Oxydrene NAD+ Enhancer by Novex Biotech

LIKELY EFFECTIVE

• Coenzyme Q10 deficiency. Taking coenzyme Q10 orally improves symptomatic deficiency. Details: Rare cases of acquired coenzyme Q10 deficiency with symptoms of weakness, fatigue, and seizures have been reported (8160,8161). In adults, deficiency can be treated with coenzyme Q10 orally, 150-2400 mg daily in up to three divided doses. In children, 30 mg/kg, or 60-250 mg daily in up to three divided doses has been used (8160,8161,89417). Data from several multinational disease registries has also evaluated the use of coenzyme Q10 in patients with primary coenzyme Q10 deficiency, a rare genetic disorder. This data indicates that patients who take coenzyme Q10 supplements have a mean reduction of 88% in proteinuria at 12 months when compared with patients who do not take coenzyme Q10. In patients under 18 years of age with primary deficiency and chronic kidney disease at baseline, taking coenzyme Q10 supplements is associated with a 5-year survival without kidney failure of 62%, compared with 19% for those not taking coenzyme Q10 (108956).
• Mitochondrial myopathies. Taking coenzyme Q10 orally seems to reduce symptoms in some patients with genetic and acquired mitochondrial dysfunction. Details: A specific coenzyme Q10 formulation (UbiQGel, Tishcon Corporation) has been evaluated for mitochondrial myopathies, including MELAS (myoclonic epilepsy with lactic acidosis and stroke-like episodes) syndrome, Kearns-Sayre syndrome, and MERRF (myoclonus epilepsy with ragged red fibers). Typical doses are 150-160 mg, or 2 mg/kg, daily, gradually increasing to 3000 mg daily in some cases. The onset of action is slow, with maximal effects around 6 months (8159,8162,8163,8912,11050,44240,97905).

POSSIBLY EFFECTIVE

• Congestive heart failure (CHF). Oral coenzyme Q10 may provide benefit to patients with CHF by improving some, but not all, measures of disease severity when given in combination with conventional therapy. Details: Population research has found that CHF is associated with low coenzyme Q10 levels that correlate with severity of disease, and may be a predictor of mortality risk (44059,44220). A 2017 meta-analysis of clinical research shows that taking coenzyme Q10 30-300 mg, or 2 mg/kg, orally daily in two or three divided doses for up to 2 years, in addition to conventional therapy, improves exercise capacity, reduces hospitalizations, and reduces mortality by about 30% when compared with placebo. Other clinical research shows that adding oral coenzyme Q10 seems to improve quality of life and decrease symptoms of CHF such as dyspnea, peripheral edema, enlarged liver, and insomnia in patients with mild to severe (New York Heart Association (NYHA) class II-IV) CHF (6037,6038,6407,6408,6409,8909,12170,43967,43971,44042)(44277,44288,44289,44304,44334,44352,95610,96542). Additional clinical research shows that taking coenzyme Q10 30 mg daily for 1 year in addition to standard care reduces the incidence of atrial fibrillation by about 73% when compared with standard care alone in patients with NYHA class II-IV CHF (95609). However, not all evidence is positive. Some research suggests that coenzyme Q10 does not improve objective measures of CHF, including left ventricular ejection fraction (LVEF), cardiac output, or NYHA classification (5090,5248,6037,6038,43904,43932,96542,43932,97902). It is possible that the benefit of coenzyme Q10 depends on the dose and duration, the severity of CHF, and the specific conventional therapies taken concurrently (43973). A meta-analysis of 11 small, low-quality studies concludes that coenzyme Q10 probably reduces risk of all-cause and cardiovascular mortality, and of hospital admission for CHF, but data on improvement in LVEF or exercise capacity and the risk for myocardial infarction and stroke are inconclusive. However, the included studies used a range of coenzyme Q10 doses, varying concurrent therapy, short follow-up periods, and variable measures of treatment effect (108954). In patients with CHF with preserved ejection fraction (HFpEF) and a LVEF of 50% or greater, taking coenzyme Q10 600 mg daily for 12 weeks reduces B-type natriuretic peptide levels and improves Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, level of vigor, and LVEF when compared with placebo (108959).
• Diabetic neuropathy. When taken alone or as add-on treatment with pregabalin, most research suggests that oral coenzyme Q10 reduces symptoms in patients with diabetes and neuropathy. Details: Clinical research shows that taking coenzyme Q10 400 mg orally daily for 12 weeks significantly improves nerve conduction and symptoms of neuropathic pain when compared with placebo in diabetic patients with polyneuropathy (44217). The beneficial effects of coenzyme Q10 have also been investigated as an add-on treatment in patients taking pregabalin 150 mg daily. Clinical research shows that taking coenzyme Q10 100 mg three times daily for 8 weeks reduces pain severity and sleep interference due to pain when compared with placebo. The proportion of patients taking coenzyme Q10 with a decline in pain of at least 50% was 47%, compared with 27% of those taking placebo. Despite these findings, there was no difference in patient global improvement (109391). However, some research disagrees. One clinical trial shows that taking coenzyme Q10 (Health Burst) 200 mg daily for 12 weeks does not affect neuropathic symptoms, including pain, sensations, and strength, when compared with placebo (109386).
• Fibromyalgia. Oral coenzyme Q10 seems to improve both physical and psychological symptoms of this condition. Details: Clinical research in women with fibromyalgia shows that taking coenzyme Q10 300-400 mg orally daily for 40 days to 3 months improves pain by 24% to 56%, fatigue by 22% to 47%, sleep disturbances by 33%, morning tiredness by 56%, and tender points by 44% when compared with placebo. Patients also experience an improvement in psychological symptoms, including depression and anxiety (89416,97912,97913).
• Ischemia-reperfusion injury. Oral or intravenous coenzyme Q10 may help reduce hypoxic damage during cardiac bypass or vascular surgery. Details: Clinical research shows that taking coenzyme Q10, 150-300 mg orally daily in up to 3 divided doses for 1-2 weeks before cardiac bypass or vascular surgery, or 5 mg/kg IV two hours prior to surgery, reduces hypoxic damage during the surgery (11902,11903,44031,44294). However, coenzyme Q10 has no effect on cardiac function or troponin levels (11904,44292).
• Migraine headache. The American Academy of Neurology considers oral coenzyme Q10 to be possibly effective for migraine prevention in adults. Its benefit in children is unclear. Details: Two small open-label, non-randomized clinical trials in adults show that taking coenzyme Q10 100-150 mg daily decreases the frequency of headaches by up to 50% when compared with baseline or control, although it can take up to 3 months to see benefit (8135,95608). Higher quality research suggests a smaller benefit. A meta-analysis of small randomized controlled trials in adults shows that taking coenzyme Q10 alone or with other supplements reduces migraine attacks by 1.5 times per month and reduces duration of migraines by about 12 minutes when compared with control (105070). In children and adolescents, some clinical research shows that taking coenzyme Q10 orally, as 100 mg daily or 1-3 mg/kg daily, for 12-16 weeks does not improve headache frequency, severity, or duration when compared with placebo. However, it may reduce migraine frequency in children with low coenzyme Q10 levels (15256,44197). However, another clinical study shows that taking coenzyme Q10 daily is less effective than amitriptyline after one month, but as effective after 3 months, for improving headache frequency, severity, or duration, as well as quality of life. In this study, the dose of coenzyme Q10 was based on weight; 30 mg daily for children weighing less than 30 kg and 60 mg daily for children weighing at least 30 kg (109388).
• Multiple sclerosis (MS). Oral coenzyme Q10 seems to reduce fatigue and depression associated with MS. Details: Clinical research shows that taking coenzyme Q10 500 mg orally daily for 3 months reduces fatigue and depression in patients with MS when compared with placebo (96539).
• Muscular dystrophy. Oral coenzyme Q10 seems to improve physical performance in patients with muscular dystrophy of various forms. Details: Two small clinical studies show that taking coenzyme Q10 orally 100 mg daily for 3 months seems to improve physical performance when compared with placebo in some patients with various muscular dystrophies (2127).
• Myocardial infarction (MI). Oral coenzyme Q10 seems to reduce cardiac events and improve survival in patients who have had an MI. It is unclear if coenzyme Q10 improves survival in patients after cardiac arrest. Details: One small clinical study in patients with acute MI shows that starting coenzyme Q10 60 mg twice daily within 72 hours of the MI appears to significantly reduce the risk of cardiac events, including non-fatal MI and cardiac death, by 52% when administered for 28 days and by 45% when administered for up to one year (10152,44330). Also, a small clinical study in patients with recent MI who received cardiopulmonary resuscitation, shows that administering a 250 mg loading dose of coenzyme Q10 solution followed by 150 mg three times daily through a nasogastric tube for 5 days improves the 3-month survival rate by 134% when compared with placebo (43935). However, another clinical study in a similar patient population conducted to replicate these results shows that administering coenzyme Q10 300 mg in 50 mL of Ensure every 12 hours for 7 days does not improve in-hospital mortality or neurological outcomes when compared with placebo (105068).
• Peyronie disease. Coenzyme Q10 taken orally may reduce Peyronie disease severity. Details: Clinical research shows that, in patients with early chronic Peyronie disease, taking coenzyme Q10 (Kaneka Nutrients, Osaka) 300 mg orally daily for 24 weeks reduces new plaque formation and plaque size and improves erectile function when compared with placebo. Additionally, disease progression is slowed in about 76% of patients (44180).

POSSIBLY INEFFECTIVE

• Alzheimer disease. Coenzyme Q10 appears to be ineffective for improving cognition. Details: One clinical study shows that taking coenzyme Q10 1200 mg orally daily for 16 weeks does not improve cognition scores when compared with placebo in patients with Alzheimer disease (19206).
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Oral coenzyme Q10 does not attenuate functional decline in ALS patients. Details: Clinical research shows that taking coenzyme Q10 2700 mg orally daily for 9 months does not significantly attenuate a decline in ALS functioning scores when compared with placebo (44131). Higher doses, up to 3000 mg daily, have been tolerated by patients with ALS for 5 months, although the effect on ALS functioning at this dose is not known (43955).
• Chemotherapy-related fatigue. Oral coenzyme Q10 does not seem to help with fatigue due to chemotherapy. Details: Clinical research shows that taking coenzyme Q10 100 mg orally three times daily for 24 weeks does not reduce chemotherapy-related fatigue or improve quality of life when compared with placebo in breast cancer patients undergoing chemotherapy with or without radiation (89420).
• Diabetes. Most clinical research does not show any benefit with oral coenzyme Q10 in patients with type 1 or type 2 diabetes. However, some research suggests a possible benefit on insulin resistance. Details: Although a recent meta-analysis and some individual clinical research shows that coenzyme Q10 modestly reduces fasting glucose levels and glycated hemoglobin (HbA1c) in patients with type 1 or type 2 diabetes, most clinical research shows that coenzyme Q10 has no clinically meaningful effect on these parameters (456,492,2126,9890,96544,97911,97918,99636,11877,17704,44023,103778,109389). However, a recent meta-analysis in patients with type 1 or type 2 diabetes shows that improvements in insulin resistance may be clinically meaningful when compared with placebo (109389). In people with type 2 diabetes and nephropathy requiring hemodialysis, coenzyme Q10 120 mg orally daily for 12 weeks does not improve blood glucose levels, HbA1c, or lipid levels when compared with placebo, although it is associated with a decrease in serum insulin levels and insulin resistance (99636).
• Parkinson disease. Most clinical research does not show any benefit with the use of oral coenzyme Q10 in patients with Parkinson disease. Details: While some conflicting evidence exists (8938,15255), a large clinical trial and a meta-analysis of 8 small clinical studies in patients with Parkinson disease show that taking coenzyme Q10 300-2400 mg daily for up to 2 years does not improve Parkinson disease symptoms at any stage of the disease, or slow progression of the disease, when compared with placebo (89421,95610). In addition, a clinical study in patients with mid-stage Parkinson disease shows that taking a specific nanoparticulate coenzyme Q10 supplement (Nanoquinon, MSE Pharmazeutilka) 100 mg orally three times daily does not reduce symptoms when compared with placebo (15395).
• Post-polio syndrome. Muscle function in people with post-polio syndrome is not improved by oral coenzyme Q10. Details: Clinical research shows that taking coenzyme Q10 100 mg twice daily for 12 weeks does not improve muscle strength when compared with baseline, nor does it improve muscle function or muscle endurance when compared with placebo, in patients with post-polio syndrome (44054). Other clinical research shows that taking coenzyme Q10 100 mg daily for 60 days does not improve levels of fatigue when compared with placebo in patients with post-polio syndrome (97917).

LIKELY INEFFECTIVE

• Athletic performance. There is some evidence that exercise can deplete coenzyme Q10 and that supplementation will prevent this depletion. However, there is no evidence that taking coenzyme Q10 is beneficial. Details: Clinical research shows that taking coenzyme Q10 orally does not improve aerobic or anaerobic power or perceived exertion in athletes and non-athletes (2109,2110,8911,44122,44227). While some evidence suggests coenzyme Q10 slightly improves tolerance to higher workloads, more research is needed to tell if coenzyme Q10 is effective for this purpose (8911). One clinical study shows that taking coenzyme Q10 300 mg orally daily for 8 days reduces exercise-induced fatigue when compared with placebo (44006); other research shows that doses of 100-200 mg do not have this effect (44122,44233,44299). Taking the ubiquinol form of coenzyme Q10 200 mg orally daily for one month prevents exercise-induced coenzyme Q10 depletion and decreases levels of reactive oxygen species in blood mononuclear cells in young male athletes performing an intense long-distance run. However, it does not affect physical performance or markers of muscle damage (99429).
• Huntington disease. The ubiquinol form of coenzyme Q10 does not seem to improve function in people with this condition. Details: Ubiquinol, a reduced form of coenzyme Q10, has been evaluated for use in Huntington disease (11873). However, a large, high-quality study shows that taking coenzyme Q10 2.4 grams orally daily for up to 5 years does not slow the progression or functional decline in patients with Huntington disease (96538). Other studies using doses up to 600 mg daily also show no benefit (1357,8940).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). Oral coenzyme Q10 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in adults with early AMD shows that taking a specific combination product (Phototrop, Sigma-tau Health Science Ltd.) containing coenzyme Q10 10 mg, acetyl-L-carnitine 100 mg, and omega-3 fatty acids 530 mg orally daily for 12 months seems to reduce the percentage of patients who experience deterioration of vision by about 50%, and the percentage who have reduced light sensitivity by about 39%, when compared with placebo (43946). The effects of coenzyme Q10 alone are unclear.
• Aging. Although there has been interest in using oral coenzyme Q10 for aging, there is insufficient reliable information about the clinical effects of coenzyme Q10 for this purpose.
• Angina. There is some limited clinical evidence that coenzyme Q10 can improve exercise tolerance and symptoms in people with this condition. Details: Preliminary clinical research shows that taking coenzyme Q10 50 mg three times daily orally for 4 weeks improves exercise tolerance in people with angina by about 18% (2121). Also, taking 60 mg once daily for 4 weeks improves heart failure scores, angina symptoms, and heart volume when compared to baseline in patients with stable angina (44336). The validity of these findings is limited by the lack of a comparator group.
• Anthracycline cardiotoxicity. Evidence on the use of coenzyme Q10 to protect against anthracycline cardiotoxicity in adults and children is conflicting. Details: Preliminary clinical research in children aged 3-12 years shows that taking coenzyme Q10 orally 100 mg twice daily might protect against anthracycline cardiotoxicity (44279). However, evidence from larger clinical trials evaluating patients aged 16-77 years is conflicting. Results from one of these studies suggests that intravenous administration of coenzyme Q10 1 mg/kg daily the day before, the day of, and for 2 days after anthracycline treatment does not protect against cardiotoxicity (44267). Differences between the studies may be due to methodological problems, or differences in doses, route of administration, and age of participants.
• Asthma. Oral coenzyme Q10 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of coenzyme Q10 (Q-Gel, Tishcon Corporation) 120 mg, vitamin E 400 mg, and vitamin C 250 mg orally daily in addition to conventional anti-asthmatic therapy for 16 weeks might reduce the dosage of corticosteroids required by patients with mild to moderate asthma. However, it does not appear to improve lung function any more than standard therapy alone (43969).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral coenzyme Q10 is beneficial in children with ADHD. Details: A small clinical study in children aged 6-16 years with ADHD who are unresponsive to atomoxetine therapy shows that taking coenzyme Q10 1-3 mg/kg with atomoxetine 0.5-1.8 mg/kg daily for 6 months improves parent-rated symptoms of ADHD, particularly hyperactivity-related symptoms, when compared with placebo plus atomoxetine (107449).
• Autism spectrum disorder. It is unclear if the ubiquinol form of coenzyme Q10 taken orally is beneficial in children aged 3-6 years with this condition. Details: A small clinical study in children aged 3-6 years suggests that taking the reduced form of coenzyme Q10, ubiquinol (Li-QH, Tishcon Corporation), 50 mg orally once daily for one week followed by 50 mg twice daily for 11 weeks, improves symptoms of autism spectrum disorder, including communication with parents, ability to play with friends, verbal communication, sleeping, food rejection, aggressiveness, and self-harm, when compared with baseline, per parent assessment (89419). The validity of these findings is limited by the small study size, the use of parent assessment, and the lack of a comparator group.
• Bipolar disorder. It is unclear if oral coenzyme Q10 is beneficial for bipolar disorder in older adults. Details: Preliminary clinical research in people 55 years of age or older with bipolar disorder shows that taking coenzyme Q10 800 mg orally daily for 4 weeks improves symptoms of depression when compared with baseline (95606). The validity of this finding is limited by the lack of a comparator group.
• Breast cancer. Low coenzyme Q10 levels may be associated with an increased risk of breast cancer. The benefit of coenzyme Q10 supplementation is unclear. Details: Population research in Chinese women has found that low plasma coenzyme Q10 levels are associated with an increased risk of breast cancer (44194).
• Cancer. Low coenzyme Q10 levels may increase the risk of cancer development and progression. Details: Population research has found that low coenzyme Q10 levels are associated with increased risk of metastatic melanoma (43959). Preliminary clinical research suggests that taking coenzyme Q10 150 mg twice daily along with vitamins A, C, and E, selenomethionine, beta-carotene, and folic acid extends survival time by 40% when compared with predicted survival in patients with end-stage cancer from various different primary sites (44159). It is unclear if this effect is due to coenzyme Q10, other ingredients, or the combination.
• Cardiovascular disease (CVD). It is unclear whether oral coenzyme Q10 has a role in preventing complications from CVD. Details: Preliminary clinical research shows that taking coenzyme Q10 300 mg 2 hours prior to an elective percutaneous coronary intervention does not reduce periprocedural myocardial injury or prevent major adverse cardiac events during one month of follow-up (96543). Other clinical research shows that taking a combination of coenzyme Q10 (Bio-Quinon, Pharma Nord) 100 mg twice daily plus organic selenium yeast tablets (SelenoPrecise, Pharma Nord) 200 mcg daily for 4-5 years reduces the risk of death from CVD by 7% when compared with placebo in elderly people living in Sweden (92904). This benefit appears to persist even after supplement discontinuation, with an 18% reduction at 10 years and an 11% reduction at 12 years (96546,97466,97906). In this same trial, post-hoc subgroup analyses in patients with elevated baseline D-dimer levels and/or hypertension or ischemic heart disease shows that taking this combination reduces cardiovascular mortality when compared with placebo (105874). It is unclear if these benefits are due to coenzyme Q10, selenium, or the combination.
• Cataracts. It is unclear if coenzyme Q10-containing eye drops are beneficial in patients undergoing cataract surgery. Details: Clinical research suggests that administering an ophthalmic solution containing coenzyme Q10 and vitamin E D-alpha-tocopheryl polyethylene glycol 1000 succinate twice daily for 9 months increases the speed of nerve regeneration when compared with saline solution in post-cataract surgery patients (44228).
• Cerebellar ataxia. It is unclear if coenzyme Q10 is beneficial for this condition. Details: Preliminary clinical research in patients with cerebellar ataxia shows that coenzyme Q10 30 mg/kg daily for 2 years improves ataxia scores by 48%, posture scores by 63%, and kinetic function scores by 37% when compared with baseline, but only in patients who are coenzyme Q10 deficient (44177). The validity of these findings is limited by the lack of a comparator group.
• Chronic fatigue syndrome (CFS). Oral coenzyme Q10 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with CFS shows that taking coenzyme Q10 200 mg plus NADH 20 mg daily for 8 weeks does not improve measures of fatigue, sleep, or quality of life when compared with placebo (107448).
• Chronic obstructive pulmonary disease (COPD). It is unclear if coenzyme Q10 is beneficial for improving exercise tolerance in people with COPD. Details: Preliminary clinical research suggests that taking coenzyme Q10 90 mg daily for 8 weeks reduces lactate production during anaerobic exercise in people with COPD, but does not improve oxygen consumption or exercise performance, when compared with baseline (44293). The validity of these findings is limited by the lack of a comparator group.
• Cocaine dependence. Oral coenzyme Q10 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study in patients with cocaine dependence shows that taking a combination of coenzyme Q10 200 mg and L-carnitine 500 mg orally daily for 8 weeks does not reduce cocaine use when compared with placebo, as measured by urine benzoylecgonine levels and self-reported usage (43940).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral coenzyme Q10 is beneficial for patients with persistent symptoms after COVID-19 infection. Details: Clinical research in individuals with previous confirmed COVID-19 infection and continued symptoms lasting more than 12 weeks shows that taking coenzyme Q10 (Pharma Nord) 100 mg five times daily for 6 weeks does not reduce the number or severity of symptoms when compared with placebo. The most common symptoms were concentration problems, mental and physical fatigue, headache, and/or muscle weakness (109392).
• Critical illness (trauma). It is unclear if oral coenzyme Q10 is beneficial in patients hospitalized due to acute trauma. Details: Preliminary clinical research in patients who are mechanically ventilated due to acute trauma and have low baseline coenzyme Q10 plasma levels shows that taking sublingual coenzyme Q10 (Nutri Q10, Nutri Century) 400 mg daily for 7 days reduces the duration of intensive care stay, mechanical ventilation, and hospitalization by 4 days, 2 days, and 6 days, respectively, when compared with placebo. Patients taking coenzyme Q10 also demonstrated larger improvements in organ function scores and coma scores than those taking placebo (105875).
• Cyclic vomiting syndrome (CVS). Limited evidence suggests oral coenzyme Q10 may reduce episodes of CVS. Details: Preliminary clinical research shows that taking coenzyme Q10 10 mg/kg orally twice daily is comparable to amitriptyline 0.5-1 mg/kg/day for reducing the number of CVS episodes in both children and adults (17703).
• Diabetic nephropathy. Although there has been interest in using oral coenzyme Q10 for diabetic nephropathy, there is insufficient reliable information about the clinical effects of coenzyme Q10 for this purpose.
• Dilated cardiomyopathy. Very small clinical studies suggest that children and adolescents with dilated cardiomyopathy may benefit from oral coenzyme Q10. Details: Preliminary clinical research in children with dilated cardiomyopathy suggests that taking coenzyme Q10 3-10 mg/kg daily, divided into 2-3 doses for up to 9 months, improves ejection fraction and New York Heart Association (NYHA) classification when compared to baseline (12199,13223). Also, in people under 20 years of age, taking a specific oral liquid formulation of coenzyme Q10 (QuinoMit Q10 Fluid, MSE Pharmazeutika GmbH), 10 mg/kg daily for 24 weeks produces a small increase in ejection fraction and improves NYHA class from II to I in 30% of patients (99427). The validity of these findings is limited by the lack of comparator groups.
• Dry eye. Ophthalmic coenzyme Q10 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research has evaluated the use of a specific eye drop (VisuXL, Visufarma) containing coenzyme Q10 and cross-linked hyaluronic acid, in a 1:1 ratio with alpha-tocopherol polyethylene glycol succinate. One study in menopausal women receiving antidepressants shows that placing 1 drop in each eye twice daily for 8 weeks reduces dry eye severity by 17% and improves tear break-up time when compared to 5 drops daily of carmellose eye drops (104553). In addition, another study in adults with mild to moderate dry eye shows that placing 1 drop in each eye four times daily for 12 weeks reduces dry eye severity by 14% and decreases some laboratory markers of dry eye when compared to hyaluronic acid alone. Both groups demonstrated similar improvement in meibomian gland function and tear break-up time (97909). The effect of coenzyme Q10 when used alone is unclear.
• Dry mouth. It is unclear if oral ubiquinol or ubiquinone improves salivary secretion. Details: Preliminary clinical research suggests that taking coenzyme Q10, as the reduced ubiquinol form or as the oxidized ubiquinone form, 100 mg orally daily for one month, improves salivary secretion by 72% to 82% when compared with baseline in patients with dry mouth (44191). The validity of these findings is limited by the lack of a comparator group.
• Erectile dysfunction (ED). It is unclear if oral coenzyme Q10 is beneficial in patients with ED. Details: A small, open-label study in patients with hypertension and complaints of ED shows that taking coenzyme Q10 200 mg daily for 3 months along with current antihypertensive therapy does not improve symptoms of ED when compared with antihypertensive therapy alone (107447).
• Fatigue. It is unclear if oral coenzyme Q10 is beneficial for reducing fatigue. Details: A meta-analysis of low- to moderate-quality clinical research in mixed populations shows that taking coenzyme Q10 modestly reduces feelings of fatigue when compared with placebo. This improvement was consistent between groups of healthy individuals and individuals with fatigue related to disease. However, a sub-group analysis shows that benefits are limited to studies in which coenzyme Q10 was studied as a single ingredient. Doses of coenzyme Q10 ranged from 60 mg to 500 mg daily for 4-12 weeks with treatment effects appearing to be both dose- and duration-dependent (109387).
• Friedreich ataxia. Oral coenzyme Q10 has been evaluated in combination with vitamin E; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking coenzyme Q10 (Bio-Quinon Q10, Pharma Nord) 200 mg orally twice daily plus vitamin E (Bio-E-Vitamin, Pharma Nord) 1050 IU twice daily for 47 months improves measures of cardiovascular function by 20% when compared with baseline. However, it does not improve posture or gait, or prevent deterioration of posture, gait, speech, or eye function, when compared with baseline (43943,44064). It is unclear if these benefits are due to coenzyme Q10, vitamin E, or the combination. Also, the validity of these findings is limited by the lack of a comparator group.
• Hearing loss. There is conflicting evidence regarding the effects of oral coenzyme Q10 on hearing loss of various etiologies. Details: Some clinical research shows that taking coenzyme Q10 terclatrate (Qter), a water-soluble formulation of coenzyme Q10, 160 mg orally daily for 30 days improves hearing thresholds when compared to baseline in patients with age-related hearing loss (44171,44184). However, taking coenzyme Q10 terclatrate 200 mg daily for 7 days does not significantly improve hearing thresholds when compared with placebo in patients with noise-induced hearing loss (44143). Also, combining coenzyme Q10 with conventional steroid therapy for 2 weeks does not improve hearing when compared with steroid therapy alone in patients with sudden sensorineural hearing loss (44185).
• Hepatitis C. It is unclear if oral coenzyme Q10 is beneficial in patients with this condition. Details: Clinical research shows that taking coenzyme Q10 up to 80 mg orally daily for 28 days does not reduce serum liver enzymes when compared with placebo in patients with chronic hepatitis C who are unresponsive to conventional treatment (44172).
• Hyperlipidemia. There is conflicting evidence regarding the effects of coenzyme Q10 on cholesterol levels in adults. However, any changes are unlikely to be clinically meaningful. Details: A meta-analysis of 50 moderate-quality clinical trials shows that taking coenzyme Q10 has small beneficial effects on levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides when compared with a control, usually placebo (109394). However, whether coenzyme Q10 produces clinically meaningful changes is unclear. In a subgroup of patients with dyslipidemia, coenzyme Q10 does not seem to have significant beneficial effects on total cholesterol (109394). Also, previous individual clinical trials and meta-analyses in specific populations, including studies in which lipoprotein A was measured, as well as populations with diabetes, coronary artery disease, and others, have not shown beneficial effects on plasma lipids (17704,44187,96545,97918,109394). The effect of coenzyme Q10 on lipoprotein A has also been investigated. Individual studies and a meta-analysis show that taking coenzyme Q10 slightly reduces plasma levels of lipoprotein A when compared with placebo (17704,44187,96545). Most studies have used doses of 100-500 mg daily for 4-24 weeks (17704,44187,96545,96547,97910,109394). Coenzyme Q10 has also been studied in combination with other ingredients. A moderate-sized, open-label clinical study in adults with mild hypercholesterolemia and low cardiovascular disease risk shows that taking a combination product containing coenzyme Q10 2 mg, red yeast rice, grape seed extract, olive tree leaf extract, and B vitamins (Arichol, Epsilon Health) daily for 8 weeks reduces total cholesterol and LDL cholesterol, but not HDL cholesterol or triglycerides, when compared with placebo (111559). The validity of this effect is limited by a lack of blinding. It is unclear if this effect is due to coenzyme Q10, other ingredients, or the combination.
• Hypertension. Most research suggests that oral coenzyme Q10 may reduce systolic blood pressure (SBP), but not diastolic blood pressure (DBP). Details: Most clinical research shows that taking coenzyme Q10 100-900 mg orally daily in divided doses, either alone or with conventional medications, for up to 12 weeks significantly lowers SBP (2122,3365,9890,17702,17650,17651,44343,109393). One meta-analysis of moderate quality clinical research in patients with cardiometabolic disorders shows that supplementation with coenzyme Q10, especially 100-200 mg daily for at least 12 weeks, reduces SBP by 5 mmHg (109393). However, some studies show conflicting results. Most clinical research shows that coenzyme Q10 supplementation does not reduce DBP (8907,96541,109393). Also, a meta-analysis of two clinical studies (17651,44211) shows that taking coenzyme Q10 100-200 mg orally daily has no significant effect on blood pressure when compared with placebo (95607). Conflicting results may be due to differences in the severity of hypertension at baseline, adjustments made to conventional medications during studies, and the presence of a variety of concomitant conditions. Some data also suggest that effects may be greater in people with low baseline levels of coenzyme Q10 (2122,17650,17651).
• Hypertrophic cardiomyopathy. It is unclear if oral coenzyme Q10 is beneficial for this condition. Details: A very small clinical study of 7 patients suggests that taking coenzyme Q10 (Vitaline) 120-240 mg orally daily with the goal of raising blood levels above 2 mcg/mL, might improve symptoms of hypertrophic cardiomyopathy, including dyspnea and fatigue, and decrease cardiac wall thickness, when compared to baseline (11031). The validity of these findings is limited by the small size of the study and the lack of a comparator group.
• Infertility. It is unclear if oral coenzyme Q10 helps women undergoing assisted reproductive technology (ART) treatment. Details: A meta-analysis of 5 small clinical studies in infertile women undergoing ART treatment shows that although coenzyme Q10 increases the odds of clinical pregnancy more than 2-fold, it does not seem to affect the rate of live births or miscarriages when compared with placebo or no treatment (103780).
• Kidney failure. Oral coenzyme Q10 has been reported to improve renal function in people with kidney failure, but not in those with less severe kidney disease. Details: Preliminary clinical research in patients with kidney failure shows that taking coenzyme Q10 180 mg orally daily for 28 days improves blood urea nitrogen, serum creatinine, and creatinine clearance when compared with placebo (44347). However, other clinical research in patients with less severe kidney disease shows that taking coenzyme Q10 200 mg daily for 8 weeks does not significantly improve kidney function parameters, including urinary albumin, total protein, or glomerular filtration rate, when compared with placebo (44128).
• Lichen planus. It is unclear if topical coenzyme Q10 is beneficial for oral lichen planus. Oral coenzyme Q10 has not been studied for this condition. Details: A small clinical study in patients with oral lichen planus conducted in Egypt shows that applying topical coenzyme Q10 (ubiquinol) 120 mg as a mucoadhesive tablet 3 times daily for 4 weeks does not improve pain scores or lesion size when compared with topical corticosteroid paste (111617).
• Male Infertility. Oral coenzyme Q10 may improve some measures of sperm function in males with infertility, but there is no convincing evidence that it can increase pregnancy rates. Details: One small clinical study in males with idiopathic asthenozoospermia shows that coenzyme Q10 200 mg orally daily for 6 months improves sperm motility when compared with baseline (12169). The validity of this finding is limited by the lack of a comparator group. Coenzyme Q10 has also been studied in males with idiopathic oligoasthenoteratozoospermia, but results are conflicting. Studies have used coenzyme Q10 or its reduced form, ubiquinol, in doses of 200-300 mg orally daily for 26 weeks. Sperm density and motility are increased when compared with placebo, but pregnancy rates do not seem to improve (17413,89422). Three studies have used coenzyme Q10 200-400 mg orally daily for 12-26 weeks, with two reporting increased sperm concentration and motility when compared to baseline, but the other finding no improvements when compared with placebo (44190,102008,107444). Coenzyme Q10 has also been investigated in combination with other ingredients. In one preliminary clinical trial, taking coenzyme Q10 10 mg and vitamin E 100 mg three times daily for 3 months modestly increases levels of testosterone and improves progressive sperm motility and morphology when compared with baseline. However, taking an L-carnitine nutrient complex 15 grams twice daily was more effective for increasing testosterone and for improving sperm parameters (109390). Other small and preliminary clinical studies have investigated the effects of a specific combination product providing coenzyme Q10 20 mg twice daily for 6 months, along with acetyl-L-carnitine, L-carnitine, selenium, zinc, vitamin C, folic acid, vitamin B12, and citric acid (Proxeed Plus). Taking this combination product has been shown to improve measures of sperm quality such as sperm count, sperm concentration, total motility, and progressive motility when compared to baseline. The effect on sperm volume and morphology is unclear. Most research has been conducted in patients with oligoasthenozoospermia, although some benefit has also been shown in patients with varicocele-related infertility, especially those with more severe varicocele (102017,107395,111296). The validity of these findings is limited by the lack of comparator group. Also, it is unclear if these effects are due to coenzyme Q10, other ingredients, or the combination.
• Maternally inherited diabetes mellitus and deafness (MIDD). It is unclear if oral coenzyme Q10 is beneficial for MIDD. Details: One small clinical study shows that taking coenzyme Q10 150 mg orally daily for 3 years might prevent progressive insulin secretory defect, exercise intolerance, and hearing loss when compared with baseline in people with this rare form of diabetes (2125).
• Metabolic syndrome. It is unclear if oral coenzyme Q10 is beneficial in patients with metabolic syndrome. Details: A small clinical study in patients with metabolic syndrome receiving healthy dietary recommendations shows that taking coenzyme Q10 60 mg daily for 12 weeks does not have beneficial effects on blood glucose, cholesterol, waist circumference, or blood pressure when compared with placebo (109284).
• Myocarditis. It is unclear if oral coenzyme Q10 is beneficial in patients with acute viral myocarditis. Details: A small observational study in Chinese patients with acute viral myocarditis has found that taking coenzyme Q10 10 mg and trimetazidine 20 mg three times daily for 2 weeks, along with standard care, is associated with higher rates of resolution and improved quality of life when compared with coenzyme Q10 plus standard care alone (107443). While coenzyme Q10 alone appeared to improve symptoms and markers of cardiac function when compared to baseline in some patients, the validity of these findings is limited by a lack of placebo control.
• Nonalcoholic fatty liver disease (NAFLD). Coenzyme Q10 may reduce liver enzymes and the severity of NAFLD. Details: Preliminary clinical research in adults with NAFLD shows that taking coenzyme Q10 100 mg orally daily for 12 weeks reduces the clinical grade of NAFLD and decreases plasma levels of liver enzymes when compared with placebo (97907).
• Obesity. Oral coenzyme Q10 does not seem to improve weight loss in adults. Details: A meta-analysis of small, highly heterogeneous clinical trials shows that taking coenzyme Q10 100-300 mg daily for up to 24 weeks does not reduce weight or body mass index when compared with placebo. However, the included studies were not designed to assess for weight loss and involved patients with type 2 diabetes, metabolic syndrome, kidney disease, liver disease, rheumatoid arthritis, and other conditions (105067).
• Periodontitis. Data on the effects of oral or topical coenzyme Q10 are conflicting. It is unclear if coenzyme Q10 is beneficial for periodontitis. Details: Some very small, low-quality studies suggest that taking coenzyme Q10 orally, 50 mg daily for 3 weeks, might be beneficial for periodontitis (8917,8918). Preliminary research with topical coenzyme Q10 suggests it is ineffective (2107,2108). However, a meta-analysis of 11 clinical trials evaluating coenzyme Q10 topical gel shows reductions in plaque index, bleeding index, pocket index, clinical attachment level, and gingival index when compared with placebo gel or scaling and root planing alone. The greatest effects are seen when coenzyme Q10 gel is applied directly into the periodontal pocket daily for at least six weeks in combination with scaling and root planing (108958). The validity of these findings is limited by a high risk of bias and the overall low quality of the included studies. Coenzyme Q10 has also been studied in combination with other ingredients for periodontitis. A small clinical study in patients with moderate or advanced periodontitis shows that taking a supplement containing 30 mg of coenzyme Q10 in addition to alpha-lipoic acid, cranberry extract, grapeseed extract, selenium, vitamin C, vitamin E, and zinc twice daily for 8 weeks in addition to standard nonsurgical therapy does not improve periodontal indices including bleeding on probing, gingival recession, plaque index, or inflammation, among others, when compared with placebo (111708).
• Physical performance. It is unclear if oral coenzyme Q10 improves physical performance in older adults with chronic kidney disease (CKD). Details: A small clinical study in mostly older adults with CKD shows that taking coenzyme Q10 1200 mg daily for 6 weeks does not improve measures of physical exercise endurance including aerobic capacity, total work, and work efficiency when compared with placebo (111558). The validity of these effects is limited by the small sample size and short study duration.
• Polycystic ovary syndrome (PCOS). Most clinical studies suggest that oral coenzyme Q10 modestly improves symptoms in patients with PCOS. Details: A meta-analysis of clinical trials in patients with PCOS shows that taking coenzyme Q10 modestly improves measures of glycemic response, as well as plasma lipids and some sex hormones, when compared with placebo (109384). However, any changes are small and the clinical relevance is unclear. Also, although nine studies were included in the review, the number of studies included for each endpoint was much lower. Most clinical studies included in the analysis used 100-200 mg daily for 8-12 weeks (107446,109384). An additional small clinical study also shows that taking coenzyme Q10 (Nature Made) 100 mg orally daily for 12 weeks reduces fasting plasma glucose, insulin, and total cholesterol and improves insulin sensitivity when compared with placebo. This study also found that taking coenzyme Q10 reduces alopecia by about 33% and acne by 48% when compared with placebo (97914). Another small clinical study shows that taking coenzyme Q10 100 mg daily for 12 weeks reduces depression, anxiety, and hirsutism when compared with placebo (107446).
• Prader-Willi syndrome (PWS). It is unclear if oral coenzyme Q10 is beneficial in patients with PWS. Details: Preliminary clinical research in children with Prader-Willi syndrome shows that taking coenzyme Q10 2.5 mg/kg orally daily for one year improves psychomotor development similarly to growth hormone therapy, although this might reflect natural changes in the condition occurring over time (44005).
• Pre-eclampsia. Taking coenzyme Q10 orally seems to reduce the rate of pre-eclampsia in women at risk for the condition. Details: Clinical research shows that taking coenzyme Q10 (Q-absorb, Jarrow Formulas) 100 mg orally twice daily during pregnancy, starting at 20 weeks gestation and continuing until term, reduces the rate of pre-eclampsia by about 44% when compared with placebo in women at risk for developing this condition (17201).
• Schizophrenia. It is unclear if oral coenzyme Q10 improves symptoms in patients with schizophrenia or schizoaffective disorder. Details: A small clinical study in patients with schizophrenia or schizoaffective disorder shows that taking coenzyme Q10 300 mg daily for 6 months does not improve attention, working memory, negative symptoms, mood disorders, or quality of life when compared with placebo (105069). This finding is limited by insufficient power and poor protocol adherence, with only 61% of the participants taking at least 90% of the study treatment.
• Sepsis. There is no strong evidence that coenzyme Q10 is helpful in the management of sepsis or septic shock. Details: Patients with septic shock have been shown to have low levels of coenzyme Q10, but the effects of supplementation are unclear. Some preliminary clinical research shows that taking coenzyme Q10 100 mg orally twice daily for 7 days reduces the risk of in-hospital mortality by 69% and improves markers of inflammation, but does not reduce length of ICU stay, when compared with conventional treatment alone (102548). However, other preliminary research shows that taking coenzyme Q10 as ubiquinol 200 mg twice daily for 7 days has no effect on inflammatory or vascular endothelial biomarkers, mortality, or length of stay when compared with placebo (96540). Both studies were small and likely underpowered to detect a meaningful change in clinical outcomes.
• Statin-induced myalgia. There is conflicting evidence regarding the effects of oral coenzyme Q10 on statin-associated muscular adverse effects, such as myalgia. Details: Some clinical research shows that taking coenzyme Q10 (Q-Sorb softgel, Nature's Bounty) 100 mg orally daily for 30 days reduces pain intensity when compared with baseline or vitamin E control in patients with statin-induced myalgia (16008,44345). Other clinical research shows that taking coenzyme Q10 (MGC Company) 50 mg orally twice daily for 30 days reduces muscle pain and pain interference with daily activities by 30% to 40% when compared with placebo (95604). One small study in adults with statin-induced myalgia shows that taking liquid coenzyme Q10 (Q-Factor, Giellepi S.p.A) 100 mg orally daily for 3 months modestly reduces pain scores, but not plasma creatine kinase (CK) levels, when compared with placebo (102007). Other clinical research shows that taking coenzyme Q10 (Bio-Quinon, Pharma Nord) 100 mg twice daily, with or without selenium, for 3 months, reduces muscle pain and weakness, cramps, and tiredness when compared with placebo (92909). However, not all studies have shown benefit. Meta-analyses of several small randomized controlled trials show that taking coenzyme Q10 100-600 mg daily for 1-3 months does not improve muscle pain, statin tolerability, or plasma CK activity in patients with statin-induced myalgia when compared with placebo (95602,103781,106050). However, the validity of these results is limited by small population size and high heterogeneity. Other clinical research shows that taking coenzyme Q10 60 mg twice daily for 3 months does not improve muscle pain when compared with placebo (44218). Also, taking coenzyme Q10 (Q-Gel, Tishcon Corporation) 200 mg daily for 12 weeks does not affect myalgia scores when compared with placebo in patients taking simvastatin (44346). Additionally, taking high doses of coenzyme Q10 600 mg daily for 8 weeks does not affect the incidence, severity, or time to onset of statin-induced myalgia when compared with placebo in patients taking simvastatin (95603). Reasons for these conflicting findings are not entirely clear. The inconsistent results do not appear to be related to the dose of coenzyme Q10 or plasma CK levels. About 50% of patients who experience statin-induced myalgia will tolerate a statin re-challenge with a lower or equivalent dose of the same or alternative statin after a statin-free interval, which is a higher response rate than seen in currently available studies with the use of coenzyme Q10. Taking coenzyme Q10 for 30 days may be a reasonable option if other attempts to improve tolerance have failed. If a significant improvement in pain related to statin use is not seen after 30 days of taking coenzyme Q10, it is unlikely to be beneficial (96548).
• Statin-induced myopathy. There is conflicting evidence regarding the effects of coenzyme Q10 on statin-associated muscular adverse effects, including myopathy. Details: Clinical research shows that taking coenzyme Q10 (Bio-Quinon, Pharma Nord) 100 mg orally twice daily, with or without selenium, for 3 months, reduces muscle weakness and pain, cramps, and tiredness when compared with placebo in patients with statin-induced myopathy due to atorvastatin, fluvastatin, rosuvastatin, or simvastatin (92909). Preliminary clinical research also shows that taking coenzyme Q10 60 mg orally four times daily decreases the rate of dose-limiting statin-induced myopathy in patients taking high-dose lovastatin as an investigational treatment for cancer (11899,11900). However, when coenzyme Q10 (Myoquinon, Pharma Nord,) 400 mg orally daily is used in combination with selenium for 12 weeks, it does not affect atorvastatin-induced myopathy when compared with placebo (92908).
• Toxin-induced liver damage. Oral coenzyme Q10 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients being treated with anti-tuberculosis drugs shows that taking coenzyme Q10 200 mg, acetyl-L-carnitine 250 mg, and alpha-lipoic acid 250 mg twice daily for 2 weeks reduces the risk of drug-induced liver injury by 73% when compared with placebo (107445). It is unclear if these findings are due to coenzyme Q10, other ingredients, or the combination.
• Ulcerative colitis. It is unclear if oral coenzyme Q10 is beneficial in patients with ulcerative colitis. Details: Preliminary clinical research in adults with ulcerative colitis shows that taking oral coenzyme Q10 (Nutri Q10, Nutri Century Company) 100 mg twice daily for 8 weeks modestly improves ulcerative colitis disease activity and quality of life scores when compared with placebo. Taking coenzyme Q10 also reduces systolic and diastolic blood pressure by 4 mmHg and 2 mmHg, respectively, when compared with placebo (106049). The clinical relevance of these changes is unclear.
• Wrinkled skin. It is unclear if topical application of coenzyme Q10 cream can reduce wrinkles. Details: A small clinical study shows that applying a coenzyme Q10 1% cream to the skin twice daily for 5 months reduces objective wrinkle scores when compared to baseline (44082). The validity of this finding is limited by the lack of a comparator group. More evidence is needed to rate coenzyme Q10 for these uses.

(Read more about COENZYME Q10)

LIKELY EFFECTIVE

• Copper deficiency. Oral or intravenous copper is beneficial for treatment of copper deficiency. Details: Taking copper orally or intravenously is effective for treating copper deficiency and anemia due to copper deficiency. Copper deficiency is rare. It is seen most commonly in people receiving prolonged parenteral nutrition (7135). Oral cupric sulfate has been used in doses up to 0.1 mg/kg daily (7135). Copper 1-2 mg per day in parenteral nutrition solution has also been used (505).

POSSIBLY INEFFECTIVE

• Alzheimer disease. Oral copper does not seem to be beneficial for Alzheimer disease. Details: Preliminary clinical research shows that taking copper orotate dihydrate, providing 8 mg of elemental copper, daily for 12 months does not improve scores on evaluation scales for Alzheimer disease when compared with placebo (45949). There is also some concern that copper could have detrimental effects. Observational research has found that people with Alzheimer disease have higher levels of copper in their blood than people without the disease (95917); the clinical significance of this finding is unclear.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral copper has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific combination product containing copper (NicAzel, Elorac Inc.) 1-4 tablets daily for 8 weeks reduces inflammatory lesions in patients with inflammatory acne when compared with baseline. Other ingredients in this product include nicotinamide, azelaic acid, zinc, pyridoxine, and folic acid; specific quantities are not known (90800). The validity of this finding is limited by the lack of a comparator group.
• Brain tumor. It is unclear if oral copper is beneficial for use in glioblastoma. Details: A moderate-sized open-label clinical study in adults with first recurrence of glioblastoma receiving alkylating chemotherapy shows that taking elemental copper 2.5 mg with disulfiram 400 mg daily for 6 months does not improve survival but does result in significantly more adverse effects (e.g., elevated liver enzymes) when compared with control. The trial was stopped early due to safety concerns (112376).
• Cardiovascular disease (CVD). Although there is interest in using oral copper for CVD prevention, there is insufficient reliable information about the clinical effects of copper for this purpose.
• Chemotherapy-induced acral erythema. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 acral erythema (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced anemia. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months does not appear to reduce the incidence of grades 3 and 4 anemia (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced diarrhea. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 diarrhea (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced leukopenia. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months does not appear to reduce the incidence of grades 3 and 4 neutropenia or febrile neutropenia (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced nausea and vomiting (CINV). Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 vomiting (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chronic venous insufficiency (CVI). It is unclear if compression stockings containing copper are beneficial for lipodermatosclerosis in patients with CVI. Details: Preliminary clinical research shows that using compression stockings impregnated with copper for 8 weeks does not improve overall symptoms of lipodermatosclerosis secondary to chronic venous disease when compared with using a compression stocking without copper. However, the affected surface area may be reduced by approximately 16% by 2 weeks when copper-impregnated compression stockings are used (101809).
• Dental plaque. It is unclear if rinsing the mouth with copper is beneficial for reducing dental plaque. Details: Preliminary clinical research shows that rinsing the mouth with a solution of copper 1.1 mmol/L for 4 days decreases plaque accumulation when compared with a placebo solution (46006).
• Diarrhea. Oral copper has only been evaluated in combination with zinc; its effect when used alone is unclear. Details: Preliminary clinical research in children 6 months to 5 years of age presenting to a hospital in India with acute watery or bloody diarrhea shows that taking a solution providing zinc 2 mg/kg and copper 0.2 mg/kg orally daily for 2 weeks does not reduce the duration of diarrhea, the weight of stool, or the need for rehydration when compared with placebo (87166). It also does not seem to reduce the recurrence of diarrhea or improve weight gain over the next 3 months (95540).
• Oral mucositis. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 oral mucositis (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Osteoarthritis. Although there is interest in using topical copper for osteoarthritis, there is insufficient reliable information about the clinical effects of copper for this condition.
• Osteoporosis. Oral copper has only been evaluated in combination with other minerals; its effect when used alone is unclear. Details: Preliminary clinical research in postmenopausal adults shows that taking copper 2.5 mg in combination with zinc 15 mg, manganese 5 mg, and calcium 1000 mg daily for 2 years can slow bone loss when compared with taking either calcium or the trace minerals alone (1994).
• Postoperative infection. It is unclear if copper-impregnated wound dressings are beneficial for the prevention of postoperative infection. Details: Preliminary clinical research shows that using a wound dressing impregnated with copper oxide 3% by weight reduces the incidence of a surgical site infection in the 30-day period following a caesarean section by 39%, but does not reduce length of hospital stay or readmission rate, when compared with a non-copper wound dressing. Eight patients would need to be treated with the copper-impregnated dressing to prevent one infection (105363). This study is limited by the use of a telephone questionnaire to assess the suspicion of infection.
• Systemic lupus erythematosus (SLE). It is unclear if oral copper is beneficial for improving symptoms of SLE. Details: Copper status does not appear to be associated with the risk of SLE (101810). Additionally, one small clinical study shows that taking copper 3 mg daily, alone or in combination with fish oil, for 24 weeks does not affect symptoms of SLE when compared with placebo (12953).
• Tinea pedis. Although there is interest in using topical copper for tinea pedis, there is insufficient reliable information about the clinical effects of copper for this condition.
• Wound healing. It is unclear if topical copper sulfate can improve the healing of umbilical granuloma. Details: A small clinical study in children 1-3 months of age with treatment-naïve umbilical granuloma shows that a single application of copper sulfate to the affected site results in complete resolution in 70% of patients, compared with 90% of patients receiving topical sodium chloride twice daily for 5 days. Some patients who received a second application of copper sulfate experienced full healing; however, it is unclear if this was due to the treatment or natural resolution (109403). More evidence is needed to rate copper for these uses.

(Read more about COPPER)

POSSIBLY INEFFECTIVE

• Depression. Although it is unclear if oral L-tryptophan is beneficial in patients with depression, there is a lack of supporting evidence and a rare risk of adverse effects such as serotonin syndrome. Details: Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that L-tryptophan is not currently recommended for adjunctive or monotherapy use for major depressive disorder. The available small and low-quality studies have not supported L-tryptophan for this use (110318). Some older research suggests that taking L-tryptophan with clomipramine might improve the effectiveness of clomipramine (10856). However, it is not clear whether L-tryptophan is beneficial when taken along with newer classes of antidepressants. Also, the CANMAT Taskforce cautions the co-use of L-tryptophan with serotonergic antidepressants due to the rare risk of serotonin syndrome (110318).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. Although there is interest in using oral L-tryptophan for anxiety, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Athletic performance. It is unclear if oral L-tryptophan is beneficial for improving athletic performance. Details: Some clinical research shows that taking L-tryptophan 300 mg orally along with a sugar and electrolyte drink twice daily for 3 days prior to exercise and on the day of exercise improves power output during the last 20 minutes of exercise when compared with taking a sugar and electrolyte drink without L-tryptophan. The improvement in power output increases distance covered by about 5% without increasing perceived exhaustion (91462). However, other clinical research shows that taking L-tryptophan 12 mg/kg after 5 minutes of warm-up and then 6 mg/kg orally every 15 minutes during exercise does not improve time to exhaustion in endurance-trained male athletes (1135). Reasons for the discrepancy are not clear. It is possible that L-tryptophan benefits some measures of athletic performance, but not others.
• Bruxism. It is unclear if oral L-tryptophan is beneficial for bruxism. Details: A very small clinical trial in adults with nocturnal bruxism shows that taking L-tryptophan 50 mg/kg daily orally for 8 days does not improve levels of teeth grinding when compared with placebo (1139).
• Cognitive impairment. It is unclear if oral L-tryptophan is beneficial in patients with cognitive impairment. Details: Clinical research in elderly individuals with mild cognitive impairment shows that taking L-tryptophan 95 mg orally with docosahexaenoic acid (DHA) 720 mg, eicosapentaenoic acid (EPA) 286 mg, vitamin E 16 mg, soy phospholipids 160 mg, and melatonin 5 mg (IBSA Farmaceutici Italia) nightly for 12 weeks improves cognitive function and sensitivity to smells by a small amount when compared with placebo. Patients treated with the combination showed a 1-point improvement in cognitive function based on the mini-mental state examination (MMSE) scale, while patients in the placebo group showed a 2-point decline (62847). However, these results might not be clinically significant. Also, it is not known if any potential benefit is due to L-tryptophan, other ingredients, or the combination.
• Fibromyalgia. It is unclear if oral L-tryptophan is beneficial in patients with fibromyalgia. Details: Preliminary clinical research in females with fibromyalgia shows that eating a standardized Mediterranean diet supplemented with walnuts, to supply L-tryptophan 60 mg daily and magnesium 60 mg daily for 16 weeks, modestly reduces anxiety, mood disturbance, eating disorders, and dissatisfaction with body image, but does not affect sleep, when compared with the Mediterranean diet alone. It is unclear if these effects are due to L-tryptophan, magnesium, other components of the added foods, or the combination (103172).
• Gout. Oral L-tryptophan has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with mild hyperuricemia shows that taking a powder containing L-tryptophan 0.2 grams and glycine 3 grams nightly for 6 weeks decreases serum uric acid levels by 0.3 mg/dL when compared with placebo. Improvements also occurred in the subgroup of patients with uric acid levels greater than 7 mg/dL, the point at which symptoms of gout can occur (99883). However, the effect of this combination for gout-related pain is unknown. Also, it is not clear if this effect is due to L-tryptophan, glycine, or the combination.
• Helicobacter pylori. A small clinical study suggests that adding L-tryptophan to treatment with omeprazole increases ulcer healing. Details: Clinical research shows that taking L-tryptophan (Ardeydorm, Ardeypharm GmbH) 250 mg twice daily in combination with omeprazole 20 mg twice daily for 21 days improves ulcer healing rates when compared with omeprazole alone in individuals with H. pylori-associated gastroduodenal ulcers (62803).
• Insomnia. Small clinical studies suggest that oral or intravenous L-tryptophan may modestly improve symptoms, particularly sleep latency, in patients with insomnia. Details: Clinical research shows that taking L-tryptophan 500 mg twice daily for 2 weeks improves insomnia in patients undergoing detoxification from methamphetamine or ketamine when compared with placebo. However, it does not seem to improve psychological symptoms in these patients (97242). One small clinical study shows that taking L-tryptophan orally, 1 gram 20 minutes before bed, might decrease sleep latency and improve mood when compared with placebo in healthy people with insomnia. Smaller doses of 250 mg and 500 mg did not demonstrate benefit (1146). Other clinical research shows that a single 5 gram intravenous infusion of L-tryptophan decreases sleep latency and increases total sleep time when compared with baseline in patients with insomnia (14896).
• Migraine headache. The incidence of migraine headaches may decrease with increased dietary L-tryptophan intake. Details: Preliminary clinical research shows that a dietary L-tryptophan intake of 0.84-1.06 grams per day reduces the odds of experiencing a migraine of any type by 54% to 60% when compared with an intake of 0.56 grams per day or less (103171).
• Myofascial pain syndrome. It is unclear if oral L-tryptophan is beneficial in patients with myofascial pain syndrome. Details: Some clinical research in adults with chronic maxillofacial pain shows that taking L-tryptophan orally 3 grams daily for 4 weeks is associated with a greater reduction in pain score and an increase in pain tolerance when compared with placebo (1145). However, other clinical research shows that L-tryptophan does not reduce pain when compared with placebo (1140).
• Obesity. Although there is interest in using oral L-tryptophan for obesity, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Premenstrual dysphoric disorder (PMDD). Limited clinical research suggests that L-tryptophan may reduce symptoms of PMDD. Details: A small clinical study in adults with PMDD shows that taking L-tryptophan orally 6 grams daily for approximately 17 days, from the time of ovulation to the third day of menstruation, for three consecutive cycles reduces mood swings, tension, and irritability when compared with placebo (6246).
• Premenstrual syndrome (PMS). Although there is interest in using oral L-tryptophan for premenstrual syndrome, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Seasonal affective disorder (SAD). It is unclear if oral L-tryptophan is beneficial in patients with SAD. Details: One very small clinical crossover study shows that taking L-tryptophan 4-6 grams orally daily in divided doses for 4 weeks improves seasonal affective disorder to a similar degree as receiving light therapy for 2 weeks (6247). However, this study was not powered to detect a difference between groups.
• Sleep apnea. Although there is interest in using oral L-tryptophan for sleep apnea, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Smoking cessation. It is unclear if oral L-tryptophan is beneficial for smoking cessation. Details: A small clinical study in adults attempting to quit smoking shows that taking L-tryptophan 50 mg/kg daily orally for 2 weeks in conjunction with standard smoking cessation treatments results in fewer daily cigarettes smoked when compared with placebo. Reported anxiety and other withdrawal symptoms were also lower in the L-tryptophan group (1138). However, the study was not powered to detect a statistically significant difference in these outcomes between groups.
• Tourette syndrome. Although there is interest in using oral L-tryptophan for Tourette syndrome, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition. More evidence is needed to rate L-tryptophan for these uses.

(Read more about L-TRYPTOPHAN)

LIKELY EFFECTIVE

• Pellagra. Oral niacinamide is approved for the treatment of pellagra and niacin deficiency. Details: Niacinamide is FDA-approved for the prevention and treatment of niacin deficiency and pellagra. Niacinamide is sometimes preferred over niacin for this indication because it lacks the vasodilating and flushing effects of niacin (15,6243).

POSSIBLY EFFECTIVE

• Acne. Topical niacinamide seems to improve acne symptoms in some patients. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study shows that applying niacinamide 4% gel twice daily for 8 weeks is as effective as clindamycin 1% gel for reducing the number and severity of acne lesions. The niacinamide gel appears to be more effective in patients with oily skin than those with non-oily skin (93360). Other preliminary clinical research in adults with mild to moderate acne vulgaris shows that applying niacinamide 5% cream twice daily, 10 minutes after applying benzoyl peroxide 2.5% gel, for 12 weeks reduces the number of acne lesions, but not erythema or inflammation, when compared with benzoyl peroxide alone (107711). Niacinamide has also been studied in combination with other ingredients. In preliminary clinical research, oral niacinamide has been reported to improve acne when used in combination with zinc, copper, and folic acid (Nicomide) (25557), or in combination with azelaic acid, zinc, pyridoxine, copper, and folic acid (NicAzel, Elorac Inc.) (90800). In a small observational study, topical niacinamide 4% combined with gallic acid 1% and lauric acid 1% was associated with some improvement in acne (104931). It is unclear if the effects in these studies are due to niacinamide, other ingredients, or the combinations.
• Diabetes. Oral niacinamide does not seem to prevent the onset of type 1 diabetes, although it might slow its progression. Details: Although some older research has suggested that taking high-dose niacinamide can reduce the risk of type 1 diabetes in high-risk children (4874), results from higher quality, more rigorous clinical trials show that taking niacinamide up to 3 grams daily for 5 years does not prevent the onset of type 1 diabetes in first-degree relatives of patients with type 1 diabetes (4875,25553,25554). However, taking niacinamide 1.2 grams/m2 daily for 5 years may prevent the loss of beta-cell function in these patients (25555). Also, there is evidence showing that niacinamide can preserve residual beta-cell function in patients with newly diagnosed type 1 diabetes (4877,4878,4879,4880,25556). Clinical trials, including one placebo-controlled trial and one vitamin E-comparison study, show niacinamide can prolong the "honeymoon period" in those newly diagnosed with type 1 diabetes, when the pancreas is still capable of producing some insulin (4877,4878,4879,4880,25556). However, some scientists have raised concerns about potential induction of insulin resistance with short-term use of niacinamide 2 grams daily for 2 weeks (4881). Niacinamide has also been evaluated in adults with type 2 diabetes. A small clinical study in lean patients with type 2 diabetes who failed sulfonylurea therapy shows that taking niacinamide 500 mg three times daily for 6 months in addition to continuing insulin or a sulfonylurea increases C-peptide release and improves insulin secretion when compared with insulin alone (4882).
• Hyperphosphatemia. Adding oral niacinamide to standard treatment with phosphate binders further lowers blood levels of phosphorus in patients on hemodialysis. Details: A meta-analysis of nine small clinical trials in patients on hemodialysis with hyperphosphatemia who are using a phosphate binder shows that taking niacinamide 250-1500 mg daily for 2-6 months lowers serum phosphorus and parathyroid hormone levels when compared with placebo (98940) Another meta-analysis of two small clinical trials in the same patient population also shows that taking niacinamide, titrated from 500 mg to 1500 mg daily over 8 weeks, reduces serum phosphorus levels by about 0.9 mg/dL when compared with placebo (94188). Other clinical research in this population shows that taking modified-release niacinamide 250-1500 mg orally daily for 12-24 weeks also lowers serum phosphate and parathyroid levels when compared with placebo. However, these effects were not maintained at 40-52 weeks follow-up (107709,110499). In addition, this product was not compared with immediate-release niacinamide. Niacinamide has also been studied in place of phosphate binders. One small clinical study in patients on hemodialysis with hyperphosphatemia shows that taking niacinamide 500-1750 mg daily for 12 weeks, beginning 2 weeks after discontinuation of phosphate binders, decreases serum phosphorus levels by 1.5 mg/dL and intact parathyroid hormone levels by 50 pg/mL, without affecting calcium levels, when compared to baseline (25561).The validity of these findings is limited due to the lack of a control group.
• Nonmelanoma skin cancer. Oral niacinamide might reduce the rate of nonmelanoma skin cancer development. Details: One clinical study in patients with a history of nonmelanoma skin cancers shows that taking niacinamide 500 mg orally twice daily for 12 months reduces the rate of new nonmelanoma skin cancers at 12 months by 23% and the number of actinic keratoses by 13% when compared with placebo (93362). Other clinical research shows that taking niacinamide (Nature's Own, Virginia) 500 mg orally once or twice daily for 4 months reduces the total number of actinic keratoses by up to 35% and decreases the odds of developing at least one nonmelanoma skin cancer by 86% when compared with placebo in patients with at least four actinic keratoses (93365). However, some conflicting research exists. One small clinical study in adults with actinic keratoses shows that taking niacinamide 500 mg twice daily for 120 days does not reduce the number of actinic keratoses when compared with control. However, the validity of this study is limited by the short study duration (107714). A meta-analysis of many small clinical trials shows that using niacinamide, up to 2000 mg orally or 4% topically, daily for 1 month to 5 years lowers the risk of skin cancer, including basal cell carcinoma and cutaneous squamous cell carcinoma by 50% when compared with control. Using niacinamide did not reduce the risk of actinic keratoses. However, the validity of this study is limited by inclusion of populations with different cancer risks and high heterogeneity (110497).
• Osteoarthritis. Oral high-dose niacinamide might be beneficial for improving osteoarthritis symptoms. Details: Clinical research in patients with osteoarthritis shows that taking niacinamide 3 grams daily in six divided doses for 12 weeks improves joint flexibility, reduces inflammation, and modestly decreases use of nonsteroidal anti-inflammatory drugs (NSAIDs) when compared with placebo (4883).

POSSIBLY INEFFECTIVE

• Brain tumor. Adding high-dose oral niacinamide to chemotherapy does not seem to improve survival in patients with brain tumors. Details: Preliminary clinical research in patients with surgically resected brain tumors shows that treatment with radiotherapy, niacinamide, and carbogen does not improve survival when compared with radiotherapy alone or radiotherapy plus carbogen (11695,11696).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. Although there is interest in using oral niacinamide for age-related cognitive decline, there is insufficient reliable information about the clinical effects of niacinamide for this purpose.
• Age-related macular degeneration (AMD). Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with early-stage age-related maculopathy shows that taking a combination of niacinamide 18 mg, vitamin E 20 mg, and lutein 15 mg daily for nearly a year improves retinal function when compared with no treatment (60134). It is unclear if this effect is due to niacinamide, other ingredients, or the combination.
• Aging skin. It is unclear if topical niacinamide improves symptoms of aging skin. Details: A small study in females with signs of facial photo-aging shows that applying niacinamide 5% cream to half of the face twice daily for 12 weeks improves blotchiness, the appearance of wrinkles, skin elasticity, and skin pigmentation when compared with applying placebo cream to the other half of the face (25551).
• Atopic dermatitis (eczema). It is unclear if topical niacinamide improves eczema symptoms. Details: A small clinical study in patients with atopic dermatitis and dry skin shows that applying niacinamide 2% cream twice daily for 8 weeks decreases skin water loss and improves skin hydration when compared with using a white petrolatum moisturizer (25560).
• Attention deficit-hyperactivity disorder (ADHD). Oral niacinamide has only been evaluated in combination with other vitamins; its effect when used alone is unclear. Details: A small clinical study in children with ADHD shows that taking a maximum of niacinamide 3 grams, ascorbic acid 3 grams, calcium pantothenate 1.2 grams, and pyridoxine 600 mg daily for 3 months seems to improve behavior in 29% of participants when compared with baseline (9957). The validity of this finding is limited by the lack of a comparator group.
• Bladder cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in advanced bladder cancer; its effect when used alone is unclear. Details: A phase II clinical study in patients with locally advanced bladder cancer shows that adding inhaled carbogen and oral niacinamide 40-60 mg/kg about 2 hours before radiotherapy shows a trend to improved survival at 3 years when compared with inhaled carbogen and radiotherapy (25558), and a larger phase III study shows that carbogen and oral niacinamide improves 3-year survival by about 13% when compared with radiotherapy alone (93366). An observational follow-up of the phase III study found a trend to increased survival at 5 years in the carbogen and niacinamide group when compared with radiotherapy alone. And in a subgroup of patients with tumor necrosis, the 5-year survival was significantly greater with carbogen and niacinamide when compared with radiotherapy alone (93356). It is unclear if these effects are due to niacinamide, carbogen, or the combination.
• Child growth. It is unclear if oral niacinamide improves child growth. Details: Preliminary clinical research in children in rural Tanzania shows that supplementing niacinamide orally from birth to 18 months of age does not improve length-for-age, weight-for-age, or head circumference when compared with control. Niacinamide was initially supplemented to breast-feeding mothers, 250 mg daily, until 6 months of age, followed by 100 mg daily taken by the child until 18 months of age (107713).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral niacinamide is beneficial for COVID-19. Details: Observational research in adults with acute kidney injury secondary to coronavirus disease-19 infection has found that taking niacinamide 1000 mg orally daily for 7 days is associated with a 55% lower risk of mortality when compared with control. However, taking niacinamide was not associated with a lower risk of renal replacement therapy (110500).
• Cutaneous lupus erythematosus (CLE). It is unclear if topical niacinamide is beneficial for CLE. Details: Preliminary clinical research in adults with discoid lupus erythematosus, a type of CLE, shows that applying topical niacinamide 2% to 4% twice daily for 12 weeks modestly improves lesion scores, but not quality of life scores, when compared with placebo. However, the study may have been inadequately powered to detect a difference between groups (110498).
• Depression. Although there is interest in using oral niacinamide for depression, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Diabetic neuropathy. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with diabetic polyneuropathy shows that taking a specific combination product (Cytoflavin, Polysan) containing niacinamide, inosine, riboflavin, and succinate daily for 12 weeks improves symptom scores, including paresthesia and numbness scores, when compared with placebo. The therapy was administered intravenously, containing niacinamide 20 mg, inosine 40 mg, riboflavin 4 mg, and succinate 200 mg, for 10 days followed by orally, containing niacinamide 50 mg, inosine 100 mg, riboflavin 10 mg and succinate 600 mg, for the remainder of the study (110503).
• Erythema. Topical niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: There is interest in using niacinamide to reduce the side effects of topical tretinoin, including erythema. A small preliminary clinical study in patients using isotretinoin for acne shows that applying a specific cream (Sebiaclear Hydra, SVr Laboratoire Dermatologique) containing niacinamide 5% and omega-ceramides 8% twice daily for 6 months reduces isotretinoin-induced erythema, dryness, and itching of the skin when compared with a glycerin placebo (98938). It is not clear if this effect is due to niacinamide, omega-ceramides, or the combination.
• Head and neck cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in laryngeal cancer; its effect when used alone is unclear. Details: A phase III clinical trial in patients with laryngeal cancer shows that treatment with accelerated radiotherapy plus carbogen and niacinamide 60 mg/kg taken orally 1-1.5 hours prior to each fraction of radiation improves local tumor control, but does not improve overall survival or 5-year disease-free survival, when compared with accelerated radiotherapy alone. In a subgroup of patients with hypoxic tumors, anemia, or high expression of epidermal growth factor receptor, receiving niacinamide and carbogen seems to improve both survival and tumor control when compared with radiotherapy alone (93358,93359,93363).
• Melasma. It is unclear if topical niacinamide improves uneven skin pigmentation. Details: A small clinical study in Japanese females with uneven facial hyperpigmentation shows that applying niacinamide 5% moisturizer to the face twice daily reduces hyperpigmentation and increases skin lightness after 4 weeks when compared with placebo moisturizer. However, further improvements are not observed after another 4 weeks of treatment (25552). Another small clinical study in Korean females with uneven facial hyperpigmentation shows that applying a moisturizer containing niacinamide 2% plus tranexamic acid 2% (Regederm RX White Project, Aestura) twice daily for 8 weeks reduces skin pigmentation by about 9% when compared with a placebo cream (93361).
• Non-Hodgkin lymphoma. It is unclear if adding oral niacinamide to chemotherapy reduces relapses of refractory lymphoma. Details: One small clinical study in patients with relapsed or refractory lymphoma shows that 24% of patients achieve complete or partial remission and 57% achieve disease stabilization when compared with baseline, following treatment with vorinostat 400 mg daily and niacinamide titrated from 20 mg/kg to 100 mg/kg over the first 14 days of a 21-day cycle for up to 18 cycles (93355). It is unclear how these outcomes compare to using vorinostat alone, or to other control treatments.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral niacinamide is beneficial for NAFLD. Details: Preliminary clinical research in adults with NAFLD and diabetes shows that taking a specific niacinamide product (Nature's Life) 1000 mg orally daily for 12 weeks does not improve liver function tests, liver steatosis, or liver fibrosis when compared with no intervention. However, some quality of life domain scores were moderately improved. However, the study may have been inadequately powered to detect a difference between groups (110502).
• Premenstrual syndrome (PMS). Although there is interest in using oral niacinamide for PMS, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Pruritus. It is unclear if oral niacinamide reduces pruritus in patients with kidney failure. Details: A small clinical study in patients with pruritus due to kidney failure shows that taking niacinamide sodium 500 mg twice daily for 4 weeks does not reduce pruritus severity when compared with placebo (93364). This study is limited due to small size and short study duration.
• Psoriasis. It is unclear if oral niacinamide is beneficial for psoriasis. Details: Preliminary clinical research in adults with mild to moderate psoriasis shows that applying niacinamide 4% cream topically twice daily for 12 weeks improves psoriasis scores by 31% when compared with baseline. The validity of these results is limited by the lack of a comparator group (110501).
• Rosacea. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that 71% of adult and adolescent patients with rosacea who take a combination product (Nicomide) containing niacinamide 750 mg, zinc 25 mg, copper 1.5 mg, and folic acid 500 mcg once or twice daily report improvement in appearance after 4 weeks when compared to baseline (25557). The validity of these findings is limited by the lack of a control group.
• Schizophrenia. Although there is interest in using oral niacinamide for schizophrenia, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Seborrheic dermatitis. It is unclear if topical niacinamide is beneficial for reducing seborrheic dermatitis symptoms. Details: One small clinical study in patients with seborrheic dermatitis shows that applying niacinamide 4% cream once daily for 12 weeks reduces the severity of symptoms such as redness and scaling by 75%, compared with a 35% reduction when using a placebo cream (93357). More evidence is needed to rate niacinamide for these uses.

(Read more about NIACINAMIDE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Altitude sickness. It is unclear if oral rhodiola is beneficial for altitude sickness. Details: Preliminary clinical research shows that taking rhodiola 447 mg four times daily for 7 days does not improve blood oxygenation or markers of oxidative stress when compared with placebo in subjects exposed to simulated high-altitude conditions (25402).
• Anthracycline cardiotoxicity. It is unclear if oral rhodiola is beneficial for epirubicin-induced cardiotoxicity. Details: Preliminary clinical research in breast cancer patients shows that taking salidroside, a constituent of rhodiola, 600 mg daily, beginning one week prior to chemotherapy and continuing throughout chemotherapy administration, reduces epirubicin-induced early left ventricular regional systolic dysfunction when compared with placebo (90434).
• Anxiety. It is unclear if oral rhodiola is beneficial for anxiety. Details: Preliminary clinical research in college students with anxiety shows that taking a specific dried rhodiola extract (Vitango, Schwabe Pharma) 200 mg twice daily for 14 days modestly reduces reported levels of anxiety, anger, confusion, negative mood, and stress when compared with a control group. However, rhodiola extract does not seem to improve cognition (96462).
• Arrhythmia. Although there has been interest in using oral rhodiola for arrhythmia, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Athletic performance. The evidence related to the use of rhodiola for athletic performance is mixed, although specific standardized extracts might be beneficial for certain performance endpoints. Details: The available evidence for rhodiola in athletic performance includes small clinical trials in recreationally active or trained athletes. Trials using rhodiola extracts standardized to 3% rosavins and 1% salidroside (eg. Finzelberg, GmbH) show that taking 3 mg/kg, 200 mg, or 500 mg prior to exercise testing, either as a single dose or with a 3-day lead-in dose, modestly improves performance endpoints on a cycle ergometer. Improved endpoints included time to exhaustion, peak oxygen use, time to completion, perceived exhaustion, anaerobic capacity, and power (13109,90432,100168). However, in trials in which rhodiola was not taken the morning of testing, or when performance endpoints included forearm endurance or marathon time and recovery, rhodiola 170 mg to 1500 mg daily did not affect perceived exertion, time to exhaustion, or peak oxygen use (15574,19284,90433). A small crossover trial shows that taking 500 mg of rhodiola extract, standardized to 3% rosavins and 1% salidroside, three times daily for 3 days followed by 500 mg 30-minutes before exercise testing increases bench press velocity but decreases bench press repetition volume when compared with placebo (110543). Furthermore, limited evidence suggests that rhodiola extract does not affect muscle strength, speed of limb movement, reaction times, or attention span (13109) but might reduce plasma creatine kinase levels (19284). Also, while some evidence suggests that rhodiola extract can reduce blood lactate levels (19284), other research shows that it increases blood lactate levels after resistance training to a greater degree than placebo (110543). In general, it appears that acute doses of rhodiola may improve specific physical performance parameters, but neither acute nor chronic doses appear to notably improve muscle function. Some research has also assessed rhodiola when used in combination with other ingredients. A small clinical study in trained male cyclists shows that taking a specific combination product (Optygen, First Endurance) containing rhodiola 600 mg (standardized to 3% rosavin and 2.5% salidroside) plus cordyceps 2000 mg (standardized to 7% cordycepic acid), daily for 6 days followed by a half-dose daily for 7 days does not improve time to exhaustion or muscle tissue oxygen saturation when compared with placebo (15573). Additionally, a small crossover study in healthy, recreationally active adult males shows that taking a 30:70 blend of rhodiola and maral root extracts at a dose of 350 mg or 175 mg, ninety minutes prior to isokinetic leg strength exercises, does not influence fatigability, performance variables, or affective responses when compared with placebo (105855).
• Bladder cancer. Although there has been interest in using oral rhodiola for bladder cancer, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral rhodiola for CFS, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Coronavirus disease 2019 (COVID-19). Oral rhodiola extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults a with confirmed history of COVID-19 infection and at least 3 of 9 long COVID-19 symptoms for at least 30 days, but no longer than 3 months, after discharge shows that taking a specific combination product (ADAPT-232/Chisan, Swedish Herbal Institute), containing rhodiola extract 90 mg, schisandra extract 300 mg, and eleuthero extract 78 mg, twice daily for 14 days increases walking duration by around 13 minutes but does not reduce the duration of cough, fatigue, headache, pain, or other respiratory problems when compared with placebo (109635). It is unclear if these findings are due to rhodiola, other ingredients, or the combination.
• Depression. It is unclear if oral rhodiola is beneficial for depression. Details: Clinical practice guidelines from the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) state that rhodiola is not currently recommended for monotherapy or adjunctive use in major depressive disorder based on mixed evidence (110318). Clinical research shows that taking a specific rhodiola extract (SHR-5, Swedish Herbal Institute) 340 mg once or twice daily reduces symptoms of mild-to-moderate depression after 6 weeks of treatment when compared with placebo. Rhodiola decreased overall depressive symptoms, emotional instability, insomnia, and somatization; however, it did not improve feelings of self-esteem (17616). Another small clinical study in patients with major depressive disorder of moderate severity shows that adding a higher dose of rhodiola 600 mg to sertraline daily for 12 weeks improves depressive symptoms when compared with either sertraline alone or sertraline with a lower dose of rhodiola (300 mg) (102283).
• Diabetes. Although there has been interest in using oral rhodiola for diabetes, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Fatigue. Preliminary clinical research suggests that oral rhodiola extract decreases fatigue in stressful situations. Details: Most preliminary clinical trials have evaluated a specific rhodiola root extract (SHR-5, Swedish Herbal Institute) in various doses and populations. Taking 50 mg of this product twice daily reduces mental fatigue and improves subjective well-being in students during an examination period (1927). Taking 144 mg twice daily for 7 days reduces fatigue, but not stress, in university students (19287). In night shift workers, 170 mg daily for 2 weeks reduces feelings of fatigue and improves mental performance (6877). In military cadets, a single dose of 370-555 mg after 24 hours without sleep improves tests of mental processing and short-term memory (16411). Finally, taking 576 mg daily for 28 days decreases symptoms of fatigue and increases attention, but does not improve quality of life or symptoms of depression, in patients with stress-related fatigue (19286). Other clinical research shows that taking a different rhodiola root extract (Rhodaxon, Teknofarm), 660 mg daily for 20 days, reduces mental fatigue by 30% in first-year university students (19288). Clinical research using another specific dried rhodiola extract (Vitango, Schwabe Pharma) also shows that taking 200 mg twice daily for 12 weeks modestly reduces perceived levels of stress, burnout, and fatigue when compared to baseline in adults experiencing symptoms of burnout. The validity of these findings is limited by the lack of a control group (96459). Rhodiola extract has also been studied in combination schisandra berry extract and Siberian ginseng root extract (ADAPT-232, Swedish Herbal Institute). However, evidence is mixed, with one study showing that 270 mg daily improves attention, accuracy, and speed in tired individuals performing stressful cognitive tasks (19289), and another study showing that 280 mg daily for 7 days does not reduce mental fatigue or stress in university students (19287).
• Generalized anxiety disorder (GAD). It is unclear if oral rhodiola is beneficial for GAD. Details: A small clinical study shows that taking a specific rhodiola extract (Rhodax, Bodyonics Ltd.) 170 mg twice daily for 10 weeks decreases anxiety and depression and improves symptom scores when compared to baseline in patients with GAD (16410). The validity of these findings is limited by the lack of a comparator group.
• Hearing loss. Although there has been interest in using oral rhodiola for hearing loss, there is insufficient reliable information about the clinical effects of rhodiola for this purpose.
• Hyperlipidemia. Although there has been interest in using oral rhodiola for hyperlipidemia, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Menopausal symptoms. Oral rhodiola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients experiencing menopausal symptoms shows that taking a combination product (Menopause Relief EP, EuroPharma USA) containing rhodiola extract 400 mg and black cohosh extract 13 mg daily for 12 weeks improves psychological symptoms of menopause when compared with placebo or black cohosh alone (103269). It is unclear if these findings are due to rhodiola, black cohosh, or the combination.
• Premature ejaculation. Oral rhodiola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with lifelong premature ejaculation shows that taking a specific combination product (EndEP) containing rhodiola 200 mg, folic acid 200 mcg, zinc 10 mg, and biotin 50 mcg once daily for 90 days increases time to ejaculation by about 29 seconds and improves control of ejaculation in about 60% of participants when compared to baseline. These improvements disappear within 90 days of discontinuing treatment. The validity of these findings is limited by the lack of a control group (96460).
• Sexual arousal. Although there has been interest in using oral rhodiola for improving sexual arousal, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Stress. Preliminary clinical research suggests that oral rhodiola extract reduces feelings of stress. Details: Preliminary clinical research in adults with general stress shows that taking a specific dried rhodiola extract (Vitango, Schwabe Pharma) modestly reduces levels of stress in certain situations. Taking 200 mg twice daily before breakfast and lunch for 4 weeks improves stress, disability, and functional impairment when compared to baseline (90431). A small study in college students with anxiety shows that taking 200 mg twice daily for 14 days modestly reduces reported levels of stress, anxiety, anger, confusion, and negative mood when compared to a control group (96462). In adults experiencing symptoms of burnout, taking this specific extract 200 mg twice daily for 12 weeks modestly reduces perceived levels of stress, burnout, and fatigue and improves sexual satisfaction when compared to baseline. The validity of these findings is limited by the lack of a control group (96459). Rhodiola has also been evaluated in combination with other ingredients in individuals with stress. A small clinical study in healthy adults with chronic stress shows that taking a specific combination product (Mg-Teadiola, Sanofi-Aventis), containing rhodiola extract 222 mg, magnesium 150 mg, green tea extract 125 mg (providing theanine 50 mg), vitamin B6 0.7 mg, vitamin B9 0.1 mg, and vitamin B12 1.25 mcg, daily for 4 weeks reduces stress scores when compared with placebo (108672). It is unclear if these findings are due to rhodiola, other ingredients, or the combination.
• Tuberculosis. Although there has been interest in using oral rhodiola for tuberculosis, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Upper respiratory tract infection (URTI). Although there has been interest in using oral rhodiola for URTI prevention, there is insufficient reliable information about the clinical effects of rhodiola for this purpose. More evidence is needed to rate rhodiola for these uses.

(Read more about RHODIOLA)

LIKELY SAFE ...when used orally and appropriately. Coenzyme Q10 has been used safely in studies lasting up to 5 years (2134,6037,6038,6407,8163,8938,8939,8940,15395,17413,17716,96538)(109391). ...when used topically on the gums (2107,2108,8916,8917,8918).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. Coenzyme Q10 in doses of 1-10 mg/kg/day has been used safely for up to 9 months under medical supervision (12199,13223,15256,44005,107449).

PREGNANCY: POSSIBLY SAFE
when used orally and appropriately. Coenzyme Q10 100 mg twice daily has been used with apparent safety during pregnancy, starting at 20 weeks gestation until term (17201).

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about COENZYME Q10)

LIKELY SAFE ...when used orally and appropriately. Copper is safe in amounts that do not exceed the tolerable upper intake level (UL) of 10 mg daily (7135).

POSSIBLY SAFE ...when copper oxide is used topically. A wound dressing impregnated with copper oxide in concentrations of 3% by weight has been used with apparent safety in one clinical trial (105363).

POSSIBLY UNSAFE ...when used orally in doses exceeding the UL of 10 mg daily. Higher intake can cause liver damage (7135,45865). Kidney failure and death can occur with ingestion of as little as 1 gram of copper sulfate (17).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Copper is safe in amounts that do not exceed the tolerable upper intake level (UL) of 1 mg daily for 1-3 years of age, 3 mg daily for 4-8 years of age, 5 mg daily for 9-13 years of age, and 8 mg daily for 14-18 years of age (7135).

CHILDREN: POSSIBLY UNSAFE
when used orally in doses exceeding the UL (7135). Higher intake can cause liver damage (7135).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. Copper is safe in amounts that do not exceed the tolerable upper intake level (UL) of 8 mg daily for those 14-18 years of age or 10 mg daily for those 19 years and older (7135).

PREGNANCY: POSSIBLY UNSAFE
when used orally in doses exceeding the UL. Higher intake can cause liver damage (7135).

LACTATION: LIKELY SAFE
when used orally and appropriately. Copper is safe in amounts that do not exceed the tolerable upper intake level (UL) of 8 mg daily for those 14-18 years of age or 10 mg daily for those 19 years and older (7135).

LACTATION: POSSIBLY UNSAFE
when used orally in doses exceeding the UL. Higher intake can cause liver damage (7135).

(Read more about COPPER)

LIKELY SAFE ...when used orally in the amounts commonly found in foods. L-tryptophan is an essential amino acid that must be obtained from the diet. A typical diet in the United States supplies 0.5-2 grams of L-tryptophan daily (1146).

POSSIBLY SAFE ...when used orally in medicinal amounts, short-term. L-tryptophan 5 grams daily for 21 days has been used with apparent safety (91460,97243). In 1989, L-tryptophan was linked to over 1500 reports of eosinophilia-myalgia syndrome (EMS) and several deaths (7067,8053,10085,11474,11478), leading to its removal from the U.S. market in 1990 (7067). The exact cause of EMS in patients taking L-tryptophan is unknown, but some evidence suggests that nearly all cases were due to contaminated L-tryptophan products from a single manufacturer (8050,8051,11477,11478). Under the Dietary Supplement Health and Education Act (DSHEA) of 1994, L-tryptophan is currently available and marketed as a dietary supplement. There is insufficient reliable information available about the safety of L-tryptophan when used orally, long-term.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods.

PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts because it may cause respiratory depression in utero (1142). Avoid using in amounts greater than those found in foods.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods. There is insufficient reliable information available about the safety of larger medicinal amounts; avoid using.

(Read more about L-TRYPTOPHAN)

LIKELY SAFE ...when prescription products are used orally and appropriately (12033). ...when niacinamide supplements are taken orally in doses below the tolerable upper intake level (UL) set by the Institute of Medicine (IOM). The UL of niacinamide is 30 mg daily for adults 18 years of age and 35 mg daily for adults 19 years and older (6243).

POSSIBLY SAFE ...when used orally in doses greater than 30 mg but less than 900 mg daily. The European Food Safety Authority has set the tolerable upper intake level (UL) of niacinamide at 900 mg daily (104937). However, oral niacinamide has been safely used in doses up to 1500 mg daily for 12 weeks in some clinical trials (25561,94188,98940,107709,110502). ...when used topically and appropriately for up to 12 weeks (5940,93360,110498,110501).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Niacinamide has been safely used in children for up to 7 years in doses below the tolerable upper intake level (UL) (4874,9957). The UL of niacinamide for children by age is: 1-3 years, 10 mg daily; 4-8 years, 15 mg daily; 9-13 years, 20 mg daily; 14-18 years, 30 mg daily (6243).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL) for niacinamide. The UL of niacinamide during pregnancy and lactation is 30 mg daily for those 14-18 years of age and 35 mg daily for those 19 years and older (6243). There is insufficient reliable information available about the safety of larger oral doses of niacinamide or topical niacinamide; avoid using.

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POSSIBLY SAFE ...when used orally and appropriately, short-term. There is some clinical research showing that taking rhodiola extract up to 300 mg twice daily has been used without adverse effects for up to 12 weeks (13109,16410,17616,71172,96459,102283,103269).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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ALKYLATING AGENTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Coenzyme Q10 has antioxidant effects. Theoretically, this may reduce the activity of chemotherapy drugs that generate free radicals.  Details Theoretically, antioxidants such as coenzyme Q10 might protect tumor cells from chemotherapeutic agents that work by inducing oxidative stress, such as alkylating agents (e.g., cyclophosphamide) and radiation therapy (5158,5159). The clinical importance of this interaction is unknown.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, coenzyme Q10 might have additive effects with antihypertensive drugs.  Details Some clinical research shows that coenzyme Q10 can significantly lower blood pressure (2122,3365,8907,9890,17702,17650,17651,44343,96541), although other studies have shown conflicting results (17651,44211,95607).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Coenzyme Q10 is chemically similar to menaquinone and might have vitamin K-like procoagulant effects, which could decrease the effects of warfarin.  Details Concomitant use of coenzyme Q10 and warfarin might reduce the anticoagulant effects of warfarin (2128,6048,6199). Four cases of decreased warfarin efficacy thought to be due to coenzyme Q10 have been reported (2128,6048,11048). However, there is some preliminary clinical research that suggests coenzyme Q10 might not significantly decrease the effects of warfarin in patients who have a stable INR (11905).

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CONTRACEPTIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking copper with contraceptive drugs might increase the levels and toxic effects of copper.  Details A meta-analysis of clinical studies suggests that chronic use of oral contraceptives increases serum copper levels by a mean of 57 mcg/dL. In most people, this resulted in levels above the normal reference range for copper (92395).

PENICILLAMINE (Cuprimine, Depen) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking copper with penicillamine might decrease the absorption of penicillamine; separate dosing by at least 2 hours.  Details Copper chelates penicillamine, which decreases its absorption and may reduce its clinical effects (4412,4453,4531,4535,9630).

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CNS DEPRESSANTS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use of L-tryptophan with CNS depressants might cause additive sedative effects.  Details Clinical research shows that L-tryptophan can cause fatigue and drowsiness (1143).

SEROTONERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining L-tryptophan with serotonergic drugs might cause additive serotonergic effects.  Details L-tryptophan is a precursor to serotonin (1141). Theoretically, combining serotonergic drugs with L-tryptophan might increase the risk of serotonergic side effects, including serotonin syndrome and cerebral vasoconstrictive disorders (8056).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, niacinamide may have additive effects when used with anticoagulant or antiplatelet drugs, especially in patients on hemodialysis.  Details Several cases of thrombocytopenia have been reported for hemodialysis patients treated with niacinamide 1 gram daily. Hemodialysis patients receiving niacinamide had almost a three-fold higher risk of developing thrombocytopenia when compared with those receiving placebo (25563,98940).

CARBAMAZEPINE (Tegretol) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Niacinamide might increase the levels and adverse effects of carbamazepine.  Details Plasma levels of carbamazepine were increased in two children given high-dose niacinamide, 60-80 mg/kg/day. This might be due to inhibition of the cytochrome P450 enzymes involved in carbamazepine metabolism (14506). There is not enough data to determine the clinical significance of this interaction.

PRIMIDONE (Mysoline) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Niacinamide might increase the levels and adverse effects of primidone.  Details Case reports in children suggest niacinamide 60-100 mg/kg/day reduces hepatic metabolism of primidone to phenobarbital, and reduces the overall clearance rate of primidone (14506); however, there is not enough data to determine the clinical significance of this potential interaction.

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking rhodiola with antidiabetes drugs might increase the risk of hypoglycemia.  Details In vitro and animal research shows that rhodiola extract can decrease blood glucose due to alpha-glucosidase activity (15717,15719).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking rhodiola with antihypertensive drugs might increase the risk of hypotension.  Details In vitro and animal research shows that rhodiola extract inhibits angiotensin-converting enzyme (ACE) and might lower blood pressure (15719,19495).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, rhodiola might increase levels of drugs metabolized by CYP1A2.  Details In vitro research shows that rhodiola inhibits CYP1A2. This effect is highly variable and appears to be dependent on the rhodiola product studied (96461). However, a clinical study in healthy young males found that taking rhodiola extract 290 mg daily for 14 days does not inhibit the metabolism of caffeine, a CYP1A2 substrate (96463).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, rhodiola might increase levels of drugs metabolized by CYP2C9.  Details In vitro research shows that rhodiola inhibits CYP2C9. This effect is highly variable and appears to be dependent on the rhodiola product studied (96461). Also, a clinical study in healthy young males found that taking rhodiola extract 290 mg daily for 14 days reduces the metabolism of losartan, a CYP2C9 substrate, by 21% after 4 hours (96463).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, rhodiola might increase levels of drugs metabolized by CYP3A4.  Details In vitro research shows that rhodiola inhibits CYP3A4 (19497,96461). This effect is highly variable and appears to be dependent on the rhodiola product studied (96461). However, a clinical study in healthy young males found that taking rhodiola extract 290 mg daily for 14 days does not inhibit the metabolism of midazolam, a CYP3A4 substrate (96463).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, rhodiola use might interfere with immunosuppressive therapy.  Details In vitro and animal research show that rhodiola has immunostimulatory effects (19498,19499,19500,19501).

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Rhodiola might increase the levels and adverse effects of losartan.  Details A clinical study in healthy young males found that taking rhodiola extract 290 mg daily for 14 days reduces the metabolism of losartan, a CYP2C9 substrate, by 21% after 4 hours (96463).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, rhodiola might increase levels of P-glycoprotein substrates.  Details In vitro research shows that rhodiola inhibits P-glycoprotein (19497). Theoretically, using rhodiola with P-glycoprotein substrates might increase drug levels and potentially increase the risk of adverse effects.

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General ...Orally, coenzyme Q10 is generally well tolerated. In clinical studies, no serious adverse effects have been reported.
Most Common Adverse Effects:
Orally: Gastrointestinal side effects such as appetite suppression, diarrhea, epigastric discomfort, heartburn, nausea, and vomiting. These generally occur in less than 1% of patients. Some of these adverse effects can be minimized if daily doses above 100 mg are divided.

Cardiovascular ...Palpitations have been reported as being possibly associated with coenzyme Q10 treatment (89421). Death due to myocardial infarction occurred in one Parkinson disease patient taking coenzyme Q10; causality is unclear (15395).

Dermatologic ...Two of 143 participants in a case series reported skin itching after starting treatment with oral coenzyme Q10 (6047). Allergic rash has also been reported (6409,11872). An itching exanthema was seen in two heart failure patients treated with intravenous coenzyme Q10 (44284).

Gastrointestinal ...Gastrointestinal side effects of coenzyme Q10 have included nausea (3365,6409,8907,10152,43982,44172,44179,44330,89421,109392), vomiting (3365,10152,44330,89421), epigastric discomfort (3365,44179,44330,89421), constipation (109392), diarrhea (44179,92904,89421,109392), stomach upset (8940,12170,109387,109388,109392), loss of appetite (2121), heartburn (2121,44179,109392), and flatulence (43982), although this occurs in less than 1% of patients. In one clinical study, gastrointestinal bleeding in association with angiodysplasia has been reported to be possibly related to coenzyme Q10 treatment (89421).

Genitourinary ...An uncomplicated urinary infection was reported in a patient taking oral coenzyme Q10 (nanoQuinon, MSE Pharmazeutika) (44020).

Hematologic ...Thrombocytopenia was noted in one patient treated with oral coenzyme Q10 (44296); however, other factors (viral infection, other medications) may have been responsible for this adverse effect.

Musculoskeletal ...Increased plasma creatine kinase with high-intensity exercise has been reported in patients taking coenzyme Q10 (44303). Muscle pain has been reported rarely in one clinical trial (109392).

Neurologic/CNS ...Headache and dizziness have been reported in human research (3365,11872,43982,44330,109392). Insomnia has been reported as being possibly associated with coenzyme Q10 treatment (89421). Cognitive decline, depression, and sudden falls were reported rarely in a clinical trial of patients with Huntington disease (8940). Increased lethargy was reported for one patient treated with oral coenzyme Q10 (44042). Feeling of internal trembling has been reported in a clinical trial for one patient treated with coenzyme Q10 (44020).

Ocular/Otic ...Visual sensitivity to light has been reported for a patient treated with coenzyme Q10. However, the association of this effect with coenzyme Q10 treatment was not clear (6409).
A burning sensation has been reported for 10% of patients treated with a topical eye solution containing coenzyme Q10 and alpha-tocopheryl polyethylene glycol 1000 succinate following cataract surgery (44228).

Psychiatric ...Worsening depression has been reported as being possibly associated with oral coenzyme Q10 treatment (89421).

Pulmonary/Respiratory ...Drug-induced pneumonitis was diagnosed in a 61 year-old woman who had been taking coenzyme Q10 and perilla leaf extract for two months (43978). Symptoms improved after she stopped taking the supplements and began taking oral prednisone. Causation from coenzyme Q10 was unclear.

Other ...In a case report, a naval aviator using a supplement containing coenzyme Q10 and niacin had reduced G tolerance (44186). G tolerance was regained with cessation of the supplement.

(Read more about COENZYME Q10)

General ...Orally, copper is generally well tolerated when consumed in doses below the tolerable upper intake level (UL).

Dermatologic ...Contact dermatitis caused by copper has been reported rarely. A case report describes a 5-year-old male who developed recurrent fingertip dermatitis and a positive skin test to copper after playing with toy cars made with a copper-containing alloy (95538). Also, in a small clinical trial in children 1-3 months of age with umbilical granuloma, 3 of 33 children receiving a single topical application of copper sulfate developed superficial burns, whereas no superficial burns occurred in those receiving topical sodium chloride (109403).
In one case report, a 68-year-old male with type 2 diabetes and peripheral neuropathy developed second- and third-degree burns after wearing a copper-containing compression sock on the right leg for 3 hours while sitting in the sun. The patient received treatment with topical silver sulfadiazine and oral clindamycin. After 6 weeks, the patient was found to have multiple persistent wounds containing necrotic tissue which required debridement, daily dressing changes, and tubular compression. It is thought that the heat conductance of copper magnified the effects of sun exposure in this case (109402).

Endocrine ...There is evidence from observational studies that people with diabetes (type 1 or type 2) have higher copper levels in their blood than people without diabetes, although not all studies have shown this (95537). It is not known if elevated copper levels contribute to development or worsening of diabetes.

Hematologic ...A case report of copper overdose in a 28-year-old male resulted in hemolysis exacerbated by glucose-6-phosphate dehydrogenase deficiency. The patient was hospitalized, received D-penicillamine chelation, blood transfusion, and ultimately, 4 cycles of plasmapheresis which led to clinical recovery (112378).

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General ...Orally, L-tryptophan is generally well tolerated.
Most Common Adverse Effects:
Orally: Belching, diarrhea, drowsiness, dry mouth, flatulence, headache, heartburn, lightheadedness, nausea, stomach pain, visual blurring, and vomiting.
Serious Adverse Effects (Rare):
Orally: L-tryptophan has been associated with the neurological disorder eosinophilia-myalgia syndrome (EMS). However, almost all cases were traced to L-tryptophan produced by a single manufacturer in Japan and are likely related to contamination.

Cardiovascular ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include cardiovascular symptoms such as myocarditis, arrhythmias, and palpitations (8053,11477).

Dermatologic ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include dermatological symptoms such as sclerodermiform skin changes, alopecia, and rash (8053,11477).

Gastrointestinal ...Orally, L-tryptophan can cause gastrointestinal side effects such as heartburn, stomach pain, belching and flatulence, nausea, vomiting, diarrhea, dry mouth, and anorexia (10853,99884).

Hematologic ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include hematologic symptoms such as eosinophilia (8053,11477).

Hepatic ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include hepatic symptoms such as hepatomegaly (8053,11477).

Musculoskeletal ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include musculoskeletal symptoms such as myalgia and inflammation of the joints and connective tissue (8053,11477).

Neurologic/CNS ...Orally, L-tryptophan can cause headache, lightheadedness, and ataxia (10853,99884).
In 1989, more than 1500 cases of the neurological disorder EMS were associated with oral L-tryptophan use in the US. About 95% of all EMS cases were traced to contaminated L-tryptophan produced by a single manufacturer in Japan (8054,10288,10289,11475,11476). In 1990, L-tryptophan was recalled in the U.S. and an FDA alert was put into force limiting the importation of all over-the-counter L-tryptophan products (7067,11477,11478). After the limitation of L-tryptophan products, the incidence of EMS dropped abruptly (11474). Symptoms of EMS associated with L-tryptophan use include intense eosinophilia; fatigue; myalgia; neuropathy; sclerodermiform skin changes; alopecia; rash; and inflammatory disorders affecting the joints, connective tissue, lungs, heart, and liver (8053,11477). Symptoms tend to improve over time, however some individuals may still experience symptoms up to 2 years after the onset of EMS and complete resolution of symptoms may not occur (8053,10287).
There is some evidence of an association between L-tryptophan-related EMS and the occurrence of chronic B-cell lymphocytic leukemia (8055).

Ocular/Otic ...Orally, L-tryptophan can cause side effects such as visual blurring (10853).

Pulmonary/Respiratory ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include respiratory symptoms such as dyspnea and cough (8053,11477).

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General ...Orally, niacinamide is well tolerated in amounts typically found in food. When used topically and orally in higher doses, niacinamide seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Dizziness, drowsiness, itching, gastrointestinal disturbances, headache, and rash.
Topically: Burning sensation, itching, and mild dermatitis.

Dermatologic ...Orally, large doses of niacinamide are associated with occasional reports of rashes, itching, and acanthosis nigricans (4880,11695,11697,14504,107709). Topically, application of niacinamide in a cream has been reported to cause a burning sensation, itching and pruritus, crusting, and mild dermatitis (93357,93360,110501,110498).

Endocrine ...Orally, niacinamide in high doses, 50 mg/kg daily, has been associated with modestly higher insulin requirements in patients with type 1 diabetes, when compared with taking niacinamide 25 mg/kg daily. Theoretically, high-dose niacinamide might increase insulin resistance, although to a lesser extent than niacin (4881,14512).

Gastrointestinal ...Orally, large doses of niacinamide can cause gastrointestinal disturbances including nausea, vomiting, heartburn, anorexia, epigastric pain, flatulence, and diarrhea (6243,11694,11695,11696,11697,107709).

Hematologic ...Orally, niacinamide supplementation might increase the risk for thrombocytopenia in patients undergoing hemodialysis (98940,107709). A meta-analysis of small clinical studies shows that taking niacinamide during hemodialysis to reduce phosphate levels is associated with a 2.8-fold increased risk for thrombocytopenia when compared with placebo. In one of the included studies, platelet levels returned to normal within 20 days after niacinamide discontinuation (98940).

Hepatic ...Orally, older reports of elevated liver function tests with high doses of niacinamide (3 grams or more daily) have raised concerns about liver toxicity. However, newer studies have not reported this concern; it is possible that some of these cases were due to contamination with niacin (4880,11694,11695,14503).

Neurologic/CNS ...Orally, large doses of niacinamide can cause dizziness, drowsiness, and headaches (11694,11695,11696,11697,107709).

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General ...Orally, rhodiola seems to be well tolerated.
Most Common Adverse Effects:
Orally: Dizziness, increased or decreased production of saliva.

Gastrointestinal ...Orally, rhodiola extract may cause dry mouth or excessive saliva production (16410,16411).

Neurologic/CNS ...Orally, rhodiola extract can cause dizziness (16410).

(Read more about RHODIOLA)