus acidophilus CUL21, Bifidobacterium lactis CUL34, Bifidobacterium bifidum CUL20, manufactured by Pharmax) associated with greater improvement on Symptom Severity Score of IBS in an 8 week RCT in 52 patients (Aliment Pharmacol Ther. 2008. 29. 97-103).
Lactobacillus acidophilus beneficial in a 4 week RCT in 40 IBS patients (Dig Dis Sci. 2008. 53. 2714-2718).
Lactobacillus GG at a dose of 10 billion cfu/day was ineffective at reducing mean symptom scores for pain, urgency or bloating in a crossover RCT in 24 patients, with 80% completing the study (Dig Liver Dis. 2000. 32. 294-301).
Lactobacillus GG and other organisms (L. rhamnosus LC705, Bifidobacterium breve Bb99 and Propionibacterium freudenreichii ssp. shermanii JS) was effective at reducing abdominal pain, distension, flatulence and borborygmi in a 6 month RCT in 103 patients. The total amount of bacteria was 8–9 x 109 CFU/day, with an equal amount of each strain (Aliment Pharmacol Ther. 2005. 22. 387-394).
Lactobacillus GG 3 billion cfu twice a day effective in an 8 week study in 140 children with functional abdominal pain or IBS. The frequency (p < 0.01) and severity (p < 0.01) of abdominal pain was less in the group administered (Pediatrics. 2010. 126. e1445-e1452).
Lactobacillus plantarum (DSM 9843) 20 billion cfu effective in a 4 week RCT in 60 patients. Flatulence was rapidly and significantly reduced in the test group compared with the placebo group, abdominal pain was reduced in both groups, and at the 12-month follow-up, patients in the test group maintained a better overall GI function than control patients. Those patients receiving the Lactobacillus plantarum had these bacteria on rectal biopsy (Am J Gastroenterol. 2000. 95. 1231-1238).
Lactobacillus plantarum LP O1 and Bifidobacterium breve BRO effective in a 4 week RCT in 24 males and 26 females using 5 billion cfu/day and Lactobacillus plantarum LP 01 and Lactobacillus acidophilus LA 02 effective in a in a separate arm, with significant improvements in pain scores and overall severity scores (J Clin Gastroenterol. 2004. 38. S104-S106).
Lactobacillus reuteri DSM 17938 at a dose of 100 million cfu daily (commercially available as Gerber Soothe Colic drops) effective in a 12 week trial of 55 children aged 5- 17 with functional abdominal pain or irritable bowel syndrome. The median number of days with pain was 26 in the treatment group versus 65 in the placebo group (p , 0.03). NOTE temperature of storage/shipping should note exceed 77 degrees F (J Pediatr Gastroenterol Nutr. 2017. 64. 925-929).
Life Start (Bifidobacterium infantis 35624 manufactured by Natren, www.natren.com) in a daily dose of 10 billion live bacterial cells in a malted milk drink significantly reduced symptom scores in an 8 week RCT in 77 patients. The probiotic also normalized an abnormal IL-10: IL-12 ratio initially suggestive of a pro-inflammatory state. The magnitude of the change in symptom scores was comparable to the benefit achieved with the prescription drugs Zelnorm and Lotronex. In contrast, Lactobacillus salivarius UCC4331 in the same dose was ineffective (Gastroenterology. 2005. 128. 541-551 and editorial pg 783). A subsequent 4 week RCT in 362 women found that administration of Life Start (Bifidobacterium infantis 35624) at a dose of 100 million cfu was associated with a significant improvement; doses of 1 million cfu and 10 billion cfu were ineffective (Am J Gastroenterol. 2006. 101. 1581-1590).
Multi-strain probiotic effective in a 5 month study in 86 patients. IBS score decreased 3 points in the placebo group and 14 points in the probiotic group (Aliment Pharmacol Ther. 2008. 27. 48-57).
Multi-strain (4 species/strains) probiotic, 10 billion cfu daily, beneficial in a 12 week RCT of 152 patients (Aliment Pharmacol Ther. 2014. 40. 51-62).
Saccharomyces boulardii lyophilized (Florastor) based on a one month RCT in 34 patients with diarrhea-predominant IBS, and an endpoint of stool consistency [p<0.05] (Med Chir Dig. 1983. 12. 77-79).
Ultra Flora Plus (Lactobacillus acidophilus NCFM 10 billion cfu, Bifidobacterium lactis Bl-07, whey globulin protein complex 2 grams per day, manufactured by Metagenics, www.metagenics.com) increased IBS-QOL scores from an average of 63.3 to an average of 84.5 (p<0.001) in a retrospective trial in 26 consecutive IBS patients, published only in abstract form (Am J Gastroenterol. 2002. 97. S163. #493).
VSL#3 powder 450 billion cfu twice a day in an 8 week RCT in 25 patients was associated with a borderline significant difference in bloating, but no difference in global symptom relief (Aliment Pharmacol Ther. 2003. 17. 895-904).
VSL#3 powder 450 billion cfu twice a day reduced colon transit time (p=0.05) and subjective score for flatulence (p=0.011) in an 8 week RCT in 48 IBS patients with bloating (Neurogastroenterol Motil. 2005. 17. 687-696; J Clin Gastroenterol. 2006. 40. 264-269).
VSL #3 powder 450 billion cfu once a day for ages 4-11, twice a day for ages 12-18 associated with statistically significant improvement in a global measure as well as 3 of 4 secondary endpoints in a 6 week crossover RCT in 59 children (J Pediatr Gastroenterol Nutr. 2010. 51. 24-30).
A systematic review identified 19 RCTs (n = 1650), 11 of which were high quality (Jadad scores of 4 or 5), and concluded that probiotics reduce symptoms of IBS in adults (Gut. 2010. 59. 325-332). A criticism of approaching this issue via a systematic review is that there is NOT evidence that benefit of probiotics is a “class effect” and thus pooling results of studies of different strains of probiotic is not justified (ACP Journal Club. 2010. 153. JC3-7).
Omni-Biotic® Stress Release reduced bowel irritability in IBS-D (Eur J Nutr. 2019. 58. 2767-2778).
Mastitis prevention in those who experienced mastitis with a prior pregnancy – in a RCT of 108 pregnant women, those who received Lactobacillus salivarus PS2, 109 cfu daily from about 30 weeks of gestation until delivery experienced a 25% incidence of mastitis during the first 3 months after delivery, compared with a 57% incidence in the placebo group (p=0.001) [Clin Infect Dis. 2016. 62. 568-573].
NASH and NAFLD – see ‘Fatty Liver’ just above
Necrotizing enterocolitis prevention
A meta-analysis of 7 RCTs (n=1393) of probiotics administered to premature infants (born at < 33 weeks of gestation and <1500 grams birthweight) found a 74% reduced incidence in the probiotic treated premies, and an associated 53% lower mortality (Lancet. 2007. 369. 1614-1620).
Cochrane review of 6 studies of variable quality concludes that administration of probiotics to premature infants probably prevents severe necrotizing enterocolitis and probably leads to fewer babies dying during their first year of life. The data failed to show an increase or decrease in bacteremia or fungemia (Cochrane Database Syst Rev. 2008. CD005496).
Positive RCT in 231 preterm infants with a combination of Lactobacillus casei and Bifidobacteria breve (Am J Clin Nutr. 2011. 93. 81-86).
Obesity - conflicting evidence. In one double-blind trial, 100 billion CFU daily of L gasseri significantly reduced BMI, total body fat mass, and abdominal visceral fat area (Eur J Clin Nutr. 2010. 64. 636-643).
Otitis media prevention - Lactobacillus salivarius PS7 100 million cfu daily for 6 months beneficial in a RCT of 61 children in Spain with recurrent otitis media reduced the number of episodes by 84%. This strain was chosen based on prior data showing antibacterial activity against organisms that cause otitis media (Nutrients. 2019. 11. E376).
Periodontitis
In a 4 week trial of individuals with periodontitis-related halitosis, those administered 2 billion cfu daily of Lactobacillus salivarus in a slow-dissolving tablet showed a significant reduction in both oral malodor and degree of bleeding upon probing of gum tissue (Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010. 110. 201-208).
Probiotic lozenges (BLIS M18) beneficial (Int J Pharm Bio Sci. 2015. 6. 242-250)
Probiotic lozenges (Prodentis) beneficial (J Periodontol. 2015. 86. 746-754)
In a RCT of pregnant women in the third trimester, a blend of two strains of L reuteri was beneficial (J Clin Periodontol. 2016. 43. 948-954). In 2017 this blend is not sold in the US, as per Dr Alan Gaby commentary (Townsend Letter. October 2017. Page 45).
In a 30 day clinical trial of 41 Brazilian patients with chronic periodontitis, Bifidobacterium animalis subsp lactis HN019 as a lozenge containing one hundred million cfu twice a day was beneficial as an adjunct to scaling and root planning (J Clin Periodontol. 2018. 45. 1198-1210).
Pneumonia (ventilator-associated) prevention - negative study. Lactobacillus rhamnosus GG 10 billion cfu (Culturelle) twice a day was ineffective is a multi-center RCT of 2563 patients in 44 ICUs (JAMA. 2021. 326. 1024-1033).
Pouchitis – VSL#3 (a patented probiotic manufactured by Sigma Tau www.VSL3.com) can prevent or reduce flare-ups
In a 9 month RCT in 40 patients with a history of pouchitis, amongst those who received VSL#3 3,000 billion cfu daily (6 grams), only 15% had a relapse of pouchitis, whereas 100% of placebo patients had a relapse of pouchitis (p<0.001) [Gastroenterology. 2000. 119. 584-587].
In a 12 month RCT in 40 patients who underwent ileal pouch-anal anastomosis for ulcerative colitis, those who received VSL#3 900 billion cfu/day had a 10% incidence of acute pouchitis whereas those who received placebo had a 40% incidence of pouchitis (p<0.05) [Gastroenterology. 2003. 124. 1202-1209].
In a 12 month RCT in 36 patients with recurrent pouchitis (at least twice in the past year), VSL#3 3,000 billion cfu daily (6 grams) was associated with a remission rate of 85% while placebo was associated with a remission rate of 6% (p<0.0001) [Gut. 2004. 53. 108-114].
Pregnancy
Lactobacillus rhamnosus HN001 6 billion cfu daily, started at 14-16 weeks of gestation and continued until delivery reduced the incidence of gestational diabetes from from 13.8% to 8.2% (p=0.03) in a RCT of 423 pregnant women with a history of atopy (Br J Nutr. 2017. 117. 804-813).
See also section just above on probiotics and “Atopic disease – prevention”
Preterm infants
In a study in 75 preterm infants <1.5 kg and mean gestational age <28 weeks, those who received Bifidobacterium breve (1) had significantly fewer infections, (2) were able to take enteral nutrition at a level of 100 ml/kg/day sooner, and (3) had shorter hospital stays (Acta Neonatologica Japonica. 2003. 39. 247).
MRSA prevention – lyophilized Bifidobacterium breve M-16V effective in a study in 266 preterm infants (Acta Neonatologica Japonica. 2002. 38. 294).
Necrotizing enterocolitis prevention – see separate section just above
Regurgitation (uncomplicated) in infants – in a 4 week RCT of 42 formula-fed infants, mean age 40 days, those randomized to receive Lactobacillus reuteri DSM 17938 at a dose of 100 million cfu/day had a reduced number of regurgitant episodes during the last 7 days of treatment (p<0.001) [Eur J Clin Invest. 2011. 41. 417-422].
Seborrheic dermatitis - in an 8-week RCT of 60 male volunteers, those supplemented with Lactobacillus paracasei NCC 2461 ST 11 (supplied by Nestle) at a dose of 1 billion cfu daily did significantly better than those treated with placebo (Benef Microbes. 2017. 8. 671-680).
Upper respiratory infection prevention - see just below ‘viral infections’
UTI prevention of recurrence
A RCT of 100 women of reproductive age with recurrent UTIs showed that those randomized to receive suppositories of L crispatus 10 billion cfu daily for 5 days and then once a week for 10 weeks experienced fewer recurrences (15% versus 27%) [Clin Infect Dis. 2011. 52. 1212-1217].
In a 12 month trial of 252 postmenopausal women who self-reported at least 3 symptomatic UTI’s within the past year, half were randomized to 480 mg trimethoprim/sulfamethoxazole daily and the other half were randomized to 1 billion cfu twice a day of L rhamnosus GR-1 and L reuteri RC-14 (Fem-Dophilus - Jarrow). During the trial, compared with the prior year, the number of UTI’s fell by 58.5% in the antibiotic group and 51.4% in the probiotic group. In the antibiotic group, but not in the probiotic group, resistance to antibiotics increased (Arch Intern Med. 2012. 172. 704-712).
Vaginal candidiasis (review paper – J Antimicrob Chemother. 2006. 58. 266-272)
NEGATIVE STUDY. A RCT in 278 women requiring systemic antibiotic therapy for non-gynecologic infections found no benefit from oral dosing of Lactobacillus rhamnosus with Bifidobacterium longum or vaginal dosing of Lactobacillus rhamnosus, Lactobacillus delbrueckii, Lactobacillus acidophilus, and Streptococcus thermophilus. The number of cfu in each dose was not specified in the study (BMJ. 2004. 329. 548-551).
However, a one year crossover trial in which women with a history of recurrent Candida vaginitis ate 8 ounces of yogurt for 6 months and no yogurt for the other six months showed a significant decrease in infections and Candida colonization while the women were eating yogurt. Of the 33 women enrolled in the study, only 13 completed it, with 12 eliminated for protocol violations and 8 refusing to enter the control phase of the crossover trial (Ann Intern Med. 1992. 116. 353-357).
L rhamnosus GR-1 and L reuteri RC-14 (Fem-Dophilus, manufactured by Jarrow, contains these species/strains) – benefit seen in a 4 week RCT of 55 women treated with a single dose of fluconazole 150 mg, with half also receiving 2 billion cfu daily of probiotic. After 4 weeks, 90% in probiotic group were symptom free, compared with 65% in antibiotic alone group (p=0.03) [Lett Appl Microbiol. 2009. 48. 269-274].
NOTE benefit of yogurt or supplements for vaginal candidiasis is hypothesized as related to a change in pH produced specifically by hydrogen-peroxide producing strains of probiotic.
Superdophilus, manufactured by Natren, has been independently verified to produce hydrogen peroxide.
B longum, which produces both lactic acid and hydrogen peroxide reduced Candida UTIs by 70% in immunocompromised women.
Vaginitis – bacterial vaginosis is most common cause, with a prevalence of 10-50% in fertile women (review paper – Clin Microbiol Infect. 2007. 13. 657-664). Probiotic as initial treatment unlikely to be effective, but much published data showing that probiotic after antibiotic therapy reduces the risk of recurrence
L acidophilus LA-14® and L rhamnosus HN0001, plus bovine lactoferrin (manufactured by HOWARU®) twice daily beneficial in a pilot RCT (De Alberti D et al. Arch Gyn Obstet. 2015), and beneficial as an add-on therapy following 7 days of metronidazole, based on a RCT of 48 women (Russo O et al. Benef Microbes. 2019).
L crispatus CTV-05 (Lactin-V) – benefit reported in a 24-week Phase 2b RCT of 228 women who received placebo versus vaginal Lactin-V 290 billion cfu daily for 11 weeks, Rate of recurrence at 12 weeks was 30% in the treatment group versus 45% in the placebo group (p=0.01). Eligibility criteria included completion of a course of vaginal metronidazole gel for a diagnosis of bacterial vaginosis (N Engl J Med. 2020. 382. 1906-1915).
L rhamnosus GR-1 and L reuteri RC-14 (Fem-Dophilus, manufactured by Jarrow Formulations)
Benefit seen in a 30 day RCT of 125 women who received either 1 billion cfu twice a day, in conjunction with Flagyl 500 mg twice a day for first 7 days. Cure rate of 88% in probiotic group and 40% in antibiotic alone group (p<0.001) [Microbes Infect. 2006. 8. 1450-1454].
Benefit seen in a second 4 week RCT of 64 women treated with a single dose of tinidazole, with half also receiving 2 billion cfu daily of probiotic. Cure rate of 87.5% in probiotic group and 50% in antibiotic alone group (p=0.001) [Can J Microbiol. 2009. 55. 133-138].
Benefit seen in a 6 week RCT of 540 women, with a dose of 2 billion cfu per day of probiotic. At the end of the trial, 61.5% of treatment women had normal vaginal flora, compared with 26.9% of placebo-treated women (p<0.001) [Eur J Obstet Gynecol Reprod Biol. 2013. 168. 75-79].
Lower recurrence rate at 30 and 60 days in a RCT of 120 Chinese women who received prophylaxis with a daily capsule containing 8 billion cfu of a combination of Lactobacillus rhamnosus, Lactobacillus acidophilus, and Streptococcus thermophilus (Probaclac Vaginal, manufactured by Nicar Laboratories) for 7 days on, 7 days off, and 7 days on (Wang Y et al. Am J Obstet Gynecol. 2010. 203. 120. e1-e6).
Long term vaginal administration of Lactobacillus rhamnosus shown in 2 studies (11 month duration and 24 month duration) to reduce risk of recurrence (Arch Gynecol Obstet. 2010. 281. 1065-1069; Parma M et al. Eur Rev Med Pharmacol Sci. In Press 2014).
A meta-analysis of 10 studies (n > 2000) concluded that probiotics alone or in combination with antibiotic are “safe and may exhibit a short-term and long-term beneficial effect” (Wang Z et al. Int J Environ Res Publ Health. 2019).
Viral infections (including URI) prevention
Supplementation with Lactobacillus in the form of a probiotic milk associated with reduced absenteeism in children attending day care, in a RCT (BMJ. 2001. 322. 1327).
Supplementation with probiotic and multivitamin associated with a 13.6% decrease in URIs, a 19% decrease in total URI symptoms, and a 54% decrease in days with fever in a 5 month RCT in 477 healthy adults (Int J Clin Pharmacol Ther. 2005. 43. 318-326).
A 12 week multicenter RCT in 201 healthy formula-fed infants in day care centers showed fewer days with fever, fewer sick visits to health care providers, fewer absences from day care, and fewer antibiotic prescriptions in the treatment group, which received Bifidobacterium lactis BB12 or Lactobacillus reuteri American Type Culture Collection 55730), 10 million cfu/gram of formula powder. Both treatment groups had fewer and shorter episodes of diarrhea, with no effect on respiratory illnesses. These effects were more prominent with L reuteri (Pediatrics. 2005. 115. 5-9).
An 80 day RCT in 262 adults in the workplace showed fewer sick days in those who received Lactobacillus reuteri 100 million cfu/day (Tubelius P. Environ Health. 2005. 4. 25).
A 3 arm RCT in Shanghai in 248 children ages 3-5 showed that the treatment group which was given L acidophilus NCFM at a dose of 1 billion colony-forming units daily as well as the treatment group given a combination of L acidophilus NCFM and Bifidobacterium lactis Bi-07 at a dose of 1 billion colony-forming units daily for 6 months from November to April had a significant reduction in the incidence and duration of respiratory tract infection symptoms. The combination was more effective than NCFM alone. This study is published in abstract form (Pediatrics. 2008. 121. S115).
A 90 day RCT in 638 children aged 3-6, attending day care or school, showed that the incidence of common infections (respiratory and GI) was 19% lower (p<0.05) in those treated with a fermented dairy drink containing Lactobacillus casei DN-114 001 (Eur J Clin Nutr. 2010. 64. 669-677).
A 3 month RCT in 280 children attending day care centers showed that the incidence of upper respiratory infections was 34% lower (p<0.05) in the group administered 1 billion cfu/day of Lactobacillus GG in 100 ml fermented milk (Clin Nutr. 2010. 29. 312-316).
A 3 month RCT in 135 French children who had suffered at least 3 episodes of ENT or GI illness during the previous winter showed that the proportion of children with at least one illness episode during the study was significantly lower (51.6% versus 68.5%, p=0.045) in the group who received the prebiotic/probiotic combination (Immunostim/Probiokid) [Ther Adv Respir Dis. 2010. 4. 271-278].
A 4 week RCT in 20 trained male distance runners showed a 58% reduction in the treatment group of the number of days per person that URI symptoms were present (p<0.001). Illness severity was also lower in the treatment group (p=0.06). The treatment group received 12.6 billion cfu Lactobacillus fermentum VRI-003 (Br J Sports Med. 2010. 44. 222-226).
A 16 week RCT in 84 highly active individuals showed that those assigned to receive a fermented drink containing 650 million live L casei twice a day had 43% fewer URI’s (1.2 vs 2.1, p<0.001) [Int J Sport Nutr Exerc Metab. 2011. 21. 55-64].
A 3 month RCT in 80 children in which the treatment group received 1 capsule twice a day of Bifidobacterium bifidum (Infloran) showed that 77% of the treatment group experienced at least one symptom of a URI, as compared with 95% of the placebo group (p<0.05). Furthermore, probiotic-treated children experienced significantly less fever, rhinorrhea, cough, and school absence (Pediatr Int. 2012. 2. 682-687).
A 6 month RCT of 57 preschoolers in Slovakia showed that a daily probiotic composite of 2 strains of Lactobacillus and 2 strains of Bifidobacterium, in combination with vitamin C 50 mg, was associated with reduced prevalence and severity of URIs (Garaiova et al. Eur J Clin Nutr. 2014).
In a 6 month RCT of 336 healthy Mexican children attending day-care centers, those randomized to Lactobacillus reuteri DSM 17938 108 cfu daily for 3 months had a significantly reduced frequency and duration of episodes of diarrhea and respiratory infections (p<0.05) at 3 months and 6 months (Pediatrics. 2014. 133. e904-e909).
A 2015 Cochrane review of 13 RCTs (n > 3720) concluded that “Probiotics were better than placebo in reducing the number of participants experiencing episodes of acute URI, the mean duration of an episode of acute URI, antibiotic use and cold-related school absence” (Cochrane Database Syst Rev. 2015. 2. CD006895).
Additional possible benefits based on anecdote, theoretical rationale, and/or open label trials include treatment of acne, autism, bloating, dyspepsia, fatigue, food cravings, GERD, herpes simplex I (decreased outbreaks), infertility, and prevention of intestinal yeast overgrowth by co-administering with antibiotics.
References (see also “Herbal Medicine” outline for books)
ConsumerLab.com’s Guide to Buying Vitamins and Supplements: What’s really in the bottle? 2003.
www.cc.nih.gov/ccc/supplements - NIH web site
www.navigator.tufts.edu - Tufts University. This site also contains quality ratings for other sites.
www.consumerlab.com - provides independent analysis of the quality of dietary supplements.
www.nnfa.org - web site includes a list of companies certified by NNFA GMP Program.
www.nsf.org/certified/dietary - allows one to search for products and companies certified by NSF.
www.uspverified.org – list of products verified by USP.
www.drugstore.com - this provides information on dietary supplements by disease.
http://nccam.nih.gov/health - fact sheets, alerts and advisories, treatment information.
http://ods.od.nih.gov/databases/ibids.html - NIH Office of Dietary Supplements (ODS) International Bibliographic Information on Dietary Supplements (IBIDS) [over 730,000 scientific citations and links to more than 1600 journal web sites, as of 2004]
http://www.usprobioticguide.com/ - resource suggested by Tieraona Low Dog, MD
https://dietarysupplementdatabase.usda.nih.gov/Conversions.php - unit conversion chart from IU to mcg to new DV unit required in 2020
Page Updated November 11. 2024