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POSSIBLY EFFECTIVE

• Cognitive function. Oral L-theanine may improve some aspects of cognitive function. It is unclear if using L-theanine in conjunction with caffeine can enhance the effects of either ingredient. Details: A single dose of L-theanine 100 mg seems to improve vigilant attention, reducing error rates in cognitive tests when compared with placebo (91747). However, taking L-theanine (Suntheanine, Taiyo Kagaku) 200 mg daily for 4 weeks does not improve verbal fluency, memory, motor speed, or executive function in an adult population, although it may moderately improve verbal fluency in a subgroup of people with lower cognitive function at baseline (101986). When L-theanine is combined with caffeine, a meta-analysis and multiple individual clinical studies show that the combination improves alertness, as well as accuracy during a test that requires switching attention between different tasks, but does not improve reaction time (38116,91750,96335,96336). Some research also shows that L-theanine plus caffeine improves cognitive performance and reduces task-induced fatigue when compared with baseline and placebo. However, it is unclear if this is due to the individual ingredients or the combination (38116,96335,96336). Some research suggests that the combination is no better than either individual ingredient alone (91747,96335,96336).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral L-theanine, taken continuously or as a single dose, improves cognition in older adults. Details: A small clinical study in healthy, Japanese adults aged 50-69 years shows that taking a specific product (Suntheanine; Taiyo International.) containing L-theanine 101 mg daily after breakfast for 12 weeks does not improve mini-mental state exam (MMSE) scores when compared with placebo. However, a single-dose analysis from this study shows that administration of L-theanine 101 mg may improve the quality of working memory and reaction times during a cognitive function test when compared with placebo (108553). Patients were permitted to consume polyphenol-rich beverages during the study period; however, consumption was not documented, limiting the validity of this finding.
• Alzheimer disease. Although there is interest in using oral theanine for Alzheimer disease, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Anxiety. It is unclear if oral L-theanine is beneficial in patients with anxiety. Results of clinical research are conflicting. Details: A preliminary clinical study shows that taking a single dose of a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg does not reduce experimentally-induced anticipatory anxiety when compared with placebo (12188). However, another preliminary clinical study in healthy adults with stress-related anxiety shows that taking L-theanine 200 mg daily for 4 weeks reduces anxiety scale scores and sleep disturbance when compared with placebo (101986).
• Attention. It is unclear if oral theanine improves attention. Details: A small clinical study in healthy males shows that taking a single dose of L-theanine 200 mg improves selective attention similar to a single dose of caffeine 160 mg (96337). However, other small clinical studies in adults show that taking L-theanine 100-400 mg does not improve most measures of attention, especially sustained attention or attention in executive control tasks, but doses of 100-200 mg may improve performance in simple attentional tasks when compared with placebo (96338,111396). Some of these studies suggest that taking L-theanine with caffeine appears to provide more benefit than either individual ingredient alone (96337,96338).
• Attention deficit-hyperactivity disorder (ADHD). Oral L-theanine seems to improve some aspects of ADHD, including cognition and sleep. Details: Some preliminary clinical research in children with ADHD shows that taking a one-time dose of L-theanine 2.5 mg/kg increases cognition scores, but does not improve results on sustained attention or inhibitory control tests, when compared with placebo. Taking L-theanine with caffeine 2 mg/kg also increases cognition scores and improves performance on a sustained attention test, but does not improve inhibitory control, when compared with placebo (104141). Other preliminary clinical research in males aged 8-12 years with ADHD shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg orally twice daily for 6 weeks increases the percent of time spent in restful sleep by about 5% and decreases the number of bouts of nocturnal activity by about 6 when compared with placebo (91744).
• Cancer. Although there is interest in using oral theanine for cancer, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Chemotherapy-induced diarrhea. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with colon cancer shows that taking L-cystine 700 mg and L-theanine 280 mg (Ajinomoto Co. Inc.) orally once daily, starting one week before chemotherapy with TS-1 (Taiho Pharmaceutical) and continuing for 28 days, increases the rate of therapy completion by 49%, reduces the incidence of diarrhea by 37%, reduces appetite loss by 33%, and improves the reported tolerability of chemotherapy when compared with chemotherapy alone (96334). However, this combination does not appear to be beneficial in patients with gastric cancer, or in those with colorectal cancer receiving 4 courses of capecitabine-based adjuvant chemotherapy. (96334,101985).
• Cognitive impairment. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One very small clinical study in adults with mild cognitive impairment shows that taking a product containing L-theanine 120 mg and green tea extract 720 mg (LGNC-07, LG Household & Health Care, Ltd) orally twice daily after meals for 16 weeks modestly improves memory and attention when compared with baseline. However, taking this product does not appear to improve memory and attention when patients with self-reported memory problems, but without mild cognitive impairment, are also considered (96339).
• Depression. It is unclear if oral L-theanine is beneficial in patients with depression. Details: A small clinical study shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku Co. Ltd.) 250 mg orally at bedtime for 8 weeks reduces symptoms and improves sleep quality when compared to baseline in individuals with mild major depressive disorder (MDD) (96331). The validity of these findings is limited by the lack of a comparator group.
• Erythema. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy females with self-perceived skin sensitivity shows that taking a specific supplement containing L-theanine, ashwagandha, and saffron (InnerCalm, Arbonne) daily for 8 weeks reduces facial pigmentation when compared to baseline (111399). The validity of this finding is limited by a lack of a placebo group. It is unclear if these effects are due to L-theanine, other ingredients, or the combination.
• Generalized anxiety disorder (GAD). It is unclear if oral L-theanine is beneficial for reducing anxiety in people with GAD. Details: One small clinical study in adults with GAD shows that taking L-theanine 225 mg twice daily for 4 weeks, then 450 mg twice daily for 4 weeks, in conjunction with prescribed antidepressants, does not reduce anxiety scores when compared with antidepressants and placebo (104976).
• Hypertension. Although there is interest in using oral theanine for hypertension, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Influenza. Oral L-theanine 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 green tea catechins (THEA-FLAN 90S, Ito-en Co.) 378 mg, standardized to contain epigallocatechin gallate 270 mg and L-theanine (Suntheanine, Taiyo Kagaku) 210 mg daily for 5 months reduces the risk of developing clinically diagnosed influenza when compared with placebo. However, the combination does not seem to prevent laboratory-confirmed influenza infection (54021).
• Insomnia. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with insomnia or disturbed sleep patterns shows that a specific product (RLX2; LiveLife Biosciences AG) containing L-theanine 50 mg and a specific casein peptide, alpha-s1-casein tryptic hydrolysate, 150 mg, taken one hour before bedtime for 4 weeks, increases sleep duration by 45 minutes and improves habitual sleep efficiency and daytime dysfunction when compared with baseline. However, it does not affect blood pressure, heart rate, or cortisol levels (108556). Another very small clinical study in healthy adults shows that taking a combination product containing tryptophan, glycine, magnesium, tart cherry powder, and L-theanine 2 hours before bedtime decreases sleep onset latency and increases total sleep duration, leading to better sleep efficiency and reduced morning sleepiness, when compared with placebo (111184). Another combination product containing L-theanine, ashwagandha, and saffron (InnerCalm, Arbonne), taken daily for 8 weeks, seems to improve sleep quality when compared to baseline (111399). However, the validity of this finding is limited by a lack of a control group. It is unclear if the effects described above are due to L-theanine, other ingredients, or the combination.
• Postoperative recovery. Oral theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study of adults with esophageal cancer undergoing esophagectomy shows that taking theanine 280 mg and cystine 700 mg daily, staring 4 days before surgery and continued for 13 days after surgery, does not improve measures of physical activity but does improve exercise tolerance and some measures of quality of life when compared with placebo (111400). It is unclear if these findings are due to theanine, cystine, or the combination.
• Schizophrenia. It is unclear if oral L-theanine is beneficial in patients with schizophrenia; the available evidence is limited and conflicting. Details: One preliminary clinical study in adults with schizophrenia or schizoaffective disorder shows that taking L-theanine (Biosynergy) 200 mg orally twice daily for 8 weeks along with antipsychotic medications improves positive symptoms, anxiety, and general psychopathology symptoms, such as poor impulse control and disorientation, when compared with placebo. However, theanine does not improve general disease severity, negative symptoms, depression, cognitive function, extrapyramidal side effects, or quality of life (96341). Another small clinical study shows that taking L-theanine 400 mg (Suntheanine, BioSynergy Health Alternatives) with pregnenolone 50 mg daily for 8 weeks, in addition to antipsychotic medications, improves negative symptoms, general psychopathology symptoms, and anxiety when compared with placebo in patients with schizophrenia or schizoaffective disorder. However, there were no improvements in positive schizophrenia symptoms or extrapyramidal side effects (97923). The inconsistency of results might be due to the small study sizes and the subjectivity of the outcomes measured.
• Stress. It is unclear if oral L-theanine is beneficial in patients with stress. Details: One very small clinical study shows that taking L-theanine 200 mg prior to a stress-inducing exam reduces tension-anxiety and may prevent blood pressure increases caused by psychological stress when compared with placebo (91746). Other preliminary clinical research in pharmacy students shows that taking theanine 200 mg twice daily for one week prior, and then for the first 10 days of a pharmacy practice period, decreases subjective stress scores when compared with placebo (91745). Another small clinical study in healthy young adults shows that drinking a beverage containing L-theanine 200 mg alone or combined with L-arginine 50 mg after a psychological stressor reduces stress, as measured by salivary alpha-amylase activity, when compared with placebo. The combination of L-arginine and L-theanine did not differ from L-theanine alone, suggesting that the combination does not act synergistically to reduce markers of stress (110393). However, not all research has been positive. A small clinical study shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg induces subjective feelings of tranquility in relaxed people, but not those with experimentally-induced anticipatory anxiety, when compared with placebo (12188). Also, a small, clinical crossover study in healthy, moderately stressed adults shows that taking a single dose of a specific product (Alphawave; Ethical Naturals) containing L-theanine 200 mg prior to a stress-inducing exam does not improve anxiety at any time point when compared with placebo (108554). Due to the single-dose nature of this study, the effects of continued administration of this product are unclear. L-theanine has also been evaluated in combination with other ingredients. A small clinical study in adults with stress shows that taking a specific combination product (Mg-Teadiola, Sanofi-Aventis Group), containing green tea extract 125 mg (providing 50 mg L-theanine), magnesium 150 mg, vitamin B6 0.2 mg, vitamin B9 0.1 mg, vitamin B12 1.25 mcg, and rhodiola 222 mg, orally once daily for 28 days modestly improves stress and anxiety scores when compared with placebo. Improvements in stress scores, but not anxiety scores, appear to persist at 28 days after treatment completion (108672). It is unclear if any effects are due to L-theanine, other ingredients, or the combination.
• Tourette syndrome. It is unclear if oral L-theanine is beneficial in children with Tourette syndrome. Details: A small, nonblinded clinical study in children aged 4-17 years with untreated Tourette syndrome or with chronic tic disorder and associated symptoms of anxiety shows that taking a liquid nutritional supplement providing L-theanine 200 mg and vitamin B6 2.8 mg daily for 2 months improves scores on the Yale Global Tic Severity Scale, but does not reduce anxiety, when compared with patients receiving psychoeducation (108555). This study may have been inadequately powered to detect a difference between groups. More evidence is needed to rate theanine for these uses.

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EFFECTIVE

• Vitamin C deficiency. Oral or intramuscular vitamin C is effective for preventing or treating vitamin C deficiency. Details: Administering vitamin C orally or intramuscularly prevents and treats vitamin C deficiency, including scurvy. Vitamin C administration can reverse complications of scurvy within 2 days to 3 weeks (4844). In newborns with transient tyrosinemia due to vitamin C deficiency, oral or intramuscular vitamin C can correct this condition (15).

POSSIBLY EFFECTIVE

• Anemia of chronic disease. Oral vitamin C seems to improve markers of anemia in patients on hemodialysis. Details: Meta-analyses of clinical research in hemodialysis patients with anemia shows that treatment with vitamin C 200-300 mg three times weekly for 3-6 months increases hemoglobin levels by approximately 0.9 grams/dL, increases transferrin saturation by about 8%, and decreases the required recombinant human erythropoietin dose by 17 U/kg weekly when compared with standard care (83447,83475).
• Atrial fibrillation. Oral and intravenous vitamin C seems to help prevent atrial fibrillation after cardiac surgeries. Details: Meta-analyses of clinical research show that taking vitamin C prior to and after cardiac surgery reduces the risk of postoperative atrial fibrillation by 27% to 53%. Most studies administered vitamin C at doses of 1-2 grams orally daily for 1-3 days prior to cardiac surgery, followed by 1-2 grams in two divided doses daily for 4-5 days after cardiac surgery. Some studies provided vitamin C intravenously at similar doses, but oral vitamin C seems to be more effective (91233,96703,96705). Despite these findings, a meta-analysis of clinical research conducted only in the U.S. does not support the benefit of vitamin C for reducing postoperative atrial fibrillation (96703). These differences may be related to lifestyle factors such as nutrition, as well as differences in hospital treatments. Vitamin C has also been studied in combination with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with evidence of benefit (90701).
• Bowel preparation. Powdered vitamin C is approved for use as part of a polyethylene glycol-based bowel preparation for colonoscopy. Details: Clinical research shows that treatment with 2 liters of oral solution containing polyethylene glycol (PEG) plus vitamin C achieves a similar quality of bowel cleansing as treatment with 4 liters of PEG when administered on the evening prior to colonoscopy or when administered in a split-dose regimen. Patients given 2 liters of PEG plus vitamin C solution also have better adherence and experience fewer adverse events, such as nausea, vomiting, or abdominal bloating, compared to patients treated with 4 liters of PEG solution without vitamin C (90413,90415,90420,90424,90428). This treatment also appears to be effective and tolerable in elderly patients aged 60-79 years, including those with poor bowel habits and a high number of comorbidities (108085). Other clinical research in older adults undergoing bowel preparation for colonoscopy also shows that taking 1 liter of PEG plus vitamin C (CleanViewAL, Taejoon Pharm) results in similar quality of bowel cleansing overall and per segment with similar tolerability and adverse effects as sodium picosulfate 170 mL plus magnesium citrate or oral sulfate solution alone (111297,112476). The most common PEG plus vitamin C preparation used in clinical research is MoviPrep (Norgine BV), which contains macrogol 3350 100 grams, sodium sulfate 7.5 grams, sodium chloride 2.7 grams, potassium chloride 1 gram, vitamin C 4.7 grams, and sodium ascorbate 5.9 grams per liter of solution (90413,90415,90424). In the U.S., MoviPrep is approved by the Food and Drug Administration (FDA) for bowel preparation prior to a colonoscopy.
• Common cold. Oral high-dose vitamin C might modestly reduce cold symptoms; however, taking vitamin C prophylactically does not seem to prevent the development of a cold. Details: There is substantial controversy about the effectiveness of vitamin C for treating the common cold (1969,1989,7100,9835,9836). The majority of evidence shows that taking high doses of vitamin C orally might decrease the duration of cold symptoms by 1-1.5 days in some patients (1966,1967,1968,1987,6458,7102,9832,83487). However, other studies have found no effect with doses up to 3 grams daily (9833). A meta-analysis of clinical research suggests that vitamin C supplementation decreases the incidence of cold in individuals exposed to physical stress, but not in the general population (83487). Other research suggests vitamin C may be more effective for treating cold symptoms in children than in adults. Also, there may be a dose-dependent response; doses of at least 2 grams daily seem to work better than 1 gram doses (9834). Taking vitamin C supplements prophylactically does not decrease the risk of catching a cold (1966,1967,1968,1987,3042,6458,7101,9832). Dietary intake of vitamin C also does not seem to affect the risk of getting a cold (10780).
• Complex regional pain syndrome. Most research shows that taking oral vitamin C after a wrist or distal radius fracture or after orthopedic surgery seems to reduce the risk of developing complex regional pain. Details: Although some research has found no benefit in patients with distal radius (i.e. wrist) fractures (90411,96702), most clinical research shows that taking vitamin C 500 mg daily, and possibly doses of up to 1500 mg daily, for 45-50 days beginning immediately after fracture can reduce the risk of developing complex regional pain syndrome (2045,16302,96700,96706). Reasons for discrepancies are unclear but might relate to differences in diagnostic criteria for complex regional pain syndrome (96702). Research in patients undergoing orthopedic surgery has also shown benefit with the use of vitamin C for the prevention of complex regional pain syndrome (90422,108076,108087). One meta-analysis of clinical research in patients undergoing wrist, foot, or ankle surgery shows that taking vitamin C 500-1000 mg for 42-50 days following surgery reduces the rate of complex regional pain syndrome, and may improve pain following ankle or foot surgery, when compared with placebo (108076). The validity of these findings is limited by the high heterogeneity of included trials. Another meta-analysis of clinical research in patients undergoing orthopedic surgery (i.e. wrist, knee, ankle, foot, lumbar, rotator cuff) suggests that oral and intravenous vitamin C may have similar effectiveness; however, this evidence is low quality (108087).
• Exercise-induced respiratory infections. High-dose oral vitamin C seems to reduce the risk of respiratory infections associated with strenuous exercise. Details: Some preliminary clinical research suggests that prophylactic use of vitamin C in doses of 600 mg to 1 gram daily for 3-8 weeks before heavy physical exercise, such as a marathon, might prevent upper respiratory infections that sometimes follow heavy exercise (9831,83370). More recently, high doses of vitamin C have been studied. A large clinical study in army recruits undergoing basic military training shows that taking vitamin C 6 grams daily for one month reduces the odds of getting a cold by 20% when compared with placebo (102975).
• Hypercholesterolemia. Oral vitamin C seems to reduce lipid levels in patients with hypercholesterolemia. Details: A meta-analysis of clinical research in patients with hypercholesterolemia shows that taking vitamin C 500 mg daily for at least 4 weeks reduces low-density lipoprotein (LDL) cholesterol by about 8 mg/dL and reduces triglycerides by about 20 mg/dL when compared with control (83445).
• Hypertension. Oral vitamin C seems to modestly reduce blood pressure in patients with hypertension. Details: Vitamin C seems to modestly reduce systolic blood pressure, without meaningful effects on diastolic blood pressure (2044,9822,13162,83483,102974). A meta-analysis of 13 clinical trials in patients with hypertension, with or without other comorbidities, shows that taking a median dose of vitamin C 500 mg daily for 8 weeks reduces systolic, but not diastolic, blood pressure by about 5 mmHg. Some of the studies used vitamin C in combination with other supplements, such as vitamin E and magnesium. When studies assessing vitamin C alone were analyzed, the magnitude of reduction in systolic blood pressure decreased (83483). A newer meta-analysis of small clinical studies in patients with essential hypertension shows that taking vitamin C 200 mg or more daily reduces systolic blood pressure by about 4 mmHg and diastolic blood pressure by about 2 mmHg (102974). However, this newer analysis omitted numerous relevant studies and included studies with normotensive patients and those without an adequate control, limiting the validity of its findings.
• Laser skin resurfacing. Topical vitamin C seems to reduce erythema occurring after cosmetic laser skin resurfacing procedures intended to reduce scars and wrinkles. Details: There is some evidence that an aqueous formulation of topical vitamin C can decrease the degree and duration of erythema following cutaneous carbon dioxide laser resurfacing for scar and wrinkle removal (1959).
• Lead toxicity. Dietary vitamin C seems to lower concentrations of lead in the blood. Details: Observational research has found that consuming more vitamin C from dietary sources is associated with lower blood concentrations of lead. People who consumed at least 340 mg of vitamin C daily as part of the diet had lower blood lead levels than those who consumed less than 100 mg vitamin C daily (3097,3098,3099).
• Nitrate tolerance. Oral vitamin C might prevent nitrate tolerance in some patients. Details: Small clinical studies show that taking vitamin C orally seems to prevent the development of nitrate tolerance in patients taking sublingual nitroglycerin. There is some evidence that short-term vitamin C supplementation can prevent tolerance to the vasodilatory effects of nitrates (1441,1961).
• Postoperative pain. Oral or intravenous vitamin C might prevent acute postoperative pain following certain surgeries. It is unclear if vitamin C reduces chronic postoperative pain. Details: A meta-analysis of 7 small clinical studies in adults undergoing elective surgery shows that receiving perioperative vitamin C, either as 1 gram orally, 2-3 grams intravenously, or 50 mg/kg intravenously, modestly reduces acute pain and opioid requirements for up to 24 hours when compared with control (105457). Most surgeries were laparoscopic and included cholecystectomy, colectomy, hysterectomy; two non-laparoscopic surgeries included uvulopalatopharyngoplasty with tonsillectomy and major abdominal surgery (90418,99840,105457). A meta-analysis of clinical trials in adults undergoing noncardiac surgery (i.e., orthopedic, abdominal, gynecologic, kidney transplantation) shows that administering perioperative vitamin C, either orally or intravenously, reduces postoperative intravenous morphine requirements at 2, 24, and 48 hours after surgery and improves pain scores at 2, 6, and 24 hours after surgery when compared with placebo. The dose of vitamin C did not appear to impact outcomes. However, when only laparoscopic surgeries are included, perioperative vitamin C does not improve pain or morphine use when compared with placebo (108087). A moderate-sized clinical study in adults undergoing transurethral resection of a bladder tumor under general anesthesia shows that administering intravenous vitamin C 1 gram after induction of anesthesia reduces the incidence and severity of catheter-related bladder discomfort immediately after surgery and at 1 and 2 hours postoperatively, but not 6 hours, when compared with placebo. However, vitamin C does not reduce postoperative pain scores or analgesic requirements when compared with placebo (111645). Further research is needed to determine the effects of vitamin C for acute postoperative pain. Vitamin C has also been evaluated for reducing chronic pain after surgery. Clinical research in patients undergoing surgery for foot or ankle trauma shows that taking vitamin C 500 mg orally twice daily postoperatively for 6 weeks reduces pain scores when compared with placebo at 2 weeks and 6 weeks. The mean total amount of diclofenac used for pain relief over the 6-week period is also reduced, from 5.7 grams with placebo to 3.4 grams with vitamin C (102131).
• Wrinkled skin. Topical vitamin C might reduce the appearance of existing wrinkles. Details: Topical preparations containing vitamin C seem to improve the appearance of wrinkled skin. Some evidence shows that vitamin C 3% applied for 12 weeks might reduce facial wrinkles (14008). A small clinical study shows that applying a dissolving microneedle patch containing vitamin C 5.6% every 4 days for 12 weeks to crow's feet on one side of the face reduces wrinkles when compared to control treatment applied on the other side of the face (98780). Other clinical research in females aged 30-60 years shows that applying an oil-soluble cream containing the vitamin C derivative tetra-isopalmitoyl ascorbic acid 1%, 2%, or 3% to the periorbital area twice daily for 8 weeks reduces visual wrinkle grading when compared with placebo. A dose analysis shows greater improvements in wrinkle parameters, average wrinkle depth, and mean depth with the lower concentration, while greater improvements in maximum roughness and maximum depth are observed with the higher concentration (108072). This study only included individuals defined as having Fitzpatrick skin type III or IV; it effects on other skin types is unclear. Preparations containing vitamin C in combination with other ingredients have also been investigated. A small low-quality trial in females with moderately photodamaged and hyperpigmented facial skin shows that applying a moisturizer with vitamin C 30%, vitamin E, and coenzyme Q10 once daily in the morning, along with applying retinol 0.5% once daily or once every other day for 12 weeks, seems to improve skin tone, photodamage, and wrinkles when compared to baseline (99085). In another small trial, a topical preparation containing vitamin C 10% as L-ascorbic acid along with acetyl tyrosine, zinc sulfate, sodium hyaluronate, and bioflavonoids (Cellex-C High Potency Serum) applied to photo-aged facial skin for 3 months improves fine and coarse wrinkling, yellowing and sallowness, roughness, and skin tone when compared with placebo (6155). It is unclear if the beneficial effects of these products are due to vitamin C, other ingredients, or the combination.

POSSIBLY INEFFECTIVE

• Acute bronchitis. Oral vitamin C doesn't seem to improve symptoms of acute bronchitis. Details: A clinical study in adults with acute bronchitis shows that taking vitamin C orally 500 mg on day 1, then 250 mg on days 2 through 5 (similar to an azithromycin regimen) doesn't seem to have any effect on quality of life or bronchitis duration when compared with azithromycin (9827).
• Asthma. Oral vitamin C doesn't seem to prevent asthma or improve lung function. Details: Although some observational research has found that some patients with asthma might have lower serum vitamin C levels (5873), other observational research found that increased dietary vitamin C intake is not associated with a reduced risk of asthma or improved lung function (15006,34567). In addition, clinical research shows that supplemental intake of vitamin C does not reduce asthma symptoms, improve lung function, or reduce the use of inhaled steroids in asthma patients (90409).
• Atherosclerosis. Oral vitamin C does not seem to reduce the progression of atherosclerosis. Details: A clinical study shows that taking a specific combination product containing slow-release vitamin C 250 mg and vitamin E 136 IU (CellaVie, Ferrosan A/S) twice daily modestly slows the 3-year progression of atherosclerosis of the carotid artery in males, but not females. This result persisted at a 6-year follow-up of this study (1918,10473). However, when this form of vitamin C is used alone, it does not slow the 3-year progression of atherosclerosis of the carotid artery (1918).
• Bladder cancer. Oral vitamin C does not reduce the risk of bladder cancer or mortality from bladder cancer. Details: Epidemiological research has found that supplemental vitamin C intake is not associated with mortality rate in patients with bladder cancer (9839). A secondary analysis of a large clinical trial, the Physicians' Health Study II, in healthy men aged at least 50 years also shows that taking vitamin C 500 mg daily alone or with vitamin E 400 IU daily for up to 10 years does not reduce the risk of developing bladder cancer or bladder cancer-related deaths when compared with placebo (90097).
• Cardiovascular disease (CVD). Oral vitamin C does not seem to be beneficial for either primary or secondary CVD prevention. Details: Vitamin C does not seem to be beneficial for primary prevention of CVD. Some population research has found that higher supplemental vitamin C or dietary vitamin C has been associated with a reduced risk of developing CVD (10358,14108,109779), while other observational research has found no benefit (34566,10358,14108). However, meta-analyses of clinical research in healthy patients show that vitamin C supplementation does not prevent CVD or coronary heart disease when compared with control (97308,104025). In 2004, the American Heart Association stated that current evidence does not justify use of antioxidants such as vitamin C for reducing the risk of CVD (12142). Evidence is also negative for secondary prevention in people with coronary heart disease. Population studies have found that higher serum vitamin C was associated with no effect or decreased CVD mortality from CVD (3910,5878). A meta-analysis of two large clinical trials shows that vitamin C supplementation does not reduce CVD events or CVD mortality when compared with control (97308).
• Colorectal cancer. Oral vitamin C does not seem to prevent colorectal cancer. Details: Population research has found that dietary vitamin C intake is not associated with a reduced risk of developing colon cancer. When total vitamin C intake from food and supplements is considered, there is a modest association (34600). However, most clinical trials show that supplemental vitamin C, alone or along with other antioxidants, does not reduce the risk of colorectal cancer development, colorectal cancer or adenoma recurrence, or colorectal cancer-related mortality (34580,34581,34594,90097,90089,92903).
• Coronavirus disease 2019 (COVID-19). Oral vitamin C, even at high doses, does not seem to speed recovery from COVID-19 in non-hospitalized patients. An analysis of clinical research suggests that oral or intravenous vitamin C might reduce mortality in patients hospitalized with COVID-19; however, given that nearly all individual studies are small and do not show benefit, larger and higher-quality studies are needed to confirm these findings. Details: A clinical study in adult outpatients with confirmed COVID-19 shows that taking oral vitamin C (ascorbic acid) 8000 mg in 2-3 divided doses daily, alone or with zinc gluconate 50 mg daily, for 10 days does not reduce symptom severity when compared with standard care (104450). The study was terminated prior to complete enrollment due to futility and apparent lack of effect from vitamin C and/or zinc supplementation. Limitations of this study include a lack of placebo control and blinding. Additionally, this study has been criticized for methodologic concerns (106624). Another small clinical trial in adult outpatients with confirmed COVID-19 shows that taking vitamin C 1000 mg daily for 14 days does not improve symptoms or quality of life when compared with placebo (109462). Vitamin C has also been evaluated in patients hospitalized with COVID-19. Individual prospective and retrospective studies in critically ill patients hospitalized with COVID-19 in various countries have found that administering vitamin C, either enterally as 500-1000 mg daily or intravenously as 8-24 grams daily or 50 mg/kg daily, does not significantly reduce in-hospital or short-term mortality, hospital length of stay, or end-organ failure when compared with control groups receiving standard care alone. Additionally, all but one study found no change in the need for mechanical ventilation (105458,105465,106937,106938,108075,108079,108081). One small study found a small improvement in survival rate when compared with standard care; however, the overall survival rate in this study was low (108075). Additionally, one clinical study in patients hospitalized in Turkey with COVID-19 shows that adding high-dose intravenous sodium ascorbate 50 mg/kg to a treatment regimen of hydroxychloroquine, azithromycin, and zinc may improve recovery time, with 57% and 39% of patients achieving total recovery at day 15 in the vitamin C and control groups, respectively (108071). However, the validity of this trial is limited due to unclear reporting. Additionally, these small studies were likely underpowered to detect differences between the vitamin C and control groups. A meta-analysis of 10 clinical trials and 9 observational studies in patients hospitalized with COVID-19 shows that receiving oral or intravenous vitamin C daily reduces the odds of in-hospital mortality by 41% when compared with control. When only clinical trials were considered, the odds of in-hospital mortality were decreased by 56%; however, this reduction was only identified in studies using vitamin C 10 grams daily or less. Conversely, supplementation with vitamin C increased the length of intensive care unit (ICU) stay by nearly 2 days and did not impact length of hospital stay or reduce the need for mechanical ventilation, liver injury, or cardiac injury (109955). Given that most individual studies in this analysis did not show improvements in mortality with vitamin C, larger and higher-quality prospective studies are needed to determine the role of vitamin C in hospitalized patients with COVID-19. Vitamin C has also been evaluated in patients with long COVID. Preliminary clinical research in adults with long COVID and persistent fatigue shows that taking a specific combination product containing vitamin C 500 mg and L-arginine 1.66 grams (Bioarginina C, Farmacetici Damor) for 28 days increases 6-minute walk test distance by 10% and reduces self-reported fatigue when compared with placebo (110390).
• Fetal and premature infant mortality. Oral vitamin C does not seem to prevent neonatal death. Details: Meta-analyses of clinical research show that taking vitamin C alone or with other supplements does not reduce the risk of neonatal death (83472,96707).
• Fractures. Oral vitamin C does not seem to improve fracture healing. Details: Clinical research shows that taking vitamin C 500 mg daily for 50 days following an acute distal radial fracture does not improve physical function, symptoms, or healing rates when compared with placebo (90411).
• Helicobacter pylori. Oral vitamin C does not seem to improve eradication of H. pylori. Details: Most clinical research shows that treatment with vitamin C, alone or in combination with vitamin E, does not improve the eradication rate of H. pylori when taken with a standard eradication regimen when compared with the eradication regimen alone (83476,90094).
• Hereditary motor and sensory neuropathy. Oral vitamin C does not seem to improve neuropathy in these patients. Details: In a meta-analysis of five studies in patients with Charcot-Marie-Tooth disease type 1A, taking vitamin C 1-4 grams orally daily for 1 year did not improve neuropathy when compared with placebo (99084). Continuing vitamin C 4 grams daily for 2 years also does not improve neuropathy in these patients (90419).
• Interferon-related retinopathy. Oral vitamin C does not seem to improve retinopathy associated with interferon therapy. Details: A small clinical study in patients with chronic hepatitis C receiving interferon therapy shows that taking vitamin C 600 daily orally does not seem to reduce the risk of retinopathy from interferon therapy when compared with control (10355).
• Leukemia. Oral vitamin C does not seem to reduce the risk of leukemia or mortality from leukemia. Details: A large clinical trial in men aged at least 50 years shows that taking vitamin C 500 mg daily, alone or along with vitamin E 400 IU daily, for up to 10 years does not reduce the risk of developing leukemia or leukemia-related deaths when compared with placebo (90097).
• Low birth weight. Oral vitamin C does not seem to reduce the risk of infants being born with a low birth weight. Details: Meta-analyses of clinical research show that maternal use of oral vitamin C alone or with other supplements does not reduce the risk of giving birth to infants with low birth weight when compared with control (83450,83472).
• Lung cancer. Oral vitamin C does not seem to reduce the risk of lung cancer. Details: Two meta-analyses of clinical research suggest that taking vitamin C, alone or in combination with vitamin E, does not reduce the incidence of lung cancer or lung cancer-related mortality (34528,34632). Also, a clinical study in females shows that taking supplemental vitamin C 500 mg daily, with or without vitamin E and beta carotene, is associated with an INCREASED risk of lung cancer when compared with placebo (34580).
• Melanoma. Oral vitamin C does not seem to reduce the risk of melanoma. Details: Clinical research shows that taking vitamin C 500 mg daily, alone or along with vitamin E 400 IU daily, for up to 10 years does not reduce the risk of developing melanoma or melanoma-related deaths when compared with placebo in men aged at least 50 years (90097).
• Miscarriage. Oral vitamin C does not seem to reduce the risk of miscarriage. Details: A meta-analysis of clinical research shows that taking vitamin C alone or with other supplements does not reduce the risk of miscarriage when compared with control (94820).
• Overall mortality. Oral vitamin C does not reduce overall mortality. Details: Although population research suggests that higher dietary intake and higher plasma vitamin C levels are associated with a reduced risk of mortality from all causes (3910,109779), vitamin C supplementation does not seem to affect overall mortality. Meta-analyses of clinical research show that taking vitamin C supplements does not reduce overall mortality when compared with control (34622,111641). Clinical studies of vitamin C used in combination with vitamin E, beta carotene, and/or selenium and zinc, also show no benefit for overall mortality (9817,14109).
• Pancreatic cancer. Oral vitamin C does not seem to prevent pancreatic cancer. Details: Observational research has found that increased dietary vitamin C intake is associated with up to a 30% reduced risk of pancreatic cancer (99083,99086). However, clinical research shows that supplemental vitamin C 500 mg daily does not reduce the risk of pancreatic cancer in females (34580). Also, taking vitamin C in combination with beta-carotene plus vitamin E does not reduce the risk of pancreatic cancer (12185,34581).
• Pre-eclampsia. Oral vitamin C does not seem to prevent pre-eclampsia. Details: Despite some early positive research in high-risk pregnancies, the majority of meta-analyses and clinical studies show that taking vitamin C alone or with vitamin E or other supplements does not reduce the risk of pre-eclampsia when compared with control. There is even some concern that vitamin C supplementation may increase the risk of gestational hypertension (3236,83450,83472,83474,96707).
• Preterm labor. Oral vitamin C does not seem to prevent preterm labor. Details: Meta-analyses of clinical research show that taking vitamin C alone or with other supplements does not reduce the risk of preterm labor when compared with control (83450,83472,96707).
• Prostate cancer. Oral vitamin C does not seem to prevent prostate cancer. Details: A large-scale clinical study (The SU.VI.MAX study) shows that a combination of vitamin C 120 mg, vitamin E (alpha-tocopherol) 30 mg, beta-carotene 6 mg, selenium 100 mcg, and zinc 20 mg, taken daily for an average of 8 years, does not reduce the risk of prostate cancer overall. However, it might reduce the risk of prostate cancer in those who have normal PSA levels. It does not seem to be beneficial for reducing the risk of prostate cancer in patients with PSA levels above 3 mcg/L (14135). Another large scale study (Physician's Health Study II) shows that taking vitamin C 500 mg daily for an average of 8 years does not significantly reduce the risk of prostate cancer when compared with placebo (16708). Similarly, results from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial seem to show that supplemental or dietary intake of vitamin C does not reduce the risk of prostate cancer when compared to individuals not taking vitamin C (14124).
• Radiation dermatitis. Topical vitamin C does not seem to prevent radiation dermatitis in cancer patients. Details: A small clinical study shows that applying a 10% vitamin C solution does not appear to protect from radiation dermatitis when applied to the scalps of patients treated with radiation for intracranial tumors (789).
• Small for gestational age (SGA). Oral vitamin C does not seem to reduce SGA. Details: Meta-analyses of clinical research show that taking vitamin C alone or with other supplements does not reduce the risk of small for gestational age birth when compared with control (83450,83472).
• Stillbirth. Oral vitamin C does not seem to prevent stillbirth. Details: Meta-analyses of clinical research show that maternal use of vitamin C alone or with other supplements does not reduce the risk of stillbirth when compared with control (83472,96707).

LIKELY INEFFECTIVE

• Sepsis. Intravenous vitamin C, alone or in combination with thiamine and/or hydrocortisone, does not prevent organ failure, reduce intensive care or hospital length of stay, or reduce mortality in sepsis or septic shock. Details: Observational research suggests that patients with septic shock are more likely to have low plasma levels of vitamin C (100317). However, two randomized clinical trials in patients with sepsis show no benefit with intravenous vitamin C, with or without thiamine, for improving organ function and preventing organ failure when compared with control treatment (102130,104027). A clinical study in patients with septic shock shows that administering an intravenous bolus of vitamin C 1000 mg followed by a continuous infusion of 250 mg/hour for 96 hours, starting within 24 hours of vasopressor initiation, does not improve 28-day or intensive care unit (ICU) mortality when compared with placebo. A subgroup analysis shows that the addition of corticosteroids does not affect outcomes in either group (108078). This study may have been inadequately powered to detect a difference between groups. Also, a larger clinical trial in adults with sepsis receiving vasopressor therapy in the ICU shows that intravenous administration of vitamin C 50 mg/kg every 6 hours for up to 4 days increases the risk of death or persistent organ dysfunction at day 28 by 14% to 21% when compared with placebo. There were no differences in mortality at 6 months (109459,111643). Vitamin C has also been frequently studied in patients with sepsis and septic shock in a specific combination regimen (HAT therapy) which includes intravenous vitamin C 1.5-2 grams with hydrocortisone 50 mg every 6 hours and thiamine 200 mg every 12 hours. While some retrospective research has found HAT therapy to be beneficial in sepsis (100315,102980), high quality, prospective clinical research has not confirmed these findings (105447,106620,109956). Several meta-analyses of randomized controlled trials and small clinical studies in patients with sepsis or septic shock show that intravenous vitamin C, either alone, as a component of HAT therapy, or in combination with thiamine, does not reduce short- or long-term mortality, ICU or hospital length of stay, kidney injury, or duration of mechanical ventilation, but modestly improves duration of vasopressor use and procalcitonin clearance, when compared with placebo or standard care. These analyses also show mixed results with respect to improvement in sequential organ failure assessment (SOFA) scores within 72 hours (105447,106620,106935,108073,109460,111298,111300,111301,111642,112479). Most studies included in the analyses administered HAT therapy for 2-10 days and compared it with normal saline control or with hydrocortisone alone (102129,102998,104027,104028,104032,105446). Although some subgroup analyses suggests that intravenous vitamin C alone in patients with sepsis may improve short-term mortality (106620,111298), other meta-analyses have not shown this benefit in subgroup analyses (111300). In addition, meta-analyses have identified significant publication bias (111298,111300). Long-term follow up from a study in patients with sepsis-induced respiratory and/or cardiovascular dysfunction shows that receiving HAT therapy does not improve cognitive, psychological, or functional status after 6 months and, for some domains, HAT therapy was worse when compared with placebo (111299). Studies evaluating intravenous vitamin C, either alone, as a component of HAT therapy, or in combination with thiamine, in mixed critically ill populations have also shown mixed findings. One such large meta-analysis of 27 randomized controlled trials and 21 observational studies shows that intravenous vitamin C reduces in-hospital mortality by 19% and ICU stay by about 1 day, but does not have a significant effect on hospital stay, mortality at 1 month, ICU mortality, or kidney injury, when compared with placebo or standard care. Also, effects on in-hospital mortality were no longer significant when data from randomized controlled trials were considered alone (106933). Other meta-analyses including 15-16 randomized controlled trials show that intravenous vitamin C, alone or as a component of HAT therapy, does not reduce overall, ICU, or in-hospital mortality when compared with control (106934,109957). A subgroup analysis in one of these analyses suggests that intravenous vitamin C as monotherapy, or in doses of at least 10 grams daily, may improve overall mortality (106934). Vitamin C also does not appear to benefit complications from sepsis, such as vasoplegic shock. A small clinical study in adults in the ICU with vasoplegic shock mostly secondary to sepsis and requiring moderate vasopressor support shows that administering intravenous vitamin C as sodium ascorbate 1.5 grams every 6 hours for 5 days or until cessation of vasoactive therapy does not reduce the duration of vasopressors, vasopressor dose, hospital or ICU length of stay, or mortality outcomes when compared with placebo (112475).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atrophic acne scars. It is unclear if applying topical vitamin C after microblading improves atrophic acne scars. Details: A clinical study in adults with mild to severe atrophic acne scarring shows that applying a serum containing vitamin C 17% to the face after a once-monthly home microblade treatment for 4 months improves the appearance of acne scars at month 5 when compared with baseline (108086). Although this study enrolled a control group that used topical insulin in place of vitamin C, no between-group statistical comparisons were conducted, limiting the validity of this study.
• Age-related macular degeneration (AMD). Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Most clinical research shows that taking the antioxidants vitamin C 500 mg, vitamin E 400 IU, and beta-carotene 15 mg daily, with or without elemental zinc 80 mg, reduces the risk of visual acuity loss by 23% to 27% and reduces the risk of progression to advanced AMD at 5 years by 25% to 32% in patients at high risk for developing advanced AMD (7303,7304,11326,90069). The antioxidant plus zinc combination seems to reduce the risk of progression to advanced AMD in these patients more than taking the antioxidants without zinc (7303,90069). There is not enough evidence to know if taking the antioxidants or antioxidants plus zinc prevents progression to advanced AMD in patients with early stage AMD (7303,7304). The effect of vitamin C intake on developing AMD is unclear. Some population studies have found no association between dietary or supplemental vitamin C intake on risk of developing AMD (14007,14257). In one population study, vitamin C intake was associated with increased odds of developing age-related maculopathy (9823); however, in another population study, intake of vitamin C along with other antioxidants and zinc was associated with a reduced risk of AMD (14257). More evidence is needed to determine what role, if any, vitamin C intake has on the risk of developing AMD.
• Aging skin. Topical vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in females aged 30-65 years shows that applying a specific liquid (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) containing vitamin C 20%, red raspberry leaf cell culture extract 0.0005%, and vitamin E 1% to the face nightly for 8 weeks, in addition to regular facial skin products, improves skin color, elasticity, radiance, smoothness, and appearance of wrinkles when compared with regular facial skin products alone (102355).
• Albuminuria. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that taking vitamin C 1250 mg plus vitamin E 680 IU daily for 4 weeks can reduce the excretion of albumin by about 19% when compared with placebo in patients with type 2 diabetes (10434).
• Allergic rhinitis (hay fever). It is unclear if oral vitamin C is beneficial in patients with hay fever. Details: Epidemiological research has found that higher vitamin C plasma levels are not associated with a decreased risk of allergic rhinitis (15200). However, clinical research shows that some forms of vitamin C might help. In one small clinical study, intranasal vitamin C administered three times daily for 2 weeks reduces nasal secretions, nasal blockage, and edema in up to 74% of patients with perennial allergic rhinitis (15201). Another small clinical study in patients with seasonal allergic rhinitis shows that taking a single oral dose of vitamin C 2 grams reduces bronchial responsiveness to histamine at one hour after ingestion (15202). However, in another small study in patients with seasonal allergic rhinitis taking vitamin C orally in doses up to 4 grams daily for 3 days does not appear to suppress cutaneous or nasal response to histamine when compared to placebo (15203).
• Alzheimer disease. It is unclear if dietary vitamin C helps to prevent this condition. Details: Most epidemiological research has found that dietary intake of vitamin C is associated with a 17% reduced risk of developing Alzheimer disease (4636,9824,10131,13165,90082).
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if oral vitamin C helps to prevent ALS. Details: Observational research has found that increased dietary or supplemental intake of vitamin C is not associated with risk of developing ALS (90412).
• Anthracycline cardiotoxicity. Although there is interest in using oral vitamin C for anthracycline-induced cardiac toxicity, there is insufficient reliable information about the clinical effects of vitamin C for this condition.
• Aspirin-associated gastric damage. It is unclear if oral vitamin C helps to prevent gastric damage caused by aspirin. Details: Some clinical research shows that vitamin C 480 mg might prevent gastric damage associated with taking aspirin 400 mg by decreasing blood loss and preventing decreased gastric blood flow (10357). However, a small clinical study in healthy patients shows that taking vitamin C 500 mg as ascorbic acid with aspirin 600 mg actually increases gastrointestinal permeability to a greater extent than either ingredient taken alone (98781).
• Athletic performance. It is unclear if oral vitamin C improves athletic performance. Details: Although some small preliminary clinical studies suggest that vitamin C might improve certain biomarkers during exercise (82922), a meta-analysis of small clinical trials in older and younger adults shows that taking vitamin C 500-1000 mg daily, with or without vitamin E, does not improve endurance, lean mass, or muscle strength when compared with placebo (102973). A more recent, small clinical study in recreationally trained males shows that taking vitamin C 1000 mg and vitamin E (as alpha-tocopherol) 235 mg daily for 10 weeks while participating in a resistance training program does not improve measures of muscle strength when compared with placebo (109959).
• Atopic disease. It is unclear if dietary vitamin C helps to prevent atopic disease. Details: Population research has found that higher intake of vitamin C is not associated with a reduced risk of eczema, wheeze, IgE-mediated food allergy, or allergic sensitization (90098).
• Attention deficit-hyperactivity disorder (ADHD). Small clinical studies suggest that high-dose oral vitamin C may not improve symptoms in patients with ADHD. Details: Some research suggests that taking megadose vitamins, including vitamin C, does not improve ADHD symptoms (9957,9958,9959). However, other preliminary clinical research shows that taking 25 mg of vitamin C in combination with flaxseed oil providing alpha-linolenic acid 200 mg twice daily might improve measures of attention, impulsivity, restlessness, and self-control in children with ADHD when compared with baseline (14443). It is not clear if these effects are due to vitamin C, flaxseed oil, or the combination.
• Autism spectrum disorder. It is unclear if oral vitamin C is beneficial in patients with autism spectrum disorder. Details: One small clinical study shows that taking vitamin C 8 grams per 70 kg daily for 10 weeks modestly reduces autism symptom severity in school children when compared with placebo (83604).
• Bleeding. It is unclear if intravenous vitamin C can reduce bleeding after total abdominal hysterectomy. Details: A small clinical study in patients undergoing total abdominal hysterectomy shows that administration of intravenous vitamin C 1 gram the night before surgery and 1 gram during surgery reduces postoperative hemorrhage volume by around 40 mL when compared with placebo (109465).
• Brain tumor. It is unclear if oral vitamin C helps to prevent brain tumors. Details: Population research has found that vitamin C intake is associated with a 14% reduced risk of glioma. This risk reduction was more prevalent in America compared to other geographic locations (98782).
• Breast cancer. It is unclear if oral vitamin C helps to prevent breast cancer, its recurrence, or breast cancer-related mortality. Details: Some epidemiological research has found that dietary vitamin C is associated with a reduced risk of breast cancer (1444,10823,10824). However, other epidemiological research has found no association with dietary or supplemental vitamin C (10825,10826,108080). One cohort study found no association between breast cancer risk and total, dietary, or supplemental vitamin C, regardless of dose, treatment duration, or formulation (single ingredient or combination product). Additionally, hormone and menopausal status did not appear to impact risk. Vitamin C intake might be associated with a reduced risk in individuals with a family history of breast cancer in first-degree relatives (108080). In patients with breast cancer, supplemental or dietary intake of vitamin C might be associated with a reduced risk of mortality. A meta-analysis of results from population research shows that vitamin C supplementation following breast cancer diagnosis is associated with a 15% lower risk of breast cancer-related mortality when compared with no supplementation (90416). A large, observational study in patients with breast cancer undergoing radiation therapy has found that vitamin C supplementation does not reduce the risk of breast cancer recurrence over a period of 5 years when compared with no supplementation. Although the vitamin C group had notably less aggressive tumor types, recurrence-free survival was similar in both vitamin C and control groups (108082). The validity of these findings is limited due to unknown doses of vitamin C and the inclusion of various breast cancer subtypes.
• Burns. Small studies suggest that intravenous vitamin C may modestly improve symptoms in patients with severe burns. Details: A small clinical study in patients with severe burns shows that administering vitamin C intravenously (IV) 66 mg/kg hourly over 24 hours, as part of fluid resuscitation using lactated ringer solution, reduces wound edema and the volume of fluid needed when compared with fluid resuscitation alone (83145). A retrospective review of adults hospitalized with severe burns has found that those who receive a continuous IV infusion of at least 10 grams of vitamin C within 2 days of admission have an in-hospital mortality rate of 46%, compared with 58% for those who do not receive vitamin C (102128).
• Cancer. It is unclear if oral or intravenous vitamin C helps to prevent cancer or cancer-related mortality. Details: Some population research has found that DIETARY intake of vitamin C is linked with a lower risk of cancer and cancer-related mortality (3910,5878,10819,109779). However, clinical research shows that taking vitamin C SUPPLEMENTS does not reduce the risk for cancer (10819,14109,34580,90097). In people with cancer, although some clinical research has shown that taking high-dose vitamin C supplements can improve survival rates (9809,96704), other clinical research has not shown this benefit (4842,4843). In 2003, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that some scientific evidence suggests that antioxidant vitamins, such as vitamin C, may reduce the risk of certain forms of cancer. However, the FDA has determined that there is little scientific evidence supporting this claim (102334). Preliminary clinical research has also evaluated vitamin C supplements in patients with cancer. High-dose oral vitamin C, 10 grams daily, in patients with advanced cancer does not seem to improve survival or decrease disease progression (4842,4843,106617). However, preliminary clinical research suggests high doses of vitamin C, given intravenously, might have a beneficial effect on some outcomes, including survival rate in some patients with cancer (9809,96704,106617). However, there is no benefit to other patients studied in the case reports and this has not been tested in well-designed clinical trials (9809,96704).
• Carpal tunnel syndrome. Vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in adults with mild to moderate carpal tunnel syndrome shows that taking a combination product containing vitamins C, E, B1, B2, B6, and B12, alpha-lipoic acid, acetyl-L-carnitine, phosphatidylserine, and turmeric twice daily for 60 days reduces symptom severity and pain but does not improve measures of hand and wrist function when compared with control (111702). The validity of these effects is limited by a lack of blinding. The study may also be inadequately powered to detect a difference between groups. Additionally, it is unclear if the effects are due to vitamin C, other ingredients, or the combination.
• Cataracts. It is unclear if oral vitamin C helps to prevent cataracts. Details: Population research has found that people with the highest total intake of vitamin C have about a 19% reduced risk of developing cataracts when compared with those with the lowest total intake. The greatest benefit is observed for nuclear cataracts (96711). A separate study found that higher supplemental intake of vitamin C for 10 years is associated with a 60% reduction in the incidence of nuclear and cortical cataracts (4208). Other population research has found that the highest blood levels of vitamin C are associated with a 33% reduced odds of developing age-related cataract, but any benefit seems to be limited to Asian populations (90944). One prospective clinical study shows that taking vitamin C plus vitamin E and beta-carotene does not prevent the development or progression of age-related loss of vision due to cataracts in well-nourished people taking the supplement for an average of 6.3 years (7304).
• Cervical cancer. It is unclear if oral vitamin C helps to prevent cervical cancer. Details: Observational research has found that higher vitamin C intake is associated with a 33% to 42% reduced odds of cervical neoplasm. Increasing vitamin C intake by 50 mg daily is associated with an 8% reduced odds of cervical neoplasm (34609,98771).
• Chronic fatigue syndrome (CFS). Although there is interest in using oral vitamin C for CFS, there is insufficient reliable information about the clinical effects of vitamin C for this condition.
• Colistin-induced nephrotoxicity. It is unclear if intravenous vitamin C helps to prevent nephrotoxicity from colistin. Details: A small clinical study shows that intravenous administration of vitamin C 2 grams every 12 hours along with colistin for around 9-10 days does not prevent nephrotoxicity when compared with colistin therapy alone (99839). However, this study was limited by a lack of statistical power to detect differences between the study groups.
• Contrast induced nephropathy. It is unclear if oral vitamin C helps to prevent contrast-induced nephropathy (CIN). Details: Some clinical research shows that taking vitamin C before and after coronary angiography reduces the risk of developing CIN by 33% to 55% when compared with placebo in patients with renal dysfunction (12234,90421). However, other clinical evidence published since 2012 suggests that vitamin C given orally and/or intravenously before and after angiography does not reduce the risk of CIN compared with control in high-risk patients with chronic renal insufficiency or diabetes (91232,91236,90410,90425). Reasons for the discrepancies are not entirely clear. However, it is possible that the lack of significant benefit from vitamin C in the latter studies results from the fact that incidences of CIN have become less common than in the past due to avoidance of dehydration, use of smaller catheters, and use of contrast agents with reduced nephrotoxicity (90429).
• Coronary artery bypass graft (CABG) surgery. It is unclear if intravenous vitamin C helps to improve patient outcomes after CABG surgery. Details: A small clinical study shows that giving vitamin C 5 grams intravenously (IV) before anesthesia induction and 5 grams in the cardioplegia solution used during surgery shortens the length of stay in the intensive care unit (ICU) by about 8 hours (102127). However, some limited research suggests that IV vitamin C does not resolve cardiac surgery complications. A small clinical study in patients with vasoplegia after receiving CABG and other cardiac surgeries shows that receiving IV vitamin C 1.5 grams every 6 hours after being admitted to the ICU does not improve vasoplegia when compared with control (102981).
• Delirium. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research in adults with septic shock has found that receiving intravenous thiamine 400 mg daily with vitamin C 6 grams daily, both in divided doses, is not associated with reduced delirium when compared with control (103001).
• Dental plaque. It is unclear if vitamin C in a chewing gum helps to reduce dental plaque formation. Details: A small clinical study in patients with calculus shows that chewing 10 pieces of gum, each containing 60 mg of vitamin C, daily for 3 months reduces the formation of dental calculus, visible plaque, and the number of bleeding sites when compared not chewing gum (83303). The validity of this finding is limited by a lack of placebo group.
• Depression. It is unclear if oral vitamin C is beneficial for the treatment or prevention of depression. Details: A small clinical study in children and adolescents shows that taking vitamin C 500 mg orally twice daily in combination with fluoxetine 10-20 mg daily for 6 months reduces most symptoms of major depressive disorder when compared with taking fluoxetine alone (90404). However, a small clinical study in adults shows that taking vitamin C up to 1000 mg daily for 2 months does not improve the response rate or decrease symptoms of depression in adults also taking citalopram when compared with citalopram alone (96708). Reasons for these conflicting results may relate to the age of the patients, study duration, or differences in antidepressant medication being taken. One clinical guideline also provisionally recommends against the use of oral vitamin C to treat patients with depression based on low-quality evidence (110318). Some research has also evaluated vitamin C intake for the prevention of depression. A secondary analysis of pre- and peri-menopausal adults enrolled in the Study of Women's Health Across the Nation (SWAN) program suggests that vitamin C intake is inversely associated with depressive symptoms. This association persisted regardless of age, race, physical activity, body mass index, antidepressant use or menopausal status (108083). The validity of these findings is limited due to the secondary nature of this study; additionally, follow-up time is unclear.
• Diabetes. It is unclear if oral vitamin C prevents diabetes. Some low-quality research suggests that vitamin C might improve glycemic control in patients with diabetes. Details: Population research has not found a link between dietary vitamin C and the risk of developing type 2 diabetes (14004). However, low certainty clinical research has found some benefit of taking vitamin C supplements for glycemic control. Two meta-analyses of several small, heterogeneous clinical studies in patients with type 2 diabetes show that taking vitamin C 200-3000 mg daily for 2-48 weeks reduces fasting blood glucose by approximately 11 mg/dL (112478) and glycated hemoglobin (HbA1c) by an average of 0.5% when compared with placebo, standard treatment, or no treatment (105461,112478). Subgroup analyses suggest that durations of supplementation longer than 12 weeks show greater glycemic benefit, and although one meta-analysis suggests there is no dose-response relationship (105461), another meta-analysis suggests that doses of vitamin C 1000 mg and higher are most beneficial for improving glycemic indices (112478). Some research has evaluated the effects of vitamin C supplementation on the lipid profile in patients with diabetes, with mixed findings. One meta-analysis of 17 small clinical studies shows that taking vitamin C 200-3000 mg daily for 2 to 48 weeks improves levels of triglycerides and total cholesterol, but not low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol. Subgroup analysis suggests that study durations of at least 12 weeks show greater benefit (106621). However, two other meta-analyses in patients with diabetes, one of 16 small heterogenous clinical studies and one of 11 small clinical studies, show no clinically important improvement in lipid levels after vitamin C supplementation (105461,105464).
• Dry mouth. Oral vitamin C has only been evaluated in combination with vitamin E; its effect when used alone is unclear. Details: A small clinical trial in patients receiving radiotherapy for head and neck cancer shows that taking vitamin E 100 IU and vitamin C 500 mg twice daily for an average of 3 months improves dry mouth when compared to baseline (99080). The validity of these results is limited by the lack of comparison with a control group.
• Endometrial cancer. Increased dietary vitamin C has been linked to reduced risk of endometrial cancer. Details: Population research has found that intake of vitamin C from dietary sources is associated with a slightly decreased risk of endometrial cancer when compared with control. However, this benefit is not observed when results from a prospective cohort study are assessed (34578).
• Endometriosis. Oral vitamin C has only been evaluated in combination with vitamin E; its effect when used alone is unclear. Details: A small clinical study in patients with endometriosis and pelvic pain shows that taking vitamin C 1000 mg and vitamin E 800 IU daily for 8 weeks improves dysmenorrhea, dyspareunia, and chronic pelvic pain scores when compared with placebo. Vitamin C and vitamin E supplementation also reduces some biochemical markers of oxidative stress when compared with placebo (106622).
• Endoscopy-associated adverse effects. It is unclear if a topical vitamin C spray reduces mucosal irritation in patients undergoing Lugol chromoendoscopy. Details: A small clinical trial in patients receiving a Lugol chromoendoscopy shows that spraying a vitamin C 2% solution after the application of the Lugol iodine 2% solution reduces the severity of mucosal irritation, heartburn, and pain when compared with using a normal saline spray after the Lugol iodine 2% solution (104030).
• Esophageal cancer. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Population research has found that higher dietary intake of vitamin C is associated with reduced odds of esophageal adenocarcinoma. A 50 gram increase in dietary vitamin C intake is associated with a 13% reduced odds of esophageal cancer (34551,98770). However, a meta-analysis of clinical research shows that taking a vitamin C supplement in combination with beta-carotene and vitamin E does not reduce the risk of esophageal cancer (34581).
• Exercise-induced asthma. Small clinical studies suggest that oral vitamin C may modestly improve symptoms in patients with exercise-induced asthma. Details: A meta-analysis of the available clinical research shows that vitamin C supplementation might reduce exercise-induced breathlessness when compared with placebo or control. However, the available research is of poor quality, and no clear conclusions can be drawn regarding its benefits for exercise-induced asthma (90409).
• Exercise-induced muscle damage. It is unclear if oral vitamin C is beneficial in exercise-induced muscle damage. Details: A small clinical study in healthy females shows that taking vitamin C 1000 mg before moderate intensity cycling does not prevent muscle damage when compared with placebo (99837). Another small clinical study in endurance-trained runners shows that taking vitamin C 1000 mg and vitamin E (as alpha-tocopherol) 235 mg 2 hours prior to an exercise protocol does not reduce delayed onset muscle soreness or improve other markers of exercise-induced muscle damage when compared with placebo (109961).
• Gallbladder disease. It is unclear if oral vitamin C reduces the risk of gallbladder disease. Details: Cross-sectional epidemiological evidence has found that vitamin C supplementation and increased vitamin C serum levels are associated with a decreased risk of developing gallbladder disease in females, but not males (5877).
• Gastric cancer. It is unclear if dietary or supplemental vitamin C reduces the risk of gastric cancer. Details: Most population research has not found an association between DIETARY intake of vitamin C and gastric cancer risk (9194,10822,10819,90083). Also, clinical research shows that taking vitamin C supplements in combination with other antioxidants does not reduce the risk of gastric cancer or precancerous gastric lesions (14447,34581,90085). However, some research suggests that it might be associated with a reduced risk for specific forms of gastric cancer (9838,90083). One clinical study shows that taking vitamin C orally 500 mg daily for 6 months after eradication of Helicobacter pylori infection decreases the incidence of precancerous changes in stomach tissue when compared with no treatment (10359). Also, other clinical research shows that taking vitamin C orally 1 gram daily helps promote the regression of precancerous gastric lesions in people at high risk for gastric cancer (2579). In 2009, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that vitamin C supplements may reduce the risk of gastric cancer. However, the FDA has concluded that it is highly uncertain that vitamin C supplements actually reduce the risk of gastric cancer (102332).
• Gastritis. There is limited evidence on the oral use of vitamin C in omeprazole-induced corpus gastritis. Details: A small clinical study shows that taking vitamin C orally 1200 mg daily along with omeprazole decreases corpus gastritis associated with omeprazole therapy in patients with H. pylori infection (10360).
• Gout. It is unclear if oral vitamin C helps to prevent or manage gout. Details: Population research in men has found that taking vitamin C 500-1500 mg daily from the diet and/or supplements is associated with up to a 34% reduced risk of gout when compared with less than 250 mg daily (16755). Also, men who ingest over 500 mg of vitamin C daily from the diet and supplements have serum uric acid levels that are slightly lower than men who consume less than 90 mg daily (16820). However, taking supplemental vitamin C 500 mg daily for 8 weeks does not seem to lower serum uric acid levels in patients who already have gout (90423).
• Hearing loss. There is limited evidence on the intravenous use of vitamin C in idiopathic sudden sensorineural hearing loss. It is unclear if dietary vitamin C intake can affect the risk of hearing loss. Details: A small clinical study in patients with idiopathic sudden sensorineural hearing loss shows that receiving intravenous high-dose vitamin C 200 mg/kg daily in combination with steroid therapy for 10 days, followed by oral vitamin C 2000 mg daily for 30 days, increases recovery rate two-fold and modestly improves hearing threshold levels when compared with receiving steroid therapy only (90417). In addition, population research in females has found that high dietary intake of vitamin C is associated with a 22% increased risk of developing self-reported hearing loss over a 22-year period when compared with low intake (109807).
• Heart transplant complications. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial shows that a combination of vitamin C 500 mg and vitamin E 400 IU, taken twice daily for 1 year starting within the first 2 years after cardiac transplant, reduced the progression of vasculopathy as measured by intravascular ultrasonography (IVUS) when compared with placebo. This suggests that the combination may help slow the progression of CAV (82826).
• Hepatitis C. It is unclear if oral vitamin C is beneficial in patients with hepatitis C. Details: A small clinical study in patients with confirmed hepatitis C shows that taking vitamin C 1000 mg daily with conventional therapy (sofosbuvir plus daclatasvir) for 4 weeks improves serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and albumin when compared with conventional therapy alone (109463).
• HIV/AIDS. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, low-quality study in men with HIV shows that taking vitamin C 250 mg daily in combination with vitamin A, beta-carotene, vitamin E, selenium, and coenzyme Q10 does not improve viral load, although it seems to improve markers of oxidative stress when compared to baseline. However, a 1000 mg dose of vitamin C, as well as higher doses of the other antioxidants, do not seem to provide any additional effect (9830).
• HIV transmission. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in HIV-positive mothers shows that taking vitamin B, vitamin C, and vitamin E daily during pregnancy and while breast-feeding for 20 weeks seems to reduce child mortality and HIV transmission through breast milk when compared with taking vitamin A (9801).
• Hyperphosphatemia. Intravenous vitamin C might be beneficial for reducing phosphate levels in patients with end-stage renal disease. Details: A small clinical study in hemodialysis patients with elevated phosphorus levels suggests that administering vitamin C 500 mg intravenously three times weekly for 8 weeks reduces phosphorus levels about seven-fold when compared with placebo (90414).
• Idiopathic interstitial pneumonia. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with idiopathic pulmonary fibrosis, a form of idiopathic interstitial pneumonia, shows that taking a combination of vitamin C 250 mg every other day, vitamin D 50,000 IU daily, and vitamin E 200 IU daily for 12 weeks improves some, but not all, measures of lung function and reduces markers of inflammation and oxidative stress when compared to baseline (109464). The validity of these findings is limited by a lack of placebo control group.
• Infertility. It is unclear if oral vitamin C is beneficial in anovulatory females. Details: A very small clinical study suggests that taking vitamin C 400-1000 mg daily might improve fertility, resulting in ovulation and pregnancy in some anovulatory females, when compared with baseline (14018). The validity of these findings is limited by the small study size and lack of a comparator group.
• Male infertility. It is unclear if oral or intravenous vitamin C is beneficial in males with infertility. Details: A meta-analysis of three small, low-quality clinical trials in males with infertility shows that taking vitamin C up to 1000 mg daily for up to 12 weeks can improve sperm count, motility, and vitality, but does not seem to increase semen volume or sperm concentration, when compared with control (109461). It is unclear if vitamin C can increase pregnancy rates, as these studies did not assess this outcome. A retrospective study in males with or without varicocele-related infertility has found that taking a specific combination product containing vitamin C 90 mg, zinc 10 mg, L-carnitine fumarate 1725 mg, acetyl-L-carnitine 500 mg, coenzyme Q10 20 mg, folic acid 0.2 mg, selenium 0.05 mg, and vitamin B12 0.015 mg (Proxeed Plus, Sigma-Tau) orally twice daily for 6 months improves sperm count, sperm concentration, and sperm motility when compared with baseline. Improvement in semen parameters were greatest in subjects with more severe varicoceles. The validity of this study is limited by the lack of a comparator group (111296).
• Mastalgia. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with mastalgia shows that taking a combination of vitamin C 100 mg, vitamin B12, and gamma-linolenic acid daily for 12 weeks does not improve the proportion of patients with minimal or no pain when compared with placebo (111059).
• Melasma. It is unclear if topical vitamin C is beneficial in patients with melasma. Details: A small clinical study in patients with bilateral symmetrically distributed facial melasma shows that topical application of 0.5 mL of vitamin C (Cosmotech, Alpha Medical Cosmotech) following dermapen microneedling every 2 weeks for 6 weeks is similarly effective to tranexamic acid for improving melasma severity and pigmented, but not vascular, findings on dermoscopic examination (106939).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin C is beneficial in patients with NAFLD. Details: A clinical study in patients with NAFLD shows that taking vitamin C 250 mg, 1000 mg, or 2000 mg daily for 12 weeks improves some biochemical markers of liver health and glucose metabolism when compared with baseline. However, the improvement from baseline was similar between groups (106942).
• Nonalcoholic steatohepatitis (NASH). Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research suggests vitamin C in combination with vitamin E might improve hepatic fibrosis in patients with NASH. However, it does not seem to decrease liver inflammation (14005).
• Non-Hodgkin lymphoma. It is unclear if oral vitamin C reduces the risk of developing diffuse large B-cell lymphoma. Details: In one population study, higher dietary or supplemental intake of vitamin C was associated with a reduced risk of diffuse large B-cell lymphoma, a type of non-Hodgkin lymphoma, when compared with lower intake in postmenopausal adults (90945).
• Oral cancer. It is unclear if oral vitamin C reduces the risk of developing oral cancer. Details: Population research has found that higher dietary intake of vitamin C is associated with a reduced risk of oral cancer (10821). However, clinical research has not shown benefit with oral vitamin C supplements. A small clinical trial in Japanese adults with oral leukoplakia shows that taking vitamin C 500 mg and beta-carotene 10 mg daily for 12 months does not reduce the development of oral cancer over 5 years when compared with vitamin C 50 mg daily (91384).
• Oral leukoplakia. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in Japanese adults with oral leukoplakia shows that taking vitamin C 500 mg and beta-carotene 10 mg daily for 12 months does not improve leukoplakia symptoms or reduce the development of oral cancer over 5 years when compared with vitamin C 50 mg daily (91384).
• Osteoarthritis. It is unclear if dietary vitamin C reduces the risk of developing osteoarthritis. Details: Observational research has found that increased vitamin C from dietary sources is associated with a reduced risk of cartilage loss and disease progression in people with osteoarthritis (5881).
• Osteoporosis. It is unclear if dietary vitamin C improves bone density or reduces fracture risk in patients at risk for osteoporosis. Details: Some cross-sectional observational research in postmenopausal patients without a history of smoking or estrogen use has found that higher serum vitamin C levels are associated with lower bone mineral density (9828). However, other observational research in a larger population of adults at risk for osteoporosis has found that higher dietary vitamin C intake is not associated with fracture risk (104415).
• Ovarian cancer. Dietary vitamin C might not affect the risk of ovarian cancer. Details: Epidemiological research has found that dietary vitamin C intake is not linked with ovarian cancer risk (9193,102977).
• Pancreatitis. It is unclear if intravenous vitamin C is beneficial in patients with acute pancreatitis. Details: A small meta-analysis of clinical studies in patients with acute pancreatitis shows that intravenous vitamin C does not improve the odds of developing organ failure when compared with placebo or no intervention. Intravenous vitamin C seems to reduce hospital stay, but not in-hospital mortality (106941).
• Parkinson disease. Dietary vitamin C might not affect the risk of developing this condition. Details: Observational research has found that moderate or high dietary intake of vitamin C is not associated with a reduced risk of Parkinson disease (83316).
• Periodontitis. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. It is also unclear if dietary vitamin C reduces the risk of periodontitis. Details: A small clinical study in patients with moderate or advanced periodontitis shows that taking a supplement containing vitamin C 100 mg, alpha-lipoic acid, coenzyme Q10, cranberry extract, grapeseed extract, selenium, 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). It is unclear if these effects are due to vitamin C, other ingredients, or the combination. There is also interest in whether dietary vitamin C intake impacts the risk of periodontitis. Observational research in US adults has found that individuals with dietary intake of vitamin C in the third quartile, but not the second or fourth quartiles, have lower odds of periodontitis when compared with vitamin C intake in the lowest quartile. Furthermore, the investigators identified a non-linear relationship between vitamin C intake and periodontitis risk, suggesting that individuals with intakes either much lower or much higher than 158 mg daily are at increased risk of developing periodontitis (109958).
• Peripheral arterial disease (PAD). It is unclear if dietary vitamin C helps to reduce the risk of developing PAD. Details: In females, epidemiological evidence has found that dietary intake of vitamin C of 142 mg daily or greater is associated with a 36% reduced risk of PAD when compared with lower intake levels of less than 80 mg daily (10130).
• Physical performance. It is unclear if oral vitamin C helps to improve physical performance and muscle strength in older people. Details: Population research has found that higher intake of dietary vitamin C is associated with improved physical performance and muscle strength in elderly people (14006). In contrast, a small clinical study in elderly men undergoing strength training shows that taking vitamin C 1000 mg and vitamin E 258IU daily for 12 weeks does not increase strength, and might even attenuate increases in muscle mass, when compared with strength training alone (96701).
• Pneumonia. It is unclear if oral vitamin C helps to prevent pneumonia. Details: A meta-analysis of two small, low-quality clinical studies in children shows that vitamin C does not seem to reduce the occurrence of pneumonia when compared to control (104033).
• Postoperative recovery. It is unclear if oral or intravenous vitamin C improves postoperative recovery. Details: Meta-analyses of clinical research show that oral or intravenous vitamin C can shorten the duration of hospitalization after cardiac surgery when compared with control (91233,96703). However, other research shows no decrease in intensive care or hospital stay with vitamin C supplementation (96705). A meta-analysis of 37 clinical trials in adults undergoing low- to high-risk noncardiac surgery (i.e., orthopedic, abdominal, gynecologic, or kidney transplantation), shows that receiving perioperative vitamin C, either orally or intravenously, does not improve duration of hospitalization or overall mortality when compared with control (108087). There's also some limited evidence that vitamin C might reduce postoperative pulmonary complications such as lung infection, pleural effusion, and pneumothorax. A small clinical trial in low-risk cardiac surgery patients shows that receiving intravenous vitamin C 1 gram 10 minutes after anesthesia might slightly reduce the rate of postoperative pulmonary complications when compared with receiving a saline injection (104034).
• Premature rupture of membranes (PROM). Oral vitamin C seems to reduce the risk of PROM in some patients; however, the addition of oral vitamin E seems to negate any benefit. Details: A meta-analysis of clinical research shows that taking vitamin C alone decreases the risk of both term and preterm PROM by 45% and 34%, respectively, when compared with placebo or control (96707). Also, a more recent clinical study in patients with a history of PROM shows that taking vitamin C 100 mg daily, starting at 14 weeks' gestation, increases the gestational age at recurrent PROM by around 1 week and increases the gestational age at birth by around 1.3 weeks when compared with placebo (109960). Taking vitamin C in combination with vitamin E, however, does not seem to reduce the risk of term or preterm PROM; some research suggests that it might even increase the risk of non-preterm PROM (83472,96707). However, other research shows that taking vitamin C 1000 mg plus vitamin E 400 IU daily, beginning at 24 to 34 weeks gestation and continuing until delivery, may help increase the latency period until delivery by 5 days and increase gestational age at delivery by almost 1 week when compared with placebo in patients with preterm PROM (90078).
• Pressure ulcers. It is unclear if oral vitamin C, when used alone or in combination with other ingredients, can improve the healing of pressure ulcers. Details: A small clinical study in institutionalized patients with pressure ulcers shows that taking vitamin C 500 mg twice daily for 12 weeks does not improve wound closure or increase healing rates when compared with vitamin C 10 mg twice daily (83617). Oral vitamin C has also been evaluated in combination with other ingredients for the treatment of grade II-IV pressure ulcers. Two small clinical studies in hospitalized patients with pressure ulcers shows that administering an oral nutritional supplement enriched with vitamin C, L-arginine, and zinc improves ulcer healing when compared with a standard diet (31953,87173). Also, clinical research in patients living in long-term care facilities shows that taking an oral nutritional supplement enriched in protein, vitamin C, L-arginine, and zinc daily for 9 weeks reduces ulcer area and decreases oozing when compared to baseline (32045). The validity of this finding is limited by the lack of a comparator group.
• Radiation proctopathy. Oral vitamin C has only been evaluated in combination with vitamin E; its effect when used alone is unclear. Details: A small clinical study in patients with chronic radiation proctitis shows that vitamin C 500 mg plus vitamin E 400 IU three times daily might improve symptoms when compared with baseline (9825). The validity of these findings is limited by the lack of a comparator group.
• Renal cell carcinoma. It is unclear if increased dietary intake of vitamin C helps to reduce the risk of renal cell carcinoma. Details: Population research has found that increased dietary intake of vitamin C is associated with a 12% reduced risk of renal cell carcinoma (98779).
• Respiratory tract infections. It is unclear if oral vitamin C is beneficial for preventing respiratory tract infections or reducing the duration of these infections. Details: A meta-analysis of clinical research in children and adults shows that, when compared with placebo, oral vitamin C supplementation reduces the average number of symptomatic days per individual, but does not reduce the average symptom days per respiratory episode. Also, vitamin C intake does not reduce the incidence or severity of respiratory disease or improve recovery in hospitalized patients with respiratory tract infections (108077). The validity of this trial is limited by the high heterogeneity of included studies, which evaluated various vitamin C regimens, ranging from 100 mg to 8 grams daily, as preventive therapy or as an adjuvant to active treatment. A clinical study in children aged 3-10 years shows that taking vitamin C 50 mg in combination with a specific product (Lab4) containing Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium animalis subsp. lactis daily for 6 months reduces the incidence of cough and sore throat by 16% and 20%, respectively, when compared with placebo. However, it did not improve total symptoms, nasal congestion, nasal discharge, or sneezing. Also, aside from a 33% reduction in the average number of days with a sore throat, daily supplementation does not reduce the duration of individual symptoms or total symptoms (106943). It is unclear if these effects are due to vitamin C, the probiotics, or the combination.
• Restless legs syndrome (RLS). It is unclear if oral vitamin C helps to reduce symptoms of stress. Details: A small clinical study in hemodialysis patients with RLS shows that taking vitamin C 200 mg daily, alone or in combination with vitamin E 400 mg, for 8 weeks reduces the severity of RLS when compared with placebo (90093). More research is needed to determine if vitamin C is beneficial in treating RLS that is not associated with hemodialysis.
• Sunburn. Topical and oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking vitamin C orally in combination with vitamin E seems to prevent ultraviolet (UV) radiation-induced erythema (sunburn) (4715,4716). Vitamin C in combination with high dose oral RRR-alpha-tocopherol (natural vitamin E) seems to protect against skin inflammation after exposure to UV radiation (4715). Also, applying topical vitamin C in combination with topical vitamin E and melatonin seems to provide modest photoprotective effects when used prior to UV exposure. However, it has no effect when used during or after UV exposure (4713,4714).
• Stress. It is unclear if oral vitamin C helps to reduce symptoms of stress. Details: A small clinical study in healthy adults shows that taking vitamin C 3000 mg daily for 14 days modestly reduces blood pressure and subjective stress response to psychological stress when compared with placebo (10353).
• Stroke. Observational research has found that although taking vitamin C supplements does not seem to be beneficial, eating more vitamin C-rich food is linked with reduced risk of stroke. Details: Lower plasma levels of vitamin C have been associated with increased stroke risk (90408). Additionally, population research has found that higher dietary intake of vitamin C is associated with a 8% to 19% reduction in stroke risk when compared to lower intake (90408,109779). This reduction appears to be dose-dependent, with each 100 mg/day increase in dietary vitamin C intake associated with about a 17% reduction (90408). However, taking vitamin C supplements has not been found to be associated with reduced stroke risk (1449,90408).
• Tetanus. It is unclear if intravenous vitamin C helps to reduce symptoms of tetanus. Details: A low quality clinical trial in children and young adults with tetanus shows that intravenous vitamin C 1 gram daily along with conventional treatment reduces fatality when compared to control (21539).
• Tooth extraction. It is unclear if oral vitamin C is beneficial for reducing pain or improving healing after tooth extraction. Details: A small clinical study in healthy patients aged 14-41 years who are undergoing bilateral premolar extraction shows that taking vitamin C 200 mg three times daily, beginning immediately after extraction and continued for 10 days, improves pain on days 1-3, and may reduce mesio-distal wound size between days 1 and 7, when compared with placebo, but not when compared with vitamin C 500 mg three times daily. A dose of 500 mg three times daily did not improve pain scores or extraction wound healing when compared with placebo (108084). The validity of this trial is limited by the short duration of treatment; additionally, this study did not report baseline vitamin C levels.
• Urinary tract infections (UTIs). Although there is interest in using oral vitamin C for UTIs, there is insufficient reliable information about the clinical effects of vitamin C for this condition.
• Vascular dementia. It is unclear if oral vitamin C reduces the risk of vascular dementia. Details: Population research has found that supplemental intake of vitamin C and vitamin E is associated with a reduced risk of vascular dementia in Japanese-American men (4636). However, when cases in which dementia was diagnosed prior to the study are excluded from data analysis, intake of vitamin C and vitamin E is not associated with a reduced risk of vascular dementia in these patients (9824).
• Wound healing. It is unclear if oral vitamin C improves the healing of chronic foot ulcers. It is also unclear if intravenous vitamin C improves healing of surgical wounds after total abdominal hysterectomy. Details: A very small clinical study in adults with chronic foot ulcers shows that taking slow-release vitamin C 500 mg daily for 8 weeks seems to result in a median of 100% ulcer healing, compared with a median of 14% ulcer healing in patients taking glucosamine 1000 mg daily (105456). This finding is limited due to the small and heterogeneous patient population, which included patients with diabetes, vascular disease, and/or vitamin C deficiency. Another small clinical study in patients undergoing total abdominal hysterectomy shows that administration of intravenous vitamin C 1 gram the night before surgery and 1 gram during surgery does not reduce the rate of surgical site infection or wound dehiscence when compared with placebo (109465). However, this study may not have been adequately powered to detect differences between groups. More evidence is needed to rate vitamin C for these uses.

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EFFECTIVE

• Familial hypophosphatemia. Oral vitamin D in combination with phosphate is effective for bone disorders in patients with familial hypophosphatemia. Details: Taking calcitriol or dihydrotachysterol orally in combination with phosphate supplements is effective for treating bone disorders in people with familial hypophosphatemia (11818).
• Hypoparathyroidism. Oral vitamin D increases serum calcium concentrations in people with hypoparathyroidism or pseudohypoparathyroidism. Details: Vitamin D2 (ergocalciferol) is effective in high doses for increasing serum calcium concentrations in people with hypoparathyroidism or pseudohypoparathyroidism (11820). Also, taking vitamin D (form unspecified) or calcitriol postoperatively is effective for preventing hypocalcemia in people with hypoparathyroidism due to thyroidectomy (39045).
• Osteomalacia. Oral vitamin D is effective for osteomalacia. Details: Oral calcifediol is effective for treating osteomalacia secondary to liver disease (hepatic osteodystrophy) and anticonvulsant-induced osteomalacia. Vitamin D2 (ergocalciferol) is effective for osteomalacia due to malabsorption syndromes, Fanconi syndrome, and corticosteroid-induced osteomalacia (11819,11821).
• Renal osteodystrophy. Oral calcitriol prevents renal osteodystrophy in patients with chronic renal failure. Details: Taking calcitriol orally manages hypocalcemia and prevents renal osteodystrophy in patients with chronic renal failure undergoing dialysis (11823).
• Rickets. Oral vitamin D prevents and treats rickets. Details: Vitamin D is effective for preventing and treating rickets, a consequence of vitamin D deficiency. Calcitriol should be used in patients with renal failure (11824).
• Vitamin D deficiency. Oral vitamin D prevents and treats vitamin D deficiency. Details: Vitamin D is effective for preventing and treating vitamin D deficiency using a wide range of doses (7555,16888,16891,17476). Optimal blood levels of 25-hydroxyvitamin D for maintaining bone density is controversial; however, it is typically estimated that blood levels of 20-100 ng/mL are needed. Toxicity usually does not occur until levels exceed 150 ng/mL (17476,93945). Vitamin D also alleviates symptoms and syndromes associated with vitamin D deficiency. Administering vitamin D2 (ergocalciferol) intramuscularly or orally seems to help treat severe proximal myopathy associated with severe vitamin D deficiency. Several case reports suggest vitamin D therapy can provide prompt relief of muscle weakness and restore mobility (11923,84348,84687).

LIKELY EFFECTIVE

• Corticosteroid-induced osteoporosis. Oral vitamin D prevents corticosteroid-induced osteopenia and osteoporosis. Details: Taking calcifediol, cholecalciferol, calcitriol, or alfacalcidol orally prevents corticosteroid-induced osteopenia and osteoporosis (7555,83933). Vitamin D3 metabolites, including calcitriol and alfacalcidol, seem to be more effective at preventing bone loss compared to cholecalciferol in these patients, although the vitamin D3 metabolites seem to be inferior to bisphosphonates (83955). Furthermore, taking activated vitamin D or other forms of vitamin D alone or along with calcium improves bone mineral density in people with corticosteroid-induced osteoporosis (38493,38581).
• Osteoporosis. Adequate intake of vitamin D in conjunction with adequate calcium intake helps to prevent the progression of osteoporosis. It might also reduce the risk of a first fracture in some patients. However, its place in the prevention of secondary facture is unclear. Details: The Bone Health and Osteoporosis Foundation (BHOF) recommends ensuring adequate vitamin D intake of 800-1000 IU daily along with adequate calcium intake for the prevention and treatment of osteoporosis in adults over 50 years of age. Supplementation can be used to augment dietary intake, with a target serum vitamin D level of 30 ng/mL (109425). In the US, foods that contain at least 120 IU vitamin D can be labelled with a health claim regarding the relationship between adequate vitamin D intake and a reduced risk for osteoporosis (97001). However, vitamin D supplementation is not recommended specifically for the primary prevention of osteoporosis. The US Preventive Task Force (USPSTF) states that the current evidence is insufficient to assess the balance of benefits and harms of vitamin D and calcium supplementation, alone or in combination, for the primary prevention of fractures in community dwelling adults without osteoporosis (95695). Clinical research shows that vitamin D3 (cholecalciferol) and calcium can decrease postmenopausal bone loss, help prevent osteoporosis, and decrease the risk of fractures (10932,12926,12930,12934,12952) (38973,39015,39026,84003). According to one analysis, taking oral vitamin D3 700-800 IU daily with or without calcium reduces fracture risk in ambulatory and institutionalized elderly people (12933). Other analyses suggest that taking vitamin D as cholecalciferol, ergocalciferol, calcifediol, calcitriol, or alfacalcidol with or without calcium can reduce the risk of all fractures by up to 17%, nonvertebral fractures by up to 49%, and hip fractures by up to 30% in older adults. However, the incidence of vertebral fractures does not appear to be reduced with vitamin D supplementation (38942,38970,38973,39015,39026,84660,109053). Despite the majority of research showing benefit, some studies have not found a positive effect of vitamin D on fracture risk. Some analyses of clinical evidence, including patients with and without osteoporosis, show that taking vitamin D3 or vitamin D2 (ergocalciferol) alone does not reduce fracture risk, suggesting that adequate calcium intake is needed for any benefit to be realized (39015,84471). Also, some evidence suggests that vitamin D3 400 IU daily is not effective for the prevention of osteoporotic fractures in elderly nursing home residents (109053). Another clinical trial found that taking vitamin D3 800 IU daily with calcium 1200-1500 mg daily for 2 years does not increase bone mineral density (BMD) in Black postmenopausal adults. This may be due to the fact that Black females have a lower rate of bone remodeling, an increased calcium absorption efficiency, and reduced calcium excretion when compared with other ethnic groups; therefore, supplementation with vitamin D3 and calcium might not be as beneficial in these patients (16878). There is concern that vitamin D might not be effective for secondary prevention of fractures in elderly patients. A meta-analysis of clinical studies, including many studies cited above, and a large clinical study in elderly adults with a previous osteoporotic fracture show that taking vitamin D3 400-4000 IU daily or as a single dose up to 500,000 IU orally or injected annually with or without calcium 480-1200 mg daily for up to 5 years does not reduce the risk of hip, vertebral, or other fractures when compared with placebo or no treatment (13073,112486). Another study also shows that taking vitamin D3 800 IU and calcium 1000 mg daily does not prevent a second fracture in elderly patients, or prevent a first fracture in elderly patients with other risk factors such as low body weight (under 58 kg, 127.6 pounds), smoking, family history of hip fracture, or fair or poor self-reported health (12929). However, these studies have been criticized for failing to measure vitamin D levels and low adherence to study protocol (12931). Also, one of these studies did not use a placebo control (12929). Taking alfacalcidol orally seems to maintain BMD in prostatic carcinoma patients at risk for osteoporosis when treated with luteinizing hormone-releasing hormone analogue (LHRH-a). Alfacalcidol maintains, but does not increase, BMD in these patients (6360).
• Psoriasis. Topical vitamin D or vitamin D analogues improve symptoms of psoriasis. This benefit is not seen with oral vitamin D. Details: Topical application of vitamin D in the form of calcitriol or other vitamin D analogues, such as calcipotriene, maxacalcitol, and paricalcitol, effectively treats plaque psoriasis in some patients, including those with chronic plaque psoriasis (11822,84325). Applying topical vitamin D or its analogues in combination with topical corticosteroids such as betamethasone seems to be more effective for treating plaque psoriasis than either agent used alone (22283,82572,84325,84536,84647). Despite evidence that patients with psoriasis have low baseline serum levels of vitamin D, taking oral vitamin D does not seem to prevent psoriasis, improve symptoms, or reduce the severity of psoriasis in general (11822,22283,82572,84325,84536,84647,98193,108426,112481,112482). An analysis of a large clinical study in older adults with mild psoriasis shows that taking a vitamin D3 (cholecalciferol) loading dose of 200,000 IU followed by vitamin D3 100,000 IU monthly for 1 year does not affect the severity or spread of psoriasis when compared with placebo (98193).

POSSIBLY EFFECTIVE

• Allergic rhinitis (hay fever). Some research suggests that oral vitamin D reduces symptoms of allergic rhinitis in children and adults. It is unclear if oral vitamin D during pregnancy is beneficial for the prevention of allergic rhinitis in the child. Details: Preliminary clinical research in adults with allergic rhinitis and vitamin D deficiency shows that taking vitamin D 50,000 IU weekly for 8 weeks along with cetirizine improves overall symptom severity when compared with placebo and cetirizine. This improvement was not significant at 4 weeks, suggesting that symptom improvement might not occur until vitamin D has been adequately replenished (102120). Another moderate-sized clinical study conducted in China in adults with moderate to severe allergic rhinitis and vitamin D levels at the low end of the normal range shows that taking vitamin D 800 IU daily for 4 weeks along with mometasone nasal spray improves runny nose, itchy nose, and nasal congestion but does not reduce sneezing when compared with placebo and mometasone (112483). In children aged 5-15 years, 4 small- or moderate-sized clinical trials show that taking vitamin D 800 IU or 1000 IU daily for 1-6 months modestly reduces symptoms such as nasal congestion and rhinorrhea when compared with placebo or no supplementation (109728). It is unclear whether these children had vitamin D deficiency at baseline. Vitamin D supplementation during pregnancy has also been evaluated. A meta-analysis of three large clinical studies shows that prenatal vitamin D supplementation does not reduce the risk of the child developing allergic rhinitis when compared with low-dose vitamin D, placebo, or no intervention (108438).
• Dental caries. Some research suggests that oral vitamin D reduces the risk of dental caries in children. Details: A meta-analysis of clinical research suggests that vitamin D3 (cholecalciferol) reduces the risk of cavities by 49%, and vitamin D2 (ergocalciferol) reduces the risk by 36% when compared with placebo in infants, children, and adolescents (84690). The validity of this finding is limited by the heterogeneity of the included trials. Also, clinical research shows an inverse correlation between cord blood vitamin D status and the number of decayed primary teeth in the infant at 12 months of age (104620). However, this same research shows that taking two oral prenatal doses of vitamin D2 50,000 IU during pregnancy does not prevent dental caries in the infant at 12 months of age or increase vitamin D levels in the cord blood (104620).
• Heart failure. Limited research suggests that oral vitamin D reduces the risk of developing heart failure in some patients. However, vitamin D does not seem to improve outcomes in patients that have already developed heart failure. Details: Population research has found that vitamin D levels below 15 ng/mL are associated with increased risk of developing heart failure (16615). A meta-analysis of 17 trials, including the landmark Randomized Evaluation of Calcium Or vitamin D (RECORD) trial, shows that vitamin D reduces the risk of heart failure by 21% compared to not taking vitamin D in patients 60 years or older (91343). This finding is limited because none of the included trials were designed to determine effects on cardiovascular outcomes. In contrast, a secondary analysis of data from the Women's Health Initiative trial shows that taking vitamin D 400 IU with calcium 1000 mg daily is not associated with a reduced risk of heart failure in postmenopausal adults. However, a subgroup analysis of that trial shows that taking vitamin D plus calcium is associated with a 37% lower risk of developing heart failure in postmenopausal adults classified as low-risk for heart failure at baseline. It is speculated that high-risk patients might not benefit from vitamin D plus calcium due to negative interactions with medications used to manage cardiovascular risk factors in this group (97307). While vitamin D might be associated with a reduced risk of developing heart failure, most evidence suggests that vitamin D is not beneficial in patients already diagnosed with heart failure. In one small clinical trial, taking vitamin D3 50,000 IU weekly along with calcium citrate 800 mg daily for 6 months was not associated with an improvement in 6-minute walk test, timed get up and go test (TGUG), electrocardiographic variables, or health status when compared with placebo in adults with heart failure; mortality was not evaluated (97299,97300). In another clinical trial, taking vitamin D3 2000 IU daily did not decrease the risk of mortality when compared with placebo in New York Heart Association (NYHA) class 2 heart failure patients (16620).
• Hyperparathyroidism-related bone loss. Limited evidence suggests that oral vitamin D is beneficial in patients with this condition. Details: Taking vitamin D3 (cholecalciferol) orally seems to help decrease secondary hyperparathyroidism and bone turnover in females. In one study, supplementation with vitamin D3 increased serum levels of 25-hydroxyvitamin D, reduced levels of parathyroid hormone, and decreased production of markers of bone turnover (3463).
• Respiratory tract infections. Oral vitamin D supplementation reduces the risk for respiratory tract infections in children. However, this benefit is not seen with the use of prenatal vitamin D supplements, or in adults taking vitamin D. It is unclear if oral vitamin D is beneficial for the treatment of respiratory tract infections. Details: Prenatally, increased levels of vitamin D during pregnancy have been associated with a lower incidence of childhood respiratory tract infections (98197). However, two meta-analyses of small clinical studies and one meta-analysis of large clinical studies show no effect of prenatal vitamin D supplementation on the incidence of infant or childhood respiratory tract infections, including lower respiratory tract infections, when compared with control. Results related to risk of wheeze are conflicting (95910,95912,108438). In children, most research shows that vitamin D supplementation reduces the risk of respiratory infections. A meta-analysis of clinical trials in children aged 1-16 years shows that taking vitamin D decreases the odds of having a respiratory tract infection by about 29% when compared with control, although this study also identified a high likelihood of publication bias (105721). Daily or weekly vitamin D doses seem to be more beneficial than single bolus doses, although the largest meta-analysis failed to confirm this result (84689,93766,105721). One clinical study in preterm Black infants shows that taking vitamin D3 (cholecalciferol) 200 IU daily and then 400 IU daily until 6 months of age does not affect the rate of respiratory tract infections, but does reduce wheeze by 11%, when compared with a normal diet without vitamin D supplementation (98191). This study may not have been powered to detect a difference in respiratory tract infection between groups. In adults, vitamin D supplementation does not seem to reduce the risk of respiratory infections. Observational research in adults has found that low levels of vitamin D are associated with worsened respiratory tract infection complications, and even increased mortality from respiratory tract infections in older adults ages 50-75 years (103659). However, meta-analyses of prospective clinical trials in adults show that taking vitamin D supplements 300-4000 IU daily for 7 weeks to 5 years does not reduce the odds of developing a respiratory infection or severe respiratory complications, such as emergency department utilization, hospitalization, and death, when compared with placebo. These results were similar in subgroup analyses evaluating overall vitamin D dose and baseline vitamin D status (84689,105721). The largest single clinical trial, conducted in adults at least 60 years of age, shows that taking vitamin D3 (cholecalciferol) 60,000 IU once monthly for up to 5 years reduces the duration of total and severe respiratory symptoms by approximately 0.5 days, but does not reduce the incidence of respiratory illness or hospitalization, when compared with placebo (105726,110825). A large meta-analysis of clinical studies in both children and adults shows that taking vitamin D does not reduce the risk of acute respiratory infections. While subgroup analyses revealed a reduced risk of acute respiratory infection in studies not exceeding 11 weeks' duration and with daily supplementation, these beneficial effects only persisted in studies considered to be of low quality (108435). Baseline vitamin D status was not assessed and the validity of these findings is limited by publication bias. Vitamin D has also been evaluated for the treatment of acute respiratory infections. A large meta-analysis of clinical studies in both children and adults shows that taking vitamin D improves outcomes (e.g., sputum conversion, survival rate, therapeutic success, need for intensive care admission) by a small, but not clinically relevant, amount. In subgroup analyses, these beneficial effects only persisted in studies considered to be of low quality (108436). The validity of these findings is limited by publication bias.
• Tooth retention. Oral vitamin D with calcium seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking vitamin D3 (cholecalciferol) 700 IU daily along with calcium citrate malate 500 mg daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

• Cardiovascular disease (CVD). Most research shows that taking vitamin D with or without calcium does not reduce the risk of CVD or CVD complications. There is some speculation that there might be modest benefit in the elderly, but more research is needed to confirm. Details: Population research has found that low vitamin D levels, especially those below 15 ng/mL, are associated with an increased risk of developing CVD (15630,16618,93944). However, taking vitamin D supplements does not seem to prevent CVD. The majority of evidence from clinical research, population research, and meta-analyses shows that vitamin D supplementation, with or without calcium, does not reduce the risk of mortality, myocardial infarction, cardiac-related hospitalizations, or stroke when compared with placebo in patients with or without CVD risk factors (91343,97296,97305,97308,98902,98916,99762,109729,110811,110827)(112021,112022). The most reliable evidence comes from two recent meta-analyses of mainly high-quality clinical research investigating the effect of supplementation with vitamin D alone or with calcium for at least 1 year. These analyses show that vitamin D does not reduce major adverse cardiovascular events, stroke, CVD mortality, or all-cause mortality, regardless of baseline vitamin D level, vitamin D dosage, sex, formulation, or concomitant calcium supplementation (99762,109729). One large clinical trial in individuals at increased CVD risk shows that taking vitamin D as cholecalciferol 60,000 IU monthly modestly INCREASES the risk of CVD- and presumed CVD-related mortality (110827). However, in some research, taking vitamin D 700-1000 IU daily shows a trend towards lower CVD events and reduced risk of major adverse cardiovascular events in elderly patients (11931,98916,99762). Larger, high-quality trials with prespecified primary outcomes are needed to determine whether or not vitamin D supplementation reduces CVD risk in elderly populations.
• Critical illness (trauma). Taking vitamin D 540,000 IU as a single oral dose does not reduce death or hospital stay in critically ill patients. However, limited research suggests that taking a smaller dose of vitamin D long-term might have a modest benefit. Details: The most robust evidence to date shows that correcting vitamin D levels in critically ill patients with vitamin D deficiency does not reduce mortality rate or duration of hospital stay. A large, multicenter clinical study in critically ill patients with vitamin D deficiency shows that administering a single, enteral dose of vitamin D 540,000 IU does not reduce 90-day all-cause mortality, duration of hospital stay, ventilator-free days, or other clinical outcomes when compared with placebo (103656). A previous meta-analysis of clinical research showed that vitamin D supplementation administered for a duration of 7 days or up to 6 months reduces the risk of death by 30% in critically ill hospitalized patients (95913). However, included studies were of low methodological quality, had high heterogeneity, assessed patients with and without vitamin D deficiency, and used variable vitamin D dose regimens and administrations methods (95913,95914).
• Fractures. Most evidence shows that oral vitamin D alone does NOT prevent factures in people who do not have osteoporosis. Some research shows that taking vitamin D with calcium prevents fractures; however, more research is needed to determine who is most likely to benefit. Details: Clinical research shows that taking vitamin D alone does not seem to prevent fractures in older adults. Most adults in these studies did not have osteoporosis, although osteoporosis status was unclear in some research (10140,12933,14282,38970,39015,84660,95822,97296,102145,104619)(109059,110827). However, several meta-analyses suggest that taking higher doses of vitamin D (about 800 IU daily) in combination with calcium might reduce overall fracture risk in older patients (38942,38970,39015,84660,102145,110809). One meta-analysis of clinical research in community- or long-term care-living males and females at least 65 years of age shows that taking vitamin D 800 IU daily in combination with calcium reduces the risk of hip and non-vertebral fractures by 25% and 20%, respectively, compared with placebo (110809). However, discrepancies exist which are possibly related to the dose and form of calcium used in combination with vitamin D and/or the patient population. Some research shows that taking vitamin D 800 IU daily in combination with calcium 1200 mg daily as tricalcium phosphate reduces fracture risk by up to 31% while taking vitamin D with calcium carbonate does not reduce fracture risk (12929,14282,16878,110809). Some individual clinical studies in postmenopausal females aged 50-79 years show that taking vitamin D plus calcium daily for 2-7 years does not prevent fractures when compared with placebo (14282,16878). Other confounding variables include the possible additional effects of hormonal therapy when given with calcium to postmenopausal adults and/or the inclusion of institutionalized patients with unclear osteoporotic status (95822,97296). Most research shows that taking vitamin D in combination with omega-3 fatty acids does not prevent fractures. A large clinical study shows that taking vitamin D 2000 IU daily alone or with omega-3 fatty acids 1 gram daily and/or strength training three times weekly does not prevent fractures in adults over 70 years of age when compared with placebo (104619). Another large clinical trial shows that taking vitamin D 2000 IU daily, alone or with omega-3 fatty acids 1 gram daily, over approximately 5 years does not prevent overall fractures, nonvertebral fractures, or hip fractures in adults over 50 (males) or 55 (females) years old when compared with placebo. Although the osteoporosis status of the population was unclear, findings were consistent in adults at high fracture risk based on use of osteoporosis medications and/or a history of fragility fractures (109059). As of April 2018, the US Preventative Services Task Force (USPSTF) recommends against supplementing with vitamin D 400 IU daily or less along with calcium 1000 mg daily or less for preventing primary fractures in community-dwelling postmenopausal adults. The USPSTF also concludes that there is insufficient evidence to determine whether supplementing with doses of vitamin D greater than 400 IU daily along with calcium doses greater than 1000 mg daily is safe or effective for preventing fractures in community dwelling adults without vitamin D deficiency, osteoporosis, or a history of fracture (95695). For information on patients WITH osteoporosis, refer to the Osteoporosis discussion. There is limited research available regarding the effects of vitamin D supplementation for fracture prevention in children. Preliminary research in children aged 2 to 17 years with vitamin D insufficiency and one or more previous fractures shows that taking vitamin D 2000 IU daily with calcium 600 mg daily for 6 months modestly reduces the risk of forearm fractures over 12 months compared with children not given vitamin D or calcium (110820).
• Hypertension. Overall, vitamin D does not seem to prevent or lower high blood pressure in most patients; however, it may lower blood pressure in hypertensive patients with vitamin D deficiency. Details: Although population research has found that lower vitamin D levels are associated with a higher risk of developing hypertension, clinical research shows vitamin D supplementation does not prevent hypertension (15630) A large clinical trial in postmenopausal adults shows that taking vitamin D3 400 IU with calcium 1000 mg daily does not reduce the risk of developing hypertension (16714). Most meta-analyses and clinical trials in patients with existing hypertension show that vitamin D supplementation does not lower blood pressure when compared with placebo, regardless of vitamin D formulation, dose, or duration of supplementation (16714,91340,96405,103657,104619). However, a meta-analysis of five clinical studies in patients with hypertension and vitamin D deficiency shows that supplementation with vitamin D reduces systolic and diastolic blood pressure by about 7 mmHg and 3 mmHg, respectively, when compared with placebo (100895). Similarly, an individual clinical study in patients with hypertension and vitamin D deficiency or insufficiency shows that taking vitamin D 50,000 IU weekly or 1000 IU daily reduces systolic blood pressure by about 6 mmHg and mean arterial pressure by about 4 mmHg, but does not affect diastolic blood pressure, when compared with baseline (108440). The validity of these findings is limited by the lack of a comparator group.
• Prostate cancer. Oral vitamin D does not appear to affect prostate cancer progression or cancer-related mortality. Details: A meta-analysis of three clinical trials shows that vitamin D supplementation does not affect prostate cancer progression as measured by prostate-specific antigen (PSA), or mortality in patients with prostate cancer (99770).
• Psychosis. Oral vitamin D does not seem to improve symptoms in patients with a functional psychotic disorder. Details: A clinical study in adults with a functional psychotic disorder shows that taking oral vitamin D3 (cholecalciferol) 20,000 IU monthly for 6 months has no effect on total positive and negative syndrome scale score (PANSS) when compared with placebo. The majority of patients included in this study were deficient in vitamin D at baseline (107226).
• Tuberculosis. Oral vitamin D seems to be ineffective for reducing the severity of tuberculosis or mortality from tuberculosis. Limited research suggests that vitamin D may have small benefits in newly diagnosed patients receiving tuberculosis treatment for the first time. Details: Although population research has found that tuberculosis is associated with vitamin D deficiency, most clinical research shows that taking vitamin D does not improve clinical outcomes in people with tuberculosis infection. Meta-analyses and individual clinical studies show that taking vitamin D as a single 100,000 IU dose, or as 400 IU daily for 2 months, along with standard care does not improve tuberculosis severity or reduce the risk of mortality in children or adults with tuberculosis, regardless of their baseline vitamin D levels (82570,82475,98913,103655,103668,104022). However, some research has identified modest benefits in newly diagnosed patients receiving anti-tuberculosis treatment for the first time. A meta-analysis of clinical research in this population shows that taking vitamin D at a dose of 1000 IU daily or 600,000 IU monthly modestly increases the odds of sputum smear conversions by 1.2-fold, but does not improve the time to sputum smear conversions, when compared with placebo (98235). A small clinical study in treatment-naïve adults with low levels of serum vitamin D shows that taking calcitriol 0.25 mcg twice daily for up to 6 months, starting with anti-tuberculosis treatment initiation, decreases the time to sputum smear conversion and 50% lesion absorption by about 3 days when compared with not taking vitamin D (109045). Additionally, a small clinical study in children aged 6-18 years with vitamin D insufficiency receiving standard treatment for newly diagnosed pulmonary tuberculosis shows that taking vitamin D 1000 IU daily reduces the duration of fever and cough by 1 and 2 weeks, respectively, when compared with placebo (108437).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if oral vitamin D is beneficial for acne. Details: A small clinical trial in patients with acne and vitamin D deficiency shows that taking cholecalciferol 1,000 IU daily for 2 months reduces the number of inflammatory lesions by about 35%, compared with 6% in those taking placebo. There was no effect on the total or non-inflammatory lesion count (106127). Other preliminary clinical research shows that taking alfacalcidol (One Alpha, LEO Company, Denmark) 0.25 mcg daily for 3 months modestly improves acne severity when compared with taking placebo (106128). In addition, population research has found that individuals with acne have modestly lower vitamin D levels than healthy controls. The odds of vitamin D deficiency were approximately three times higher in patients with acne when compared with healthy controls (106105).
• Age-related cognitive decline. It is unclear if oral cholecalciferol is beneficial for preventing age-related cognitive decline. Details: Pooled results of two large clinical sub-studies in community-dwelling adults aged 60 years or older show that taking cholecalciferol 2000 IU daily for 2-3 years has no effect on cognitive decline when compared with placebo. A subgroup analysis in Black patients suggests a modest effect of vitamin D when compared with placebo (108428).
• Alzheimer disease. It is unclear if oral vitamin D is beneficial for this condition. Details: Some population research has found that lower serum concentrations of vitamin D are associated with higher risk of Alzheimer disease, and also with decreased cognition. People with Alzheimer disease seem to have serum concentrations of vitamin D that are about 2.5 ng/mL lower than patients without Alzheimer disease (84672,103666). However, other population research has found that vitamin D deficiency (<25 nmol/L) or insufficiency (25-50 nmol/L) is not associated with increased risk of Alzheimer disease (100899).
• Asthma. Oral vitamin D might reduce asthma exacerbations in adults and children with mild, but not severe or persistent, asthma. Vitamin D supplementation during pregnancy or the first 6 months of an infant's life does not seem to prevent the development of asthma later in infancy or childhood. Details: Population research in patients with asthma suggests that low vitamin D levels are associated with an increased risk of exacerbations and increased need for medication therapy (94693). However, findings from clinical research are mixed. Some meta-analyses of clinical trials in adults and children with asthma show that taking vitamin D for 3 months to 1 year reduces the rate of asthma exacerbations by 31% to 36% when compared with control (92690,94686). However, findings from more recent meta-analyses show that vitamin D supplementation does not reduce the risk of asthma exacerbations when compared with placebo (109728,109732,110833). The reasons for this discrepancy are not clear. However, some clinical research suggests that vitamin D supplements might only prevent asthma in people with non-persistent asthma (92690,94685,94686,94688,104020). Also, many studies are small and do not represent patients with severe asthma exacerbations (92690,94687). Baseline levels of vitamin D may play a role. A clinical study in children aged 6-16 years with persistent asthma and low vitamin D levels shows that taking vitamin D 4000 IU daily for 48 weeks does not reduce severe asthma exacerbations when compared with placebo (104020). However, a meta-analysis including this study shows that taking vitamin D does reduce risk of asthma exacerbations in children with low baseline vitamin D levels (109728). One meta-analysis shows that taking vitamin D seems to modestly improve pulmonary function when compared with placebo (109732). Vitamin D doses have varied, with oral doses of 500-4000 IU daily, 1000 IU once weekly, 60,000 IU once monthly, 120,000 IU every 2 months, 100,000 IU 14 days apart, or 100,000 to 600,000 IU as a bolus dose followed by 400-4000 IU daily (92690,94686,104020,109728,110833). Vitamin D supplementation for the prevention of asthma in infants has also been evaluated. A meta-analysis of 4 large clinical studies shows that taking vitamin D 400-1200 IU daily for the first 6 months of life does not reduce the risk of asthma or wheezing at 6-30 months of age when compared with control (112031). Vitamin D supplementation during pregnancy has also been evaluated (97306,99763,102146,112031). A meta-analysis of 3 large clinical studies shows that taking vitamin D 2800-4400 IU daily during the 2^nd and 3^rd trimesters of pregnancy reduces the risk of recurrent wheezing by 23% but does not reduce the risk of asthma diagnosis within the first 3-6 years of life when compared with vitamin D 400 IU daily (112031). Some research suggests that the dose of vitamin D plays a role. A meta-analysis shows that prenatal vitamin D 800 IU daily reduces the odds of wheeze or asthma by 32%, while lower or higher vitamin D doses were not beneficial (103661).
• Athletic performance. It is unclear if oral vitamin D is beneficial for athletic performance. Details: One small clinical trial in athletes shows that taking vitamin D 20,000 or 40,000 IU once weekly for 2 doses does not affect performance on vertical jumps, sprints, or leg and bench presses when compared with placebo (98188). Another small clinical trial in professional rugby players shows that taking vitamin D3 (cholecalciferol) 50,000 IU once every two weeks over 12 weeks does not improve sprinting speed or the ability to perform bench presses, bench pulls, and chin-ups when compared with placebo (98189). Also, most research shows that taking vitamin D does not improve measures of cardiorespiratory fitness. One small study in young males undergoing resistance training shows that taking vitamin D 8000 IU daily for 12 weeks does not improve cardiorespiratory fitness compared with taking placebo (110812).
• Atopic dermatitis (eczema). Most research shows that oral vitamin D reduces eczema severity in children. However, most research shows that oral vitamin D, taken during pregnancy or infancy, does not prevent eczema in the child. Details: A meta-analysis of eight moderate-quality clinical trials in children shows that taking vitamin D, most commonly 1000-2000 IU daily for 4-12 weeks, modestly reduces severity of eczema when compared with placebo (109728). Most of the children in these studies were also given conventional medications. Oral vitamin D has also been evaluated for eczema prevention. A meta-analysis of two clinical studies shows that consuming vitamin D 2800-4400 IU daily during the 2^nd and 3^rd trimesters of pregnancy is not associated with a reduced risk for eczema in children during the first 3 years of life when compared with vitamin D 400 IU daily (97306). Another meta-analysis of five large clinical studies shows that prenatal or infant vitamin D supplementation does not reduce the risk of developing eczema when compared with low-dose vitamin D, placebo, or no intervention (108438).
• Atrial fibrillation. It is unclear if oral vitamin D is beneficial for preventing atrial fibrillation. Details: A large clinical trial in adults without cardiovascular disease shows that taking vitamin D 2000 IU daily for an average of 5 years does not reduce the incidence of atrial fibrillation when compared with placebo or fish oil 840 mg daily (105209). However, observational research in postmenopausal adults with osteoporosis found that vitamin D supplementation is associated with a lower occurrence of atrial fibrillation when compared with not taking vitamin D (98922). Also, one large observational study in vitamin D-deficient patients with no history of atrial fibrillation has found that vitamin D supplementation for at least 6 months is associated with up to a 16% decreased risk of atrial fibrillation when compared with not taking vitamin D. There were also modest improvements in atrial fibrillation-free survival. In males 65 years and older with hypertension or diabetes at baseline, blood levels of at least 30 ng/mL following vitamin D supplementation were associated with decreased risk of atrial fibrillation; a post-supplementation blood level of 21-29 ng/mL was not associated with decreased risk (109043).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral vitamin D is beneficial for ADHD. Details: A small clinical trial in children 5-12 years of age with ADHD and vitamin D insufficiency shows that taking vitamin D 2000 IU daily along with methylphenidate for 8 weeks seems to improve parental ratings of evening, but not morning or overall, symptoms of inattentiveness and impulsivity when compared with methylphenidate alone. Vitamin D insufficiency was defined as levels less than 30 ng/mL (98196). Based on these and other preliminary findings, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that vitamin D in doses of 1500 to 4000 IU daily is weakly recommended for adjunctive use in children with ADHD, especially those with insufficient intake or skin exposure to sunlight (110318).
• Autism spectrum disorder. It is unclear if oral vitamin D is beneficial for autism spectrum disorder. Details: A small clinical study in children aged 2.5-8 years with autism spectrum disorder shows that taking vitamin D 2000 IU daily for 12 months modestly reduces irritability and hyperactivity when compared with placebo (99767).
• Bacterial vaginosis. It is unclear if oral vitamin D is beneficial for bacterial vaginosis. Details: Preliminary clinical research in females at high risk for sexually transmitted disease shows that taking vitamin D along with standard therapy for bacterial vaginosis does not reduce the prevalence of bacterial vaginosis when compared with placebo. Patients in this study had been treated with metronidazole 500 mg orally twice daily for 7 days along with vitamin D3 (cholecalciferol) 50,000 IU each week for 4 weeks and then every 4 weeks for the remaining 20 weeks (91348).
• Breast cancer. It is unclear if oral vitamin D is beneficial for the prevention of breast cancer. Details: Some population research evaluating intake of calcium plus vitamin D suggests that higher vitamin D intake is not associated with a reduced risk of breast cancer in premenopausal or postmenopausal adults (15631). Similarly, a large observational study in females with a biological sibling with breast cancer has found that taking vitamin D recently or prior to enrollment is not associated with a reduced risk of breast cancer when compared with nonrecent vitamin D use or never taking vitamin D, respectively (107215). However, other research found that higher vitamin D intake is associated with a 17% reduced risk of breast cancer in premenopausal and perimenopausal, but not postmenopausal, adults (39001). Observational research has also examined the association between blood levels of vitamin D and risk of developing breast cancer. A meta-analysis found that those with serum levels of about 52 ng/mL had a 50% lower risk of developing breast cancer when compared with those with serum levels of less than 13 ng/mL. This high serum level of vitamin D corresponds to a high dose of about 4000 IU daily (16049). Other observational research has found that baseline vitamin D levels of more than 20 ng/mL are associated with a 48% reduced risk of developing breast cancer over approximately 9 years in Latina females in the US when compared with levels below 20 ng/mL; however, this association was not present in Black females (109058). Despite the contradictory findings from observational research, results from clinical research are generally negative. Evidence from one large-scale clinical trial (Women's Health Initiative) shows that postmenopausal adults who take vitamin D3 (cholecalciferol) 400 IU daily plus calcium 1000 mg daily for 7 years do not have a significantly reduced risk of developing breast cancer (16715,98895). Also, a meta-analysis of two large-scale clinical trials, which did not include the Women's Health Initiative trial, shows that taking vitamin D 800-1000 IU daily, alone or with calcium, for 3-4 years does not reduce the incidence of breast cancer in postmenopausal adults, although there was a trend towards reduced risk with higher doses of vitamin D supplementation (97301). While vitamin D and calcium supplementation during the intervention period of the Women's Health Initiative trial was not associated with a reduced risk of developing breast cancer or ductal carcinoma in situ (DCIS), a precursor to breast cancer, a secondary post-hoc analysis of the data shows that supplementation reduces the risk of developing DCIS by 18% over a median follow-up of 19 years (107216). Additional research is needed regarding an optimal dose of vitamin D, timing of initiation, and whether any benefit is affected by menopausal status.
• Bronchopulmonary dysplasia. Limited research suggests that vitamin D deficiency is linked with bronchopulmonary dysplasia in the infant. Details: Observational research has found that vitamin D deficiency at birth is associated with about a 2-fold increased odds of developing bronchopulmonary dysplasia (104021). However, it is unclear if vitamin D supplementation is beneficial.
• Cancer. Vitamin D does not seem to reduce overall cancer risk. However, some research shows that vitamin D might slightly reduce the risk of metastatic cancer and cancer-related mortality. Details: There is interest in vitamin D for cancer PREVENTION, as observational research suggests that higher vitamin D intake and higher 25-hydroxyvitamin D levels are associated with a lower risk of cancer (111150). While individual clinical trials evaluating vitamin D for cancer have produced inconsistent findings, most meta-analyses and clinical trials show that taking vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol) alone or with calcium does not significantly reduce the risk of developing cancer (15629,91344,93943,97296,98916,104024,104618,110811). However, vitamin D supplementation might reduce the risk of metastatic cancer and cancer-related mortality. A large clinical trial shows that taking vitamin D3 2000 IU daily for a median of 5.3 years slightly reduces the risk of advanced metastatic or fatal cancers when compared with placebo (104618). Additionally, meta-analyses of several large clinical trials show that taking vitamin D 400-4000 IU daily, with or without calcium, for 1-7 years reduces the risk of cancer-related mortality by 12-13% when compared with control, while intermittent bolus dosing of vitamin D at high doses for 1-5 years does not appear to reduce the risk of cancer-related mortality (104024,111149). The role of vitamin D in cancer TREATMENT is unclear. A meta-analysis of clinical and observational research suggests that supplementation of vitamin D after a cancer diagnosis is associated with a modest improvement in overall survival, but not progression-free or cancer-specific survival (109726). Doses used in clinical research ranged between 1200 IU and 8000 IU daily or 100,000 IU every 50 days, after surgery and/or during treatment (99195,99196,109726). Other clinical research in patients with luminal gastrointestinal cancers shows that taking vitamin D 2000 IU daily does not reduce the risk of relapse when compared with placebo (99195). It is unclear which, if any, types or stages of cancer respond best to vitamin D, and what dose of vitamin D is optimal.
• Child growth. It is unclear if oral vitamin D is beneficial for improving infant growth or bone structure. Details: Meta-analyses and individual clinical trials show that vitamin D supplementation during pregnancy modestly increases length at birth and bone mineral density at up to 6 years of age when compared with control, usually placebo or vitamin D 400 IU daily. However, there was no effect on length in the infant up to one year of age, weight at birth or up to one year of age, head circumference at birth or up to 6 years of age, bone mineral content at up to 6 years of age, or neonatal bone mineral density, bone mineral content, bone area, or femur or humoral length (98198,109737,112028). In the available research, vitamin D was taken in doses of 200 IU to 4400 IU daily, 4200 IU to 50,000 IU weekly, 50,000 IU every 2 weeks, or 60,000 IU every 4-8 weeks, starting from the early to late stages of pregnancy and usually continued until birth (98198,109737).
• Chronic kidney disease (CKD). It is unclear if oral vitamin D is beneficial in patients with CKD. Most research suggests that it does not reduce the risk for adverse cardiovascular events. Details: Population research in patients on dialysis has found that vitamin D levels less than 17.8 ng/mL are associated with a higher risk of all-cause mortality compared with higher levels (16619). A meta-analysis and individual clinical studies show that vitamin D and vitamin D analogues decrease parathyroid hormone (PTH) levels and urine protein levels in people with CKD (84376,84377,84628,98233,98236). However, taking vitamin D does not appear to decrease the risk of death or parathyroidectomy in CKD patients (84376,84377). Also, taking vitamin D increases the risk for hypercalcemia and hyperphosphatemia in this patient population (84376,84377,98236). Vitamin D has also been evaluated for the prevention of cardiovascular events in adults with CKD. Observational research has found that vitamin D deficiency in patients with CKD is associated with adverse cardiovascular events. However, vitamin D supplementation does not seem to be beneficial. One clinical study shows that taking paricalcitol, an active form of vitamin D, titrated to maintain adequate serum calcium levels, for 48 weeks does not affect the size of the left ventricle or heart function when compared with placebo (98233). Other clinical research in Japanese patients on hemodialysis for CKD shows that adding alfacalcidol, another active form of vitamin D, 0.5 mcg daily to standard treatment for 4 years does not affect mortality or cardiovascular events such as myocardial infarctions, stroke, aortic dissection, and others compared to standard treatment only (98920). Also, a large clinical trial in patients with CKD shows that taking vitamin D as cholecalciferol 2000 IU daily, alone or with omega-3 fatty acids 1 gram daily, does not affect major cardiovascular events or invasive cancer when compared with placebo (110811). Vitamin D has also been evaluated for musculoskeletal health in adults with CKD. A small clinical study shows that taking cholecalciferol 4000 IU daily, with or without physical activity, for 3 months improves bicep strength, but not back flexibility or aerobic fitness capacity, when compared with baseline. In patients taking cholecalciferol in combination with physical activity, musculoskeletal health was similar when compared with cholecalciferol alone (108431). However, this study was inadequately powered to detect a difference between groups, and it is unclear if the improvement from baseline differed between groups. Vitamin D has also been evaluated for the improvement of iron status in adults with CKD and secondary hyperparathyroidism. Clinical research shows that taking Vitamin D as cholecalciferol (Vitamin D3 Forte Renapharma) 8000 IU daily for 12 weeks does not improve iron status compared with taking placebo. However, a sub-analysis shows that hemoglobin levels are modestly improved in patients with a low Vitamin D status at baseline suggesting that Vitamin D might improve iron availability in these patients (110819).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral vitamin D is beneficial for COPD; benefits may be limited to patients with vitamin D deficiency. Details: Population research has found an association between low vitamin D levels and reduced lung function, increased risk of developing COPD, and worsening COPD severity (17685,96401). In contrast, 2 meta-analyses of clinical research in adults with COPD and with or without vitamin D deficiency show that oral vitamin D does not have beneficial effects on mortality, rate of COPD exacerbations, pulmonary function, or most measures of symptom severity when compared with placebo (109732,112485). However, other research suggests that vitamin D may be beneficial in patients with vitamin D deficiency. Some clinical research in patients with moderate to severe COPD and severe vitamin D deficiency shows that taking a specific vitamin D supplement (D-Cure, Laboratoires SMB) 100,000 IU once every 4 weeks for 1 year seems to reduce the rate of exacerbations by 43% when compared with placebo (98194).
• Cognitive function. It is unclear if oral vitamin D is beneficial for cognitive function. Details: Population research has found that low vitamin D levels are associated with worse cognitive performance and cognitive decline when compared to high vitamin D levels in healthy adults (84672,95916). However, the effect of vitamin D supplementation on cognitive function is unclear. One small meta-analysis of clinical research shows that vitamin D supplementation does not improve cognitive function (95916). However, the included trials evaluated a widely heterogeneous study population and utilized variable measures of cognitive function.
• Cognitive impairment. It is unclear if oral vitamin D is beneficial for older adults with mild cognitive impairment. Details: A small clinical study in older adults with mild cognitive impairment shows that taking vitamin D3 10,000 IU three times weekly for 20 weeks in addition to exercise and cognitive training does not improve cognitive function when compared with placebo and exercise with or without cognitive training. However, most participants had sufficient serum vitamin D levels at baseline (112489).
• Colorectal cancer. It is unclear if oral vitamin D is beneficial for the treatment or prevention of colorectal cancer. Details: Epidemiological research has found that a higher serum vitamin D level is associated with decreased risk of mortality and increased survival in patients with colorectal cancer (16101,99196). However, it is unclear whether vitamin D supplementation improves survival in patients with colorectal cancer, as research has generally involved small populations and results are somewhat conflicting. A subgroup analysis of one clinical study shows that taking vitamin D 2000 IU daily does not reduce the risk of relapse or death, death due to any cause, or relapse over 5 years when compared with placebo in patients with colorectal cancer (99195). However, this subgroup may have been underpowered to detect between-group differences. Another small clinical trial in patients with advanced or metastatic colorectal cancer shows that taking high-dose vitamin D 8000 IU daily during the first cycle of chemotherapy, and then 4000 IU daily for subsequent cycles, does not increase median progression-free survival when compared with taking vitamin D 400 IU daily. However, patients taking high-dose vitamin D were 36% less likely to experience disease progression or death during follow-up when compared with patients taking the lower dose of vitamin D (99196). This latter result suggests that high-dose vitamin D supplementation might be beneficial for patients with advanced or metastatic colorectal cancer, but larger, multicenter studies are needed to confirm. The role of vitamin D in colorectal cancer prevention has also been investigated. A meta-analysis of epidemiological research has found that a higher serum vitamin D level is associated with a decreased colorectal cancer risk; however, sub-analyses suggest that this association only occurs in females, not males (109740). Most studies have evaluated vitamin D supplements in combination with calcium; the effects of vitamin D supplementation alone are unclear. One meta-analysis of clinical research suggests that taking vitamin D plus calcium is not associated with a decreased incidence of colorectal cancer in people with a low baseline risk of colorectal cancer (39042). Another meta-analysis of clinical research shows that vitamin D supplementation, with or without calcium, does not reduce the incidence of colorectal cancer or colorectal adenomas (109730). Additionally, a large clinical trial suggests that postmenopausal adults who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290,98895). One clinical study shows that taking calcium supplements reduces the risk of colorectal adenomas, but not in people with lower than average vitamin D levels (12118).
• Coronavirus disease 2019 (COVID-19). The evidence is mixed with respect to oral vitamin D supplementation for the prevention and treatment of COVID-19. Also, although some observational research has suggested a correlation between vitamin D status and risk for COVID-19, not all studies agree, and this association may be due to other confounders such as age and comorbidities. Details: Clinical and observational research has evaluated vitamin D supplementation for COVID-19 prevention. A preliminary clinical trial shows that oral vitamin D 800 IU or 3200 IU daily for 6 months in individuals with lower serum levels of vitamin D does not reduce the risk of COVID-19 or any respiratory tract infection when compared with no vitamin D supplementation (109721). However, groups were not matched for baseline vitamin D status and many individuals in the untreated group took their own vitamin D supplements. Two meta-analyses of clinical and observational studies show no relationship between vitamin D supplementation and the primary prevention of COVID-19 infection, although baseline vitamin D status is unclear (109040,112488). Also, a quasi-experimental cohort study in Italian adults who had supplemented with vitamin D in the 3 months prior to COVID-19 diagnosis found no reduction in risk for hospitalization, as well as a trend towards increased risk for in-hospital mortality, when compared with those who had not received vitamin D supplementation (104625). However, some research disagrees. Clinical research in highly exposed healthcare workers shows that taking vitamin D as cholecalciferol 4000 IU daily for 30 days reduces the risk of COVID-19 infection by 77% when compared with placebo (109052). Also, in the UK population, observational research has found that habitual use of vitamin D supplements between 2006 and 2010 is associated with a 34% lower risk of COVID-19 infection. This finding remained positive after adjusting for baseline health status and use of other micronutrients (104717). Further research is needed to determine whether vitamin D supplementation prevents COVID-19 infection. Vitamin D supplementation as treatment in outpatients with COVID-19 has also been evaluated. Preliminary clinical research discussed in a systematic review suggests that supplementation might be associated with less severe symptoms; however, there is inadequate information to determine if supplementation in patients with mild symptoms is associated with reduced hospital admission (109040). Conversely, a large cross-sectional study found an association between pre-hospital supplementation and increased risk for COVID-19, as well as increased rates of death and/or invasive mechanical ventilation. However, this association was no longer significant after adjusting for sex, age, and comorbidities (107205). Most research on vitamin D supplementation has been conducted in children and adults hospitalized with COVID-19. However, meta-analyses of clinical and observational research in these patients provides conflicting results on whether vitamin D supplementation as single dose or multiple doses is associated with a reduced risk of mortality, length of hospitalization, admission to the intensive care unit (ICU), or need for ventilation when compared with placebo or standard care alone (109040,109733,112488,112490). The quality of evidence of most individual clinical trials is low to moderate due to a lack of placebo and blinding in many of the studies. Most individual studies evaluating single doses of vitamin D, administered either after diagnosis or after hospital admission, have not identified benefit for major outcomes, such as hospital length of stay, in-hospital mortality, or ICU admission. Many of these studies were small, low quality, and conducted in heterogenous populations, with doses ranging from 80,000 IU to 500,000 IU (104624,104626,107208,108434,109051,112490). One small, unblinded study in at-risk older adults admitted to the hospital or living in a long-term care facility shows that taking a single dose of 400,000 IU within 72 hours of diagnosis modestly improves survival at 14 days, but not 28 days, when compared with 50,000 IU (109039). The evidence related to multi-dose regimens in hospitalized patients is mixed. A cohort study shows that giving calcifediol 0.532 mg at hospital admission, followed by calcifediol 0.266 mg on days 3 and 7 and then weekly until discharge or ICU admission, reduces odds of in-hospital death within 30 days by 78% when compared with those not given vitamin D (106099). A small clinical trial in patients with vitamin D deficiency shows that taking vitamin D 25,000 IU daily for 4 days and then weekly for up to 6 weeks reduces length of hospital stay and duration of supplemental oxygen by 4 days and 3 days, respectively, and also reduces disease severity and ICU admission after 7 days (109050). A small, unblinded study in patients with suboptimal vitamin D status and mild to moderate COVID-19 shows that taking vitamin D3 5,000 IU daily for 2 weeks reduces the time to recovery from cough and loss of taste by 2.9 and 5.5 days, respectively, when compared with vitamin D3 1,000 IU daily. However, there was no difference in time to recovery from fever, dyspnea, body aches, or other symptoms (106117). However, some research disagrees. A small unblinded study has found that although vitamin D status at 9 days is negatively associated with the number of bed days, vitamin D 50,000 IU on days 1 and 8 does not affect the number of bed days, time to discharge, or ICU admission when compared with no supplementation (109047). An additional preliminary study in patients with severe COVID-19 and low blood levels of vitamin D shows that taking vitamin D (Plivit D3, Pliva) 10,000 IU daily while in the ICU or for at least 14 days does not reduce the number of days on respiratory support, or in the ICU or hospital, or improve survival rates when compared with no supplementation (110813). The relationship between vitamin D levels and COVID-19 has also been evaluated in pregnant patients. A meta-analysis of observational research suggests that, while lower vitamin D levels are not associated with an increased risk of COVID-19, the presence of severe COVID-19 symptoms in pregnant patients may be linked to lower vitamin D levels when compared with non-severe COVID-19 symptoms (112025). Limited research has investigated the effect of vitamin D in combination with other ingredients. Preliminary clinical research in patients with mild to moderate COVID-19 shows that taking vitamin D3 (Davalindi, Medical Union Pharma, Cairo, Egypt) 2000 IU daily in combination with black seed (Baraka, Pharco Pharmaceuticals, Cairo, Egypt) 900 mg twice daily for 14 days modestly reduced the severity of some symptoms, including cough, diarrhea, fatigue, and pharyngitis, as well as the percent patients with viral positivity at day 7, but not headache, rhinorrhea, anosmia, or shortness of breath, or vomiting, when compared to standard care alone. However, taking vitamin D alone did not provide significant benefit (110265). The validity of individual studies is limited by generally poor designs. More research is needed to evaluate varying vitamin D dosing levels and schedules, as well as evaluated outcomes, and whether patients with vitamin D insufficiency are more likely to benefit from vitamin D supplementation. The relationship between vitamin D status and risk of COVID-19 infection or severe disease is unclear. Despite some observational research suggesting that low vitamin D levels are associated with an increased risk for COVID-19 mortality, development of severe disease, such as pulmonary involvement, and extended hospitalization or admission to intensive care (107206,107207,108434), several meta-analyses of observational research as well as individual observational studies have found that vitamin D deficiency in adults is not associated with a higher risk for COVID-19 infection or with disease severity or mortality (104627,107208,107209). Additional observational research has found no association between vitamin D status and hospital length of stay, need for mechanical ventilation, mortality, or experiencing persistent feelings of fatigue or reduced exercise tolerance, otherwise known as "long-COVID" (106102,106116,106120,107206). However, one meta-analysis has found that when compared with mild disease, 65% more individuals with severe disease had vitamin D deficiency. Also, vitamin D insufficiency, defined as blood levels less than 30 ng/mL, is associated with a more than 80% increased chance of hospitalization or mortality due to COVID-19. Notably, many of these studies did not control for patient age or other comorbidities (104627). A more recent observational study has found that vitamin D status in patients with severe COVID-19 symptoms is inversely correlated with both ICU admission and death, with a 1% reduction in risk of ICU admission and 4% reduction in risk of death for every 1 ng/mL increase in 25-hydroxyvitamin D (106112). In one individual observational study, the association between vitamin D status and COVID-19 infection is no longer significant after adjusting for socioeconomic status, age, health status, body mass index, ethnicity, and other covariates (104628). In contrast, a small observational study of adults admitted to the hospital with COVID-19 has found that low vitamin D levels are associated with an increased risk of mechanical ventilation and in-hospital mortality, even after adjustment for ethnicity and pre-existing conditions, such as cardiovascular disease, respiratory disease, and diabetes. However, this study is small and does not adjust for socioeconomic factors (105720). Also, another individual observational study has found that the likelihood of testing positive for COVID-19 is increased in Black, but not White, adults who had a vitamin D level of 30-40 ng/mL at some point in the past year when compared with a level of at least 40 ng/mL, with risk decreasing as levels increased from 30 ng/mL to 40 ng/mL (104716). Patients should be encouraged to maintain adequate vitamin D levels. A joint task force has recommended 400-1000 IU (10-25 mcg) daily for those who are unable to spend 15-30 minutes in the sun each day (103659,104629).
• Crohn disease. Limited evidence suggests that vitamin D reduces relapses in patients with Crohn disease. Details: A meta-analysis of small, low-quality clinical studies in patients with IBD, including Crohn disease and ulcerative colitis, shows that taking high- or low-dose vitamin D for up to 1 year reduces the rate of relapse when compared with control (98915). The validity of these findings is limited by the heterogeneity of the included studies.
• Dementia. It is unclear if oral vitamin D is beneficial for dementia. Details: Population research has found that patients with any type of dementia have serum concentrations of vitamin D that are about 2.5 ng/mL lower than patients without dementia (84672). However, it is unclear if vitamin D supplementation is beneficial.
• Depression. It is unclear if oral vitamin D is beneficial for treating depression. Vitamin D does not seem to prevent the development of depression. Details: The role of vitamin D in the treatment of depression is unclear. Earlier meta-analyses of clinical research show that vitamin D supplementation does not improve overall symptoms of depression. However, some subgroup analyses suggest that vitamin D may be beneficial for improving the symptoms of depression in people with clinically significant symptoms, as well as those with baseline vitamin D deficiency (97295,97298). More recent meta-analyses of several clinical trials, that include some of the same studies, show that vitamin D modestly improves symptoms of depression in adults; however, subgroup analysis suggests that vitamin D does not improve depressive symptoms in older adults (110832,112786). These analyses are mixed over whether baseline vitamin D status affects results (110832,112786) and one of these analyses shows no evidence that the type of depression affects findings (110832). Another meta-analysis of generally small clinical trials in patients with type 2 diabetes and depression shows that taking vitamin D modestly improves depressive symptoms when compared with placebo or no intervention (110814). Although, results of an individual clinical trial in patients with type 2 diabetes are in contrast (108423). The evaluated research implemented one-time doses of 150,000-500,000 IU, as well as daily and weekly doses ranging between 400-5000 IU daily or 5000-100,000 IU weekly for 6 weeks to 2 years, with the most evidence of benefit related to one-time high doses. Cholecalciferol was the most common form of vitamin D used (97295,97298,108423,110814,110832,112786). Significant heterogeneity between studies and the wide variability in dosing strategies limit the validity of these findings, as well as identification of an effective dose or target population. Vitamin D has also been evaluated for the prevention of depression. One large clinical study (VITAL-DEP) in healthy patients 50 years and older shows that taking vitamin D 2000 IU daily for about 5.3 years does not prevent depression or depressive symptoms, or improve mood, when compared with placebo (103670). An analysis of a cohort of patients from the VITAL-DEP trial also shows that taking vitamin D 2000 IU daily for 2 years does not reduce the risk of major depressive disorder or improve mood scores in patients with subthreshold depression or risk factors for late-life depression when compared with placebo (112032). In addition, a meta-analysis of several clinical studies suggests that vitamin D supplementation does not prevent depression based on subgroup analysis of patients without depression at baseline (112786). Based on these and other preliminary findings, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that vitamin D in doses of 1500 to 4000 IU daily is weakly recommended for adjunctive or monotherapy use in patients with depression, especially those with insufficient intake or skin exposure to sunlight (110318).
• Diabetes. Oral vitamin D might improve glycemic indices in some patients with type 2 diabetes and gestational diabetes. It is unclear if oral vitamin D is beneficial for the prevention of type 1 or gestational diabetes. It is also unclear if intramuscular vitamin D is beneficial for the treatment of gestational diabetes. Details: Most meta-analyses of mainly small clinical trials show that vitamin D supplementation is beneficial for measures of glycemic control in patients with diabetes. However, the best evidence of benefit is in patients with baseline vitamin D deficiency. Three meta-analyses of small trials in patients with type 2 diabetes show that vitamin D supplementation reduces glycated hemoglobin (HbA1c) by 0.20% to 0.25%, and improves serum insulin, fasting blood glucose, and measures of insulin resistance when compared with control (96403,110822,112487). Supplemental vitamin D seems to be most beneficial in patients with baseline vitamin D deficiency (96403,110822,112487). Furthermore, correlation analysis suggests an inverse relationship between serum vitamin D levels and serum insulin, fasting blood glucose, and measures of insulin resistance (112487). However, another meta-analysis of small trials in patients with vitamin D insufficiency or deficiency and type 2 diabetes shows that oral vitamin D modestly improves fasting blood glucose and postprandial blood glucose, but not HbA1c, when compared with control (107210). Most of the evaluated research implemented daily or weekly doses of vitamin D for 4-48 weeks (96403,107210,110822). However, one meta-analysis of clinical research in patients with diabetes shows that vitamin D improves HbA1c, insulin resistance, and insulin measures in studies lasting less than 6 months, but not in studies lasting longer than 6 months (99764). An additional meta-analysis suggests that most evidence of benefit is associated with doses of more than 2000 IU daily for 4-12 weeks (110822). One small, long-term clinical study in middle-aged and elderly patients with type 2 diabetes shows that taking vitamin D 800 IU daily for 30 months reduces insulin levels and insulin resistance when compared with no supplementation. However, there was no effect on HbA1c or fasting blood glucose levels (109734). Thus, conflicting results may be related to the dose and duration of vitamin D supplementation, as well as patient characteristics at time of study entry, such as vitamin D status, baseline HbA1c levels, obesity, and medication regimen (97304,99764,109734,110822). Vitamin D has been evaluated for the prevention of type 1 diabetes. There is preliminary evidence that daily vitamin D supplementation (form not specified) in infants during the first year of life is associated with a reduced incidence of type 1 diabetes development later in life (10139). Also, a meta-analysis of population studies has found that vitamin D supplementation in early childhood is associated with a 29% reduced risk of developing type 1 diabetes later in life (84225). Vitamin D has been evaluated in patients with gestational diabetes. Some research has evaluated the effects of oral or intramuscular vitamin D on glycemic indices. The evidence from clinical research comparing vitamin D with placebo is mixed. Most studies show modest evidence of benefit for some markers of glycemic control. One clinical trial shows that vitamin D modestly reduces levels of insulin, as well as measures of insulin resistance, with no effect on fasting blood glucose (106125). However, other clinical research shows that taking vitamin D modestly reduces levels of fasting blood glucose and HbA1c, with no effect on insulin measures (106126). Two other trials show that taking vitamin D modestly improves all measures of glycemic indices (101775,106122). Additionally, a large clinical trial shows that taking vitamin D 1600 IU daily modestly reduces fasting blood glucose when compared with vitamin D 400 IU daily (112020). Some clinical research has also evaluated the effects of oral vitamin D on lipid indices in patients with gestational diabetes. Although some individual clinical research disagrees (106126), most research shows that taking vitamin D modestly improves levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides when compared with control (106125,110823). Also, a meta-analysis of clinical research in patients with gestational diabetes shows that taking vitamin D reduces the risk of premature birth and neonatal hospitalization by approximately 63% and 62%, respectively (110823). Oral vitamin D 50,000 IU (eg. D-Vitin50000; Zahravi Pharm Co.) once or twice monthly, starting at week 24 of gestation and continuing for 6 weeks, 8 weeks, or until delivery, has been used in most of these studies (106122,106125,106126). One study provided oral vitamin D 500 IU twice daily in yogurt from the beginning of the second trimester for 16 weeks (101775). However, other preliminary clinical research shows that giving vitamin D 300,000 IU as a single intramuscular injection at 24-28 weeks' gestation does not affect HbA1c (106124). Some research has examined the effect of vitamin D supplementation on insulin resistance during pregnancy in the absence of gestational diabetes. A meta-analysis of clinical research shows that taking vitamin D for 6 to 26 weeks modestly decreases measures of insulin resistance when compared with placebo. However, there was no evidence to suggest that higher doses were more beneficial than lower doses. Although this population did not have gestational diabetes, these results suggest that adequate vitamin D might be beneficial for its prevention (110821). Vitamin D has also been evaluated in combination with omega-3 fatty acids in adults with gestational diabetes. One study evaluated vitamin D in combination with eicosapentaenoic acid (EPA) 360 mg plus docosahexaenoic acid (DHA) 240 mg twice daily. There is some evidence that this combination offers benefit over vitamin D alone and plasma triglyceride levels were also improved (106122). Other clinical research in patients with gestational diabetes shows that taking vitamin D with omega-3 fatty acids 8,000 mg twice daily for 6 weeks modestly improves glycemic indices and most lipid markers when compared with placebo (106114). Vitamin D has also been evaluated for the prevention of gestational diabetes. A meta-analysis of four clinical trials shows that vitamin D supplementation reduces the risk of gestational diabetes by 49% when compared with placebo (100897). In addition, a meta-analysis of population studies has found that there is a U-shaped association between serum vitamin D concentrations and the risk of developing gestational diabetes, with serum concentrations between 40 and 90 nmol/L associated with the lowest risk (106109).
• Diabetic foot ulcers. It is unclear if oral vitamin D is beneficial for diabetic foot ulcers. Details: A meta-analysis of clinical research in patients with diabetic foot ulcers shows that taking vitamin D modestly reduces ulcer size and improves glycemic and lipid indices when compared with placebo (110835). This meta-analysis is limited by the availability of three small clinical trials, as well as the heterogeneous doses of vitamin D in the included studies.
• Diabetic nephropathy. Limited evidence suggests that vitamin D improves some markers of kidney function in patients with diabetic nephropathy. Details: A meta-analysis of small clinical studies in patients with diabetic nephropathy shows that taking vitamin D or its analogs reduces inflammatory markers and protein in the urine, but does not affect measures of kidney function such as serum creatinine or glomerular filtration rate, when compared to control (99771).
• Dysmenorrhea. Limited evidence suggests that oral vitamin D reduces pain in patients with dysmenorrhea. Details: A meta-analysis of 9 small clinical studies in patients with dysmenorrhea shows that taking vitamin D in doses ranging from 5000 IU daily to 300,000 IU monthly modestly reduces pain when compared with control (112029). However, the validity of these findings is limited by a high degree of heterogeneity across the studies, including differences in blinding and control interventions, vitamin D doses and frequency of supplementation, and baseline vitamin D levels. Another small clinical study in adolescent patients with dysmenorrhea shows that taking vitamin D3 50,000 IU weekly for 9 weeks modestly reduces pain when compared to baseline (98912). The validity of this finding is limited by the lack of a control group.
• Exercise-induced muscle damage. Small studies suggest that vitamin D does not improve exercise-induced muscle damage. Details: A meta-analysis of 6 small studies shows that taking vitamin D before and/or during exercise does not improve circulating levels of creatine kinase, lactate dehydrogenase, or myoglobin when compared with placebo (107218).
• Fall prevention. The role of vitamin D in fall prevention is confusing and controversial. Oral vitamin D should be considered for those with vitamin D deficiency. Details: Higher serum levels of vitamin D have been associated with improved lower-extremity function in elderly adults (15636). Clinical research shows that taking vitamin D or vitamin D analogues, with or without calcium, reduces the number of people who have a fall by up to 19% (39038,84215,84374,84539,94130,104023). Other research shows that vitamin D, with or without calcium, reduces number of falls by 19% to 50% (11939,16275,84404,93941,109053). In these studies that show beneficial effects, the form of vitamin D (ergocalciferol, cholecalciferol) does not appear to influence results (39038,84374). Some clinical research shows a decreased rate of falls in patients with low baseline levels of vitamin D, but not in those with adequate vitamin D levels (84670,84684,109053). One meta-analysis also suggests that taking vitamin D as cholecalciferol up to 1000 IU daily reduces fall risk by up to 19%, whereas studies using higher doses did not reduce the risk of falling (109053). Also, daily dosing, but not intermittent dosing, seems to be associated with a reduced risk of falling (109053). Despite a substantial amount of positive research, more recent clinical studies show that vitamin D does not reduce the risk of falling (84404,84670), the rate of falls overall (84670,93942), or the rate of injurious falls (93942) in elderly patients (93942). One study in adults over 70 years of age with a history of falling actually found that taking high-dose vitamin D, either as 60,000 IU monthly or 24,000 IU plus calcifediol 300 mcg monthly, increased both the risk of falling and the mean number of falls compared to a lower dose of 24,000 IU monthly (93940). One meta-analysis of 20 trials including nearly 30,000 patients shows that taking vitamin D, with or without calcium, does not reduce the risk of falling in elderly patients, regardless of baseline 25-hydroxyvitamin D levels, level of 25-hydroxyvitamin D achieved with treatment, duration of treatment, or residential status of the patients (91342). While a meta-analysis of 10 trials in nearly 6,000 patients shows that taking vitamin D 700-1000 IU daily with calcium 1000-2000 mg daily reduces the risk of falling in the elderly by 12% when compared with placebo or no treatment, a meta-analysis of 21 trials in nearly 52,000 patients shows that vitamin D alone is only associated with a reduced risk of falls in patients with baseline vitamin D levels of less than 50 nmol/L when compared with placebo or no treatment (107224). The 2018 US Preventative Services Task Force (USPSTF) guidelines for fall prevention acknowledges this research by recommending AGAINST vitamin D supplementation for fall prevention in community dwelling adults 65 years of age and older who do not have osteoporosis or vitamin D deficiency (95703). The reasons for the disparate study results may have to do with the way in which clinical trials have reported outcomes. Clinical trials assessing the effect of vitamin D on fall risk may report results as the number of patients who experience one or more falls, the total number of falls, or the rate of falls per individual. This can affect ultimate conclusions and, in some cases, can be misleading. For example, when studies report on only the total number of falls, it is unclear if vitamin D reduces the rate of falls across the study population, or if it only reduces falls in a small subset of patients. Also, analyses of research suggest that the size of the clinical study appears to affect the trial results. Most trials showing significant reductions in fall risk have been small and of short duration (91342,94132); whereas larger and longer-term studies tend to show no benefit (13073,84399).
• Fetal and premature infant mortality. Taking vitamin D during pregnancy might reduce the risk of fetal or early infant death. Details: A meta-analysis of clinical research shows that vitamin D supplementation during pregnancy reduces the risk of intrauterine or neonatal death by 31% when compared with not supplementing with vitamin D. A sub-analysis shows that this benefit was limited to doses of up to 4000 IU daily (109055).
• Fibromyalgia. A small clinical study suggests that vitamin D might improve pain in patients with fibromyalgia. Details: A small clinical study in fibromyalgia patients with low vitamin D levels shows that taking vitamin D3 (cholecalciferol) 1200-2400 IU daily seems to reduce pain, but not mood or quality of life, when compared with placebo (91349).
• Food allergies. It is unclear if prenatal or infant oral vitamin D supplementation reduces the risk of developing food allergies. Details: A meta-analysis of two large clinical studies shows that prenatal or infant vitamin D supplementation does not reduce the risk of developing food allergies when compared with low-dose vitamin D or no intervention (108438).
• Frailty. It is unclear if oral vitamin D is beneficial for the prevention or treatment of frailty in older adults. Details: Frailty involves a combination of muscle loss and weakness, with exhaustion and reduced ability for physical activity. Some observational research has found that low vitamin D status is associated with frailty occurrence. However, clinical research in community dwelling older adults shows that taking vitamin D as 1000 IU, 2000 IU, or 4000 IU daily for 24 months does not prevent frailty or attenuate the worsening of frailty when compared with low-dose vitamin D 200 IU daily. Baseline vitamin D status did not affect these findings. Also, a sub-analysis suggests that vitamin D 2000 IU might increase frailty; however, only a small number of participants were randomized to this dose (109046). Other clinical research in community dwelling adults at least 70 years of age shows that taking cholecalciferol 2000 IU daily for 3 years does not reduce the odds of becoming pre-frail or frail over 36 months when compared with placebo. However, when taken in combination with omega-3 fatty acids 1 gram daily and a home exercise program, the odds of becoming pre-frail is reduced by 39% (110829).
• Generalized anxiety disorder (GAD). A small clinical study suggests that vitamin D may modestly improve anxiety in patients with GAD. Details: A small clinical study in patients with GAD shows that taking vitamin D 50,000 IU once weekly for 3 months, in addition to taking an antidepressant and an anxiolytic, moderately reduces anxiety scores when compared with taking these medications alone (103654).
• Hematopoietic stem cell transplant (HSCT). It is unclear if oral vitamin D is beneficial for improving outcomes in patients receiving HSCT. Details: A small clinical study in patients who have undergone an autologous HSCT shows that taking calcitriol 0.25 mcg three times daily for 30 days can reduce the time to absolute lymphocyte count recovery, but does not affect time to recovery of absolute neutrophil and platelet counts, when compared with placebo (103665).
• Hepatitis C. Low levels of vitamin D have been associated with an inadequate response to hepatitis C therapy. Adding vitamin D to standard therapy for hepatitis C may improve viral response, especially in specific genotypes. Details: A small clinical trial in patients with hepatitis C genotypes 2-3 receiving standard therapy with PEG-interferon and ribavirin shows that adding vitamin D 2000 IU daily for 24 weeks results in 95% of patients achieving undetectable levels of hepatitis C RNA, compared to only 77% of patients treated with standard therapy alone (98917). Another small clinical study in patients with hepatitis C genotype 1b receiving the same standard therapy shows that adding vitamin D 1000 IU daily for 16 weeks results in about 79% of patients achieving undetectable levels of hepatitis C RNA, compared to about 55% of patients treated with standard therapy alone. The TT genotype seems to be especially susceptible to vitamin D supplementation, while TG/GG genotype does not seem to be susceptible (98923).
• HIV/AIDS. It is unclear if oral vitamin D is beneficial for improving bone mineral density (BMD) in children and young adults with HIV. Details: Vitamin D deficiency and hyperparathyroidism are common in children and young adults with HIV. A meta-analysis of two clinical trials in this population shows that taking cholecalciferol for 12 months does not improve spine BMD when compared with placebo. Also, an analysis of two clinical trials shows that taking doses of 1600 IU to 4000 IU daily does not improve spine BMD when compared with taking doses of 400-800 IU daily. However, taking higher dose vitamin D has a small beneficial effect on total BMD when compared with taking lower doses. There was no improvement on parathyroid hormone levels (110824). This meta-analysis is limited by the availability of small clinical trials, as well as the heterogeneous doses of vitamin D used in the included studies.
• Hyperlipidemia. Although population research has found that higher vitamin D levels are associated with improved lipid levels, it is unclear if vitamin D supplementation is beneficial. Details: Population research has found that higher vitamin D levels are associated with lower low-density lipoprotein (LDL) cholesterol and triglyceride levels and higher high-density lipoprotein (HDL) cholesterol levels when compared with lower vitamin D levels (15630,98919). However, supplementation might not be beneficial. A meta-analysis of small clinical studies suggests that taking vitamin D as cholecalciferol, ergocalciferol, alfacalcidol, or calcitriol slightly increases LDL cholesterol, but does not affect total cholesterol, triglycerides, or HDL cholesterol, when compared with placebo (84642). The validity of these findings is limited by the variability in patient populations, vitamin D dose and formulation, and study duration. Also, none of the included studies were prospectively designed to test the effect of vitamin D on lipid levels. Another meta-analysis of clinical studies in a mixed population of healthy patients and patients with metabolic disease shows that taking vitamin D 1400-50,000 IU weekly with calcium 500-2000 mg daily results in very modest improvements in total cholesterol, triglyceride, and HDL cholesterol levels, but not LDL or very low-density lipoprotein (VLDL) cholesterol levels, when compared with placebo. Subgroup analyses suggest that effects are more pronounced in patients with metabolic disease (107227). The validity of these findings is limited by the heterogeneity of the included studies, which persisted throughout subgroup analyses.
• Hyperthyroidism. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research suggests that serum vitamin D levels are decreased in patients with newly diagnosed Graves' disease. A small preliminary clinical trial in patients with newly diagnosed Graves' disease taking methimazole and low levels of selenium and vitamin D shows that taking vitamin D as cholecalciferol for 270 days, in combination with selenium for the first 180 days, modestly reduces levels of serum free thyroxine and improves quality of life when compared with no vitamin D or selenium. However, taking vitamin D and selenium did not affect levels of free triiodothyronine or positive thyroid stimulating hormone (TSH) receptor antibody (109049).
• Hypothyroidism. It is unclear if vitamin D is beneficial in the treatment of subclinical hypothyroidism. Details: A preliminary clinical study in patients with vitamin D deficiency and subclinical hypothyroidism shows that taking vitamin D 50,000 IU weekly for 2 weeks improves mean thyroid stimulating hormone levels by 3.55 mIU/L from baseline. The validity of this finding is limited by the lack of a comparator group (107213).
• Ichthyosis. It is unclear if oral vitamin D is beneficial in patients with inherited ichthyosis. Details: A small clinical study in patients with congenital non-syndromic ichthyosis shows that taking vitamin D 2000 IU daily for 24 weeks reduces the clinical severity of disease at 12 weeks, but not 24 weeks, when compared with baseline. When compared with patients taking acitretin 0.5 mg/kg daily, results were similar at both 12 and 24 weeks, but it is unclear if the improvement from baseline differed between groups (108441).
• IgA vasculitis. It is unclear if oral alfacalcidol is beneficial in children with IgA vasculitis. Details: A clinical study in children with IgA vasculitis shows that taking alfacalcidol 0.25 mcg daily along with vitamin C, rutin, dipyridamole, cimetidine, calcium, and glucocorticoids for 4 weeks improves rates of recurrence and incidence of kidney damage when compared with those receiving the same regimen without alfacalcidol. Alfacalcidol also improves cellular immune function and reduces levels of inflammatory biomarkers (107212).
• Irritable bowel syndrome (IBS). It is unclear if oral vitamin D is beneficial for IBS; the available research is conflicting. Details: Although some meta-analyses show that taking vitamin D is moderately more effective than placebo for improving IBS symptom severity and quality of life, other analyses disagree. Doses of vitamin D have included 50,000 IU weekly or every 2 weeks or 2000-4000 IU daily for up to 6 months (109041,109054,109057). The reasons for these discrepancies might be attributed to the inclusion criteria related to the individual trials, the small sample sizes, and varied dosing strategies used in the available research.
• Kidney transplant. It is unclear if oral cholecalciferol is beneficial for improving allograft function or preventing non-skeletal complications in kidney transplant recipients. Details: Following a kidney transplant, patients are at increased risk of vitamin D insufficiency and related outcomes. A large clinical trial shows that taking a high dose of cholecalciferol for 2 years does not reduce the composite risk of developing type 2 diabetes, major cardiovascular events, or cancer, or death when compared to taking a lower dose. The high and low doses of vitamin D were 100,000 IU or 12,000 IU, respectively, every 2 weeks for 2 months, followed by monthly doses for the next 22 months (110830). The effect of a high dose of vitamin D on these outcomes individually is not clear. However, taking vitamin D does not seem to improve allograft function. A clinical study in kidney transplant recipients shows that taking cholecalciferol 4000 IU daily, beginning 1-month posttransplant and continuing for 11 months, has no effect on allograft function when compared with placebo (108425).
• Kidney transplant-related bone loss. Oral vitamin D might be beneficial for preventing bone loss associated with kidney transplantation. Details: A large clinical trial shows that taking a high dose of cholecalciferol for 2 years modestly reduces the odds of a fracture by 76% when compared to taking a lower dose. The high and low doses of vitamin D were 100,000 IU or 12,000 IU, respectively, every 2 weeks for 2 months, followed by monthly doses for the next 22 months (110830). A prespecified secondary analysis of a clinical study in patients at 1-month post-kidney transplant from a living donor in Japan shows that taking vitamin D (cholecalciferol) 4000 IU daily for months 1-12 posttransplant reduces whole blood parathyroid hormone levels by 15%, but does not alter levels of tartrate-resistant acid phosphatase 5-b or bone-specific alkaline phosphatase, when compared with placebo. The greatest effects on parathyroid hormone levels are observed in those with more severe vitamin D deficiency, hypocalcemia, and more preserved kidney function. Vitamin D supplementation also attenuates changes in bone mineral density (BMD) at the lumbar spine, but not the distal radius, from prior to transplant. Patients taking vitamin D had a loss of only 0.2%, compared with a loss of 2% in those receiving placebo. The greatest effects are observed in those with osteoporosis or osteopenia (107220). Conversely, a small clinical trial shows that taking calcitriol (1,25-dihydroxyvitamin D3) 0.25 mcg daily in combination with calcium carbonate 500 mg daily does not decrease bone loss associated with kidney transplantation. However, calcitriol might reduce osteoclast suppression, help maintain trabecular bone volume and wall thickness, and improve axial BMD (4823).
• Impaired glucose tolerance (prediabetes). Taking vitamin D might slow prediabetes progression to diabetes in people with low baseline levels of vitamin D or in people achieving high levels of vitamin D following supplementation. It is unclear if vitamin D supplementation is beneficial in people with prediabetes and sufficient vitamin D levels. Details: Observational research has found that low vitamin D levels are linked with a higher risk of prediabetes and higher dietary vitamin D is linked with a lower chance of developing diabetes (84594,103669). Meta-analyses and individual clinical studies in patients with prediabetes and unclear or sufficient vitamin D levels show that vitamin D supplementation might improve some glycemic indices, but does not seem to prevent progression of prediabetes to diabetes (84594,91347,99769,108421). However, a more recent meta-analysis of three clinical studies that were designed to evaluate the preventative effects of oral vitamin D in patients with type 2 diabetes shows that taking vitamin D reduces the risk of developing diabetes with an absolute risk reduction of 3.3% over 3 years compared with taking placebo. However, the actual risk reduction was highly dependent on the intra-trial vitamin D status. Patients achieving the highest serum vitamin D levels had absolute 3-year risk reductions of 11.4% to 18.1%. Doses of vitamin D used in this research include cholecalciferol 4000 IU daily or 20,000 IU weekly or eldecalcitol 0.75 mcg daily (110810). In patients with vitamin D deficiency and prediabetes, vitamin D might improve beta-cell function, suggesting reduced disease progression (99768,107210). One clinical study in adults with vitamin D deficiency shows that taking vitamin D 50,000 IU weekly for 3 months, and then monthly for 3 months, modestly improves insulin resistance and beta-cell function as measured by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), but does not affect fasting or postprandial glucose levels when compared with placebo (99768). Further, a meta-analysis of randomized controlled trials in patients with vitamin D deficiency and prediabetes shows that oral vitamin D at a median dose of 50,000 IU weekly for 26 weeks modestly improves fasting blood glucose and some markers of islet function, but not postprandial blood glucose or glycated hemoglobin (HbA1c) levels, when compared with control. Additionally, a significantly greater proportion of patients receiving vitamin D supplementation regressed from prediabetes to normal glucose status (107210). Conversely, a study in females with vitamin D deficiency and prediabetes shows that taking vitamin D 60,000 IU weekly for 8 weeks, followed by a maintenance dose of 200 IU daily after repletion, has no effect on the incidence of type 2 diabetes at 2 years (107211).
• Infant development. It is unclear if giving oral vitamin D in doses above the recommended dietary allowance during infancy is beneficial for improving neurodevelopment. It is also unclear if oral vitamin D during pregnancy is beneficial for improving cognitive development in the offspring. Details: Clinical research shows that giving vitamin D 1200 IU daily to healthy term infants of Northern European ethnicity starting at 2 weeks of age does not improve measures of neurodevelopment at 2 years of age when compared with giving the standard dose of vitamin D 400 IU (106121). Overall, the evidence from population research is mixed as to whether vitamin D status during gestation is associated with infant developmental outcomes. However, some population research has found that increased vitamin D status during pregnancy is associated with improved anthropomorphic and neurodevelopmental outcomes (104621,105724). Two meta-analyses of observational research show that low vitamin D status during pregnancy is associated with reduced head circumference and cognitive development scores, and higher odds of the offspring developing autism and attention deficit hyperactivity disorder (105724,105725). However, one meta-analysis suggests these risks may be limited to those with very low vitamin D status (serum level < 12 ng/mL) (105724). Multiple meta-analyses show that vitamin D status during pregnancy does not appear to affect motor development (105724,105725). In one observational study, plasma vitamin D concentrations in the second trimester of pregnancy was associated with increased IQ scores in the offspring at age 4-6 years. Each 10 ng/mL increase in vitamin D levels was associated with a 1.17-point increase in IQ (104621). In contrast, clinical research shows that taking vitamin D3 2800 IU daily during the third trimester does not improve neurodevelopmental outcomes in the first 6 years of life when compared to taking lower doses of 400 IU daily (104623).
• Infertility. It is unclear if oral or intramuscular vitamin D is beneficial in females with infertility. Details: A meta-analysis of clinical research in infertile females shows that although there was no effect of taking vitamin D on implantation rate or miscarriage, taking vitamin D increases the odds of clinical pregnancy by 49% compared with taking placebo. However, sub-analyses of clinical and observational research found that benefits on clinical pregnancy rates were limited to populations with vitamin D insufficiency, but not vitamin D deficiency, and for doses between 1000 to 10,000 IU daily for 30-90 days (110818). Most studies included in the analysis used oral vitamin D; however, intramuscular vitamin D was used in one cohort study. A smaller meta-analysis of clinical studies in females with infertility and vitamin D insufficiency undergoing IVF shows that taking vitamin D increases the rate of chemical pregnancy by 50%, but has no effect on the clinical pregnancy rate (108432).
• Lung cancer. It is unclear if oral vitamin D prevents lung cancer or improves lung cancer prognosis. Details: A small meta-analysis of randomized controlled trials and observational research has found that high intake of vitamin D is associated with a 10% reduction in the risk of developing lung cancer when compared with low vitamin D intake. In terms of prognosis, high vitamin D intake is associated with improvements in both overall survival and relapse-free survival (107217).
• Low birth weight. It is unclear if oral vitamin D can reduce the risk for low birth weight; the available evidence is conflicting. Details: A meta-analysis of observational research has found that a very low vitamin D status (serum level <12 ng/mL) during pregnancy is associated with lower birth weight and increased odds of SGA births. However, these risks have not been demonstrated in those with less severe vitamin D deficiency (serum level <20 ng/mL) (105724). Most research also shows that vitamin D supplementation during pregnancy reduces the risk of low birth weight. A meta-analysis of three clinical trials shows that supplementation with vitamin D 800-1000 IU daily starting between 27 and 32 weeks' gestation, or 200,000 IU administered as a single dose or in two divided doses during the seventh and eighth month of pregnancy, reduces the risk of delivering a low birth weight infant by 60% (84659). Other meta-analyses of clinical research confirm that supplementation with vitamin D during pregnancy results in a 45% to 60% reduced risk of low birth weight and a 103 gram greater average birth weight (99766,100897). However, some meta-analyses show that vitamin D supplementation during pregnancy does not reduce the risk of low birth weight when compared with no supplementation (95910,109055). One meta-analysis that included studies that did not directly measure birth weight shows no effect of vitamin D supplementation during pregnancy on the rate of low birth weight, despite showing an increase in overall birth weight of about 58 grams (95910).
• Male infertility. It is unclear if oral cholecalciferol is beneficial in males with infertility. Details: A small clinical study in males with infertility shows that taking cholecalciferol 2500 IU daily for 6 months modestly improves progressive sperm motility, sperm concentration, and sperm morphology when compared with baseline (108427). The validity of these findings is limited by the lack of a comparator group.
• Melanoma. It is unclear if oral vitamin D is beneficial in patients with melanoma. Details: A meta-analysis of 14 observational studies suggests that vitamin D deficiency is associated with a 45% greater risk of melanoma when compared with normal vitamin D levels (112027). However, a small clinical study in patients with newly resected stage II melanoma shows that taking vitamin D3 100,000 IU every 50 days for 3 years does not improve disease-free survival when compared with placebo. Most patients in this study had vitamin D deficiency or insufficiency at baseline (106113).
• Metabolic syndrome. It is unclear if oral vitamin D is beneficial for preventing or treating metabolic syndrome. Details: In patients with metabolic syndrome, clinical research shows that taking vitamin D 50,000 IU weekly for 16 weeks does not affect most metabolic or anthropometric factors when compared with placebo, although there was a modest decrease in triglyceride levels (106123). However, almost all of the individuals in this study were vitamin D deficient or insufficient, and many remained in that category even after supplementation. It is unclear if vitamin D supplementation is beneficial in vitamin D sufficient patients with metabolic syndrome. There is conflicting evidence about the association between vitamin D and metabolic syndrome (14265,16713,98234). Some population research has found that higher vitamin D levels are associated with a lower risk of metabolic syndrome, while other research found no association (14265,16713). Furthermore, a small clinical trial in patients with metabolic syndrome shows that taking vitamin D 20,000 IU or 40,000 IU weekly for 8 weeks does not affect metabolic risk factors when compared with placebo (98234).
• Migraine headache. It is unclear if oral vitamin D reduces the frequency of migraine. Details: A meta-analysis of three small high-quality clinical studies in patients with migraine shows that taking vitamin D 2000 or 4000 IU daily for 12-24 weeks or 500,000 IU weekly for 2 months reduces the frequency of migraines by 2-3 attacks monthly when compared with usual care or placebo (108439).
• Multiple sclerosis (MS). Although vitamin D supplementation has been linked with a lower risk of developing MS, taking oral vitamin D supplements does not seem to reduce MS relapses. Details: Population research suggests that long-term supplementation with vitamin D 400 IU is associated with a 40% lower risk of MS in females. The effect seems to be dose-dependent. Consumption of at least 400 IU daily, mainly in the form of a multivitamin supplement, appears to have the greatest protective effect (11356). Additional population research in over 7 million people suggests that higher levels of calcifediol are associated with a lower risk of developing MS. In White adults, for every 20 ng/mL increase in vitamin D levels, there appears to be a 41% decrease in MS risk. However, this was not found in Black and Hispanic adults (15159). Vitamin D supplementation has also been examined in patients with MS. Population research suggests that taking vitamin D supplements and the maintenance of optimal blood levels of vitamin D are associated with a reduction in the development of new areas of demyelination detected by magnetic resonance imaging (MRI) over 24 months. However, there were no correlations between taking vitamin D or vitamin D blood levels and clinical outcomes (110816). Also, vitamin D supplementation does not seem to impact MS relapses or most symptoms in patients with MS. Meta-analyses of preliminary clinical research show that vitamin D supplementation does not affect the rate of MS relapses, overall symptoms, or the number of MS nerve lesions detected by MRI, regardless whether the vitamin D was low-dose or high-dose (98192,98914,106119). However, one meta-analysis of 6 small clinical studies shows that taking vitamin D for 8-96 weeks slightly improves fatigue scores when compared with placebo (112024). These analyses are limited by the small size and heterogeneity of most of the included studies and variability in dosing and duration of vitamin D regimens.
• Muscle strength. It is unclear if oral vitamin D improves muscle strength in middle aged or older adults with low or sufficient levels of vitamin D. The available research is conflicting. Details: Clinical research in healthy older adults who are not deficient in vitamin D shows that oral vitamin D3 (cholecalciferol) supplementation, with 800 IU, 1000 IU, or 2000 IU daily or 50,000 IU monthly, alone or in combination with a resistance training program, does not increase muscle strength when compared with placebo (11814,104619,108429). In patients 40-80 years of age with low vitamin D levels, taking vitamin D3 100,000 IU (2500 mcg) once, followed by 20,000 IU (500 mcg) weekly for 4 months, does not improve muscle strength when compared with placebo (103658). Similarly, one meta-analysis of clinical research shows that vitamin D does not increase grip strength, muscle mass, or muscle power when compared with control (91341). However, some research has found some benefit with the use of vitamin D supplements. One meta-analysis shows that taking vitamin D increases grip strength after menopause when compared with placebo or low-dose vitamin D, although a sub-analysis shows that beneficial effects are limited to individuals aged 60-69 years, when vitamin D is taken without calcium, when baseline vitamin D levels are at least 30 ng/mL, or when the treatment consists of the vitamin D analog alfacalcidol. This suggests heterogeneity between studies (109048). Another meta-analysis in elderly adults shows that taking vitamin D as calcifediol 10-30 mcg daily for a median of 24 weeks modestly improves hand grip strength and leg extension, but not leg flexion, when compared with baseline (109042). Also, some individual clinical research in older adults with low levels of vitamin D at baseline shows that taking vitamin D3 800 IU daily or vitamin D2 (ergocalciferol) 1000 IU daily for 12 months in combination with calcium 1000 mg daily modestly improves lower extremity or hip strength by 8% to 23% when compared with calcium alone (38915,84530).
• Myalgia. It is unclear if oral vitamin D is beneficial for reducing myalgia associated with obesity. Details: Preliminary clinical research in obese individuals with vitamin D deficiency who are on a low-calorie diet shows that taking vitamin D 50,000 IU weekly, alone or in combination with an aerobic exercise program three times weekly for 12 weeks, modestly reduces muscle pain when compared with only aerobic exercise three times weekly (106118).
• Myelodysplastic syndromes. It is unclear if oral vitamin D is beneficial for patients with myelodysplastic syndromes. Details: A small observational study in patients with myelodysplastic syndromes has found that taking calcitriol or calcifediol orally is associated with slowed disease progression (11825).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral or intramuscular vitamin D is beneficial in children or adults with NAFLD. Details: Although findings from individual research are mixed, one meta-analysis of mainly small clinical trials in patients with NAFLD shows that vitamin D modestly improves insulin resistance and serum alanine aminotransferase (ALT) levels, with no effect on serum aspartate aminotransferase (AST) levels. Most studies included in the analysis used oral vitamin D 1000 IU daily or 50,000 IU weekly or biweekly for 3-6 months and compared with placebo; however, one study used a single intramuscular injection of vitamin D 600,000 IU compared with lifestyle modifications (109056). Vitamin D has also been evaluated in combination with fish oil. A clinical study in adults with NAFLD shows that taking oral vitamin D3 1680 IU daily in combination with fish oil or fish oil alone for 3 months improves serum ALT levels similarly to a control group (107186). Vitamin D has also been evaluated for use in children with NAFLD. One clinical study in children with obesity and biopsy-proven NAFLD shows that taking oral vitamin D3 2000 IU daily for 6 months with a hypocaloric diet improves liver histopathology in terms of steatosis, lobular inflammation, and NAFLD activity score at 6 months, but not hepatocyte ballooning or fibrosis, when compared with baseline. These improvements were not seen in the group receiving placebo with a hypocaloric diet, but it is unclear if the improvement from baseline differed between groups (107222).
• Nonmelanoma skin cancer. It is unclear if oral vitamin D is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking vitamin D3 1000 IU daily for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking vitamin D3 with calcium 1200 mg daily as calcium carbonate reduces the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but has no effect on the risk of basal cell carcinoma. Vitamin D taken alone has no effect on the risk for either type of cancer (104622).
• Obesity. The evidence for the use of oral vitamin D in obesity is conflicting and unclear. Details: Population research has found that people with lower vitamin D levels are significantly more likely to be obese when compared to people with higher vitamin D levels (15630). Also, a large-scale, high-quality clinical trial in postmenopausal adults taking calcium 1000 mg plus vitamin D3 (cholecalciferol) 400 IU daily for 3 years shows that these patients are more likely to lose weight and maintain their weight when compared with those taking placebo. This beneficial effect is mainly seen in females who have inadequate intake of calcium, less than 1200 mg/day, before starting a calcium supplement (15604). However, other evidence suggests that vitamin D alone does not improve weight loss. One clinical trial shows that taking vitamin D3 2000 IU/day without calcium for 12 months does not increase weight loss when compared with placebo in overweight and obese postmenopausal adults who are deficient in vitamin D at baseline (91345).
• Orthostatic hypotension. It is unclear if oral vitamin D is beneficial for prevention of orthostatic hypotension. Details: A secondary analysis of a clinical study in older patients with vitamin D insufficiency who are at an increased risk for falls shows that taking vitamin D 1000-4000 IU daily for up to 2 years has no effect on the risk of orthostatic hypotension or orthostatic symptoms when compared with those receiving vitamin D 200 IU daily (107223).
• Osteoarthritis. It is unclear if oral vitamin D is beneficial for osteoarthritis. Details: The evidence for the use of vitamin D in osteoarthritis is conflicting. Some clinical research shows that taking vitamin D3 (cholecalciferol) 2000 IU daily, or at a higher dose to reach serum vitamin D levels over 36 ng/mL, for 2 years does not reduce knee pain or loss of cartilage when compared with placebo in patients with symptomatic osteoarthritis (84688). However, another clinical study shows that taking vitamin D3 daily for 10 days and then vitamin D3 60,000 IU monthly for 12 months modestly reduces pain and improves function when compared with placebo in patients with osteoarthritis and vitamin D insufficiency (98199). It is possible that higher doses of vitamin D have an effect on osteoarthritis, while lower doses do not. Due to this conflicting and low-quality evidence, the American College of Rheumatology (ACR) recommends against the use of vitamin D for any form of osteoarthritis (102114).
• Otitis media. It is unclear if oral vitamin D is beneficial in patients with otitis media. Details: The relationship between vitamin D status and otitis media is unclear. Population research has found that having otitis media is associated with lower blood levels of vitamin D; however, lower vitamin D levels were not associated with greater risk of otitis media (98194).
• Overactive bladder. It is unclear if oral vitamin D is beneficial for overactive bladder. Details: A large clinical trial in older males shows that taking vitamin D3 (cholecalciferol) 2000 IU daily for 5 years does not reduce the odds of weekly overactive bladder when compared with placebo. In males with low serum vitamin D, taking vitamin D reduces the odds of overactive bladder at 5 years by 49%, including 34% reduced odds of overactive bladder with urinary incontinence and 81% reduced odds of overactive bladder without incontinence. However, urinary incontinence while sleeping or napping was increased (109738).
• Overall mortality. Taking oral vitamin D alone does not seem to reduce mortality; however, there is some evidence that taking certain forms of vitamin D with calcium might have a modest benefit. Details: While higher vitamin D levels have been associated with a small reduction in mortality when compared with lower vitamin D levels (98187), clinical research shows that taking vitamin D does not reduce the risk of mortality. The most comprehensive meta-analysis to date shows that vitamin D supplementation alone does not reduce all-cause mortality when compared to control (100900). However, giving vitamin D with calcium may modestly reduce the risk of mortality. Meta-analyses show a 4% to 9% reduced risk of mortality when trials of vitamin D alone and vitamin D with calcium are pooled together (16102,97296,98186,112022). Finally, some research suggests that the type of vitamin D supplementation might influence the results. A meta-analysis of clinical research found that vitamin D3 (cholecalciferol) with or without calcium reduces mortality risk by 6%, while alfacalcidol, calcitriol, and vitamin D2 (ergocalciferol) do not have benefit (84595,98186).
• Pain (chronic). It is unclear if oral vitamin D is beneficial for chronic pain. Details: A meta-analysis of clinical research in patients with chronic pain shows that taking vitamin D for 1-24 months produces a 43% greater decrease in pain score when compared with placebo. However, the final follow-up pain score is similar for both groups (96402). The effect of vitamin D on pain based on pain-related diagnosis, vitamin D status, or dose is unknown.
• Parkinson disease. It is unclear if oral vitamin D is beneficial for this condition. Details: Population research found that higher levels of vitamin D are associated with milder Parkinson disease symptoms, while deficiency is associated with increased risk of Parkinson disease (97000,99772). One small study shows that taking vitamin D3 (cholecalciferol) 1200 IU daily for one year might modestly slow the progression of Parkinson disease based on the Hoehn and Yars staging criteria. However, there was no improvement in disease severity according to the more widely used Unified Parkinson Disease Rating Stage (UPDRS). The UPDRS includes measures of activities of daily living and non-motor symptoms. Vitamin D had no effect on most quality of life measures (95915).
• Periodontitis. It is unclear if oral vitamin D is beneficial for periodontal disease. Details: A meta-analysis of mostly observational research suggests that vitamin D levels are not associated with an increased or decreased risk of periodontitis (112026). Other population research suggests that higher blood levels of vitamin D may be associated with a reduced risk of periodontal disease in adults 50 years of age or older. However, this association was not found for adults younger than 50 years (15634).
• Physical performance. It is unclear if oral vitamin D improves muscle strength in elderly adults. Details: Some clinical research in healthy older adults who are not deficient in vitamin D shows that oral vitamin D3 (cholecalciferol) supplementation, with 800 IU, 1000 IU, or 2000 IU daily or 50,000 IU monthly, alone or in combination with a resistance training program, does not improve physical performance when compared with placebo (11814,104619,108429). Also, results from one meta-analysis of clinical research in postmenopausal females with low levels of vitamin D shows that taking vitamin D does not improve the timed up and go test when compared with placebo or low-dose vitamin D (109048). One meta-analysis that included studies specifically evaluating the use of calcifediol in older adults shows a large benefit on gait speed; however, only one study included in the analysis used this endpoint and other measures of physical performance were not affected (109042).
• Pneumonia. High-dose oral vitamin D does not reduce pneumonia severity in children. Details: Although vitamin D supplementation might prevent respiratory tract infections in children, it might not prevent recurrent pneumonia. A small clinical study in children under 5 years of age with recurrent pneumonia and variable vitamin D blood levels shows that taking vitamin D 300,000 IU quarterly for 1 year does not reduce respiratory infections, severity of pneumonia, hospital admissions, or disease complications when compared with placebo (103667). However, it's unknown if vitamin D supplementation using lower and more frequent doses, or supplementation in patients with vitamin D deficiency, might be beneficial. Some observational research has found that having vitamin D deficiency is linked to a higher risk for developing community-acquired pneumonia (CAP) (102118). For information on other respiratory infections, refer to the Respiratory Tract Infection discussion.
• Polycystic ovary syndrome (PCOS). It is unclear if vitamin D improves pregnancy outcomes and symptoms in patients with PCOS. Details: A meta-analysis of several mostly low quality clinical studies in patients with PCOS and vitamin D deficiency at baseline shows that intramuscular or oral vitamin D 200-10,000 IU daily for up to 24 weeks in addition to fertility treatment improves certain pregnancy outcomes including the rate of pregnancy, premature miscarriage, and premature delivery but does not impact the incidence of pregnancy complications including gestational hypertension or gestational diabetes mellitus when compared with control. This analysis also suggests vitamin D supplementation improves certain IVF-related outcomes including ovulation rate, fertilization rate, and number of mature oocytes (112787). Observational research in infertile adults with PCOS and insulin resistance suggests that normal vitamin D levels are associated with better embryo quality and increased pregnancy rate when compared with vitamin D deficiency or insufficiency (100834). It is unclear if supplementation with vitamin D improves pregnancy rates in patients with PCOS. Some research has evaluated the effects of vitamin D supplementation on menstruation and follicular development in these patients. A meta-analysis of clinical research shows that taking vitamin D 400-12,000 IU daily for 2-6 months improves follicular development when compared with placebo. Taking vitamin D in combination with metformin 1500 mg daily also appears to increase the number of regular menstrual cycles by 85% when compared with metformin alone. However, no effect on follicular development was seen with the combination. Vitamin D alone does not appear to improve menstrual cycle regularity. Most studies included calcium supplementation as well; therefore, the benefits of vitamin D alone in patients with PCOS are unclear (96404).
• Post-stroke fatigue. It is unclear if oral vitamin D is beneficial for post-stroke fatigue. Details: A retrospective study in patients with post-stroke fatigue and vitamin D deficiency suggests that vitamin D (cholecalciferol) 600 IU daily is associated with improvements in fatigue severity at months 1 and 3 when compared with control. Neurologic disability also showed improvement at 3 months, but not at 1 month, when compared with control. It is unclear if improvements from baseline differed between groups (107225).
• Pre-eclampsia. It is unclear if oral vitamin D during pregnancy is beneficial for pre-eclampsia prevention. Details: A meta-analysis of four small clinical trials shows that supplementation with vitamin D alone or with calcium during pregnancy reduces the risk of pre-eclampsia in pregnant adults by about 50% when compared with placebo (100897).
• Precocious puberty. It is unclear if oral vitamin D is beneficial for the prevention or treatment of precocious puberty. Details: A meta-analysis of 43 studies, most of which are observational and involve young female subjects in China, suggests that vitamin D deficiency or insufficiency is associated with 2.25-fold greater odds of precocious puberty when compared with normal vitamin D levels. Further, this analysis suggests that taking vitamin D 200-1000 IU daily for 3-12 months along with a gonadotropic-releasing hormone analog (GnRHa) is associated with lower luteinizing hormone, follicle-stimulating hormone, and estradiol levels and reduced bone age when compared with GnRHa therapy alone (112019).
• Pregnancy-induced hypertension. It is unclear if oral vitamin D is beneficial for patients with gestational hypertension. Details: A subgroup meta-analysis of two low-quality clinical trials shows that vitamin D supplementation during pregnancy does not reduce the risk for gestational hypertension when compared with control (95910).
• Premenstrual syndrome (PMS). It is unclear if oral vitamin D is beneficial in patients with PMS. Details: Observational research has found that increasing dietary intake of vitamin D above 706 IU daily is linked to a reduced risk of developing PMS when compared with consuming 112 IU daily (13094). Furthermore, a clinical study shows that taking vitamin D 400 IU daily in combination with calcium 1000 mg daily can decrease the severity of PMS symptoms (16869). But it's unclear if the effects are due to vitamin D, calcium, or the combination. Another clinical study in adolescent females with PMS shows that taking vitamin D3 50,000 IU weekly for 9 weeks modestly reduces PMS symptoms when compared to baseline (98912). The validity of this finding is limited by the lack of a control group.
• Preterm labor. It is unclear if oral vitamin D is beneficial for preterm labor. Details: Vitamin D deficiency, defined as serum levels less than 20 ng/mL, during pregnancy has been associated with a 25% increased risk of preterm birth (95911). The risk seems to be especially prominent in those with darker colored skin (103662). However, meta-analyses of clinical research show that vitamin D supplementation during pregnancy does not reduce the risk of a preterm birth when compared with no supplementation with vitamin D (84659,95910,100897,109055). The effect vitamin D specifically in vitamin D-deficient patients is still unclear. Some small, heterogeneous, and low-quality studies show that vitamin D supplementation might reduce the rate of preterm birth in vitamin D-deficient patients (84659,95910,100897). Additional studies are needed to determine the effect of vitamin D supplementation on the risk of preterm birth.
• Rheumatoid arthritis (RA). Small clinical studies suggest that oral vitamin D may not improve symptoms in patients with RA. Details: Population research has found that higher intake of vitamin D from foods or supplements is associated with a lower risk of developing RA (12206,98200). However, a meta-analysis of two small clinical trials shows that vitamin D supplementation does not reduce pain or recurrence of RA when compared with placebo (98190).
• Rhinosinusitis. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients over 12 years of age with chronic sinusitis shows that taking 1 or 2 sachets of a specific combination product (Flogostop Forte, Humana Italia) containing vitamin D 600 IU, black currant, Boswellia serrata, and bromelain along with a nasal corticosteroid daily for 15-30 days reduces symptoms of nasal hyperemia and rhinorrhea when compared with corticosteroid nasal spray alone (111501). It is unclear if these findings are due to vitamin D, other ingredients, or the combination.
• Sarcopenia. It is unclear if oral vitamin D is beneficial in older adults with sarcopenia. Details: A meta-analysis of randomized trials in older adults with sarcopenia shows that taking vitamin D3 (cholecalciferol) 100-800 IU daily, with protein 10-44 grams daily or amino acids 2.5-6 grams daily, for 2-6 months moderately improves muscle strength, but not muscle mass or walking speed, when compared with placebo (105727). The validity of this study is limited by high heterogeneity and an unreported baseline vitamin D status. Similarly, a small network meta-analysis of randomized trials shows that taking vitamin D 500-1600 IU daily or 2500-5000 IU weekly with protein 20-80 grams daily or amino acids 3-32 grams daily with and without exercise for 3-18 months increases hand grip strength and shortens time to chair-stand, respectively, but not gait speed or lower-limb mass when compared with usual care (107221). It is unclear if these effects are due to vitamin D, protein/amino acid supplementation, exercise, or the combinations.
• Schizophrenia. It is unclear if oral vitamin D is beneficial for schizophrenia. Details: Based on preliminary clinical evidence, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that vitamin D in doses of 1500 to 4000 IU daily is not recommended for adjunctive use in patients with schizophrenia (110318).
• Seasonal affective disorder (SAD). One small study suggests that a large dose of oral vitamin D can improve symptoms of SAD. Details: A small clinical study in patients with SAD suggests that a single dose of vitamin D2 (ergocalciferol) 100,000 IU improves symptoms after one month when compared to baseline (83791). The validity of this finding is limited by the lack of a control group.
• Seborrheic keratosis. It is unclear if topical vitamin D analogues improve symptoms of seborrheic keratosis. Details: Preliminary clinical research suggests that topical ointments containing activated vitamin D in the form of tacalcitol, calcipotriol or maxacalcitol, applied for 3-12 months, can reduce tumor volume by at least 40% in 75% of patients with seborrheic keratosis. Additionally, over 30% of patients seem to experience complete tumor resolution or a reduction in tumor volume of at least 80% (84033). The validity of this finding is limited by the lack of a control group.
• Sexual dysfunction. One small study suggests that injecting a large dose of vitamin D might improve sexual function. Details: A small clinical study in females with vitamin D deficiency and sexual dysfunction shows that receiving an intramuscular injection of vitamin D as cholecalciferol 300,000 IU once at baseline and a second time 4 weeks later improves sexual function at 4 and 8 weeks when compared with placebo (100896).
• Sickle cell disease. One small study suggests that oral vitamin D reduces pain and improves quality of life in children with sickle cell disease with vitamin D insufficiency or deficiency. Details: A small clinical study in children with sickle cell disease shows that taking vitamin D3 (cholecalciferol) 40,000-100,000 IU weekly for 6 weeks reduces days with pain and improves physical activity and quality of life for up to 6 months when compared with placebo. Of the children included in the study, 82.5% had vitamin D insufficiency, while 52.5% were deficient in vitamin D (98918). It is unclear if vitamin D is effective for patients with sickle cell disease who have adequate levels of vitamin D.
• Small for gestational age (SGA). It is unclear if oral vitamin D can reduce the risk for SGA births; the available evidence is conflicting. Details: Two meta-analyses of clinical research show no effect of vitamin D on the risk of SGA birth (84659,109055). However, one meta-analysis shows a 40% reduction in the risk of SGA births with vitamin D supplementation (95910). Also, one meta-analysis shows that when vitamin D supplementation is initiated before the 20^th week of gestation, the risk of SGA is reduced by 54% (109055). Most individual clinical trials are small and heterogeneous. Also, the formulation of vitamin D and/or vitamin D status at baseline may explain part of the discrepant findings. For example, a meta-analysis of observational research has found that a very low vitamin D status (serum level <12 ng/mL) during pregnancy is associated with increased odds of SGA births. This association does not seem to be present with less severe vitamin D deficiency (serum level <20 ng/mL) (105724).
• Statin-induced myalgia. It is unclear if oral vitamin D is beneficial for patients with statin-induced myalgia. Details: Observational research has found that taking oral vitamin D supplements is associated with decreased symptoms of myalgia in patients taking statin drugs. In a small case series, patients who discontinued statins due to myalgia were able to resume statin therapy after starting vitamin D supplements. The majority of patients with myalgia were found to be vitamin D deficient, with vitamin D levels less than 12 ng/mL at baseline (16829). An observational study has also found that administering 50,000 units of vitamin D2 (ergocalciferol) once a week for 12 weeks reversed symptoms of myalgia in 92% of statin treated patients with low serum vitamin D levels of less than 32 ng/mL (16831).
• Stroke. Although low vitamin D levels are associated with higher risk of stroke, taking vitamin D supplements does not seem to reduce stroke risk. Details: Population research has found that low vitamin D levels are associated with an increased risk of stroke. Furthermore, increased dietary intake of vitamin D is associated with a reduced risk of stroke (15630,16618,93944,97303,106106). However, clinical research shows that vitamin D supplementation does not reduce stroke risk. Several meta-analyses and randomized controlled trials show that taking vitamin D alone or with calcium does not reduce the risk of stroke in patients with or without cardiovascular disease risk factors (16616,91343,97296,97308,106106,112022). It is difficult to draw firm conclusions from these studies, as they did not assess whether patients had adequate vitamin D levels at baseline. It is unclear if vitamin D supplementation might prevent strokes in patients with vitamin D deficiency.
• Sunburn. Although there is interest in using oral vitamin D for the treatment of sunburns, there is insufficient reliable information about the clinical effects of vitamin D for this purpose.
• Systemic lupus erythematosus (SLE). It is unclear if oral vitamin D is beneficial in patients with SLE. Details: While some observational research has found that adults with SLE are more likely to have vitamin D deficiency than healthy controls (102119), a small cross-sectional study in females has found no association between serum levels of 25-hydroxyvitamin D, SLE disease activity, and the presence or absence of lupus nephritis (107214). A meta-analysis of three small clinical studies shows that taking vitamin D3 (cholecalciferol) 2000 IU daily or 50,000 IU weekly seems to reduce anti-dsDNA positive, a marker of disease activity, when compared with placebo in patients with SLE (98190). However, the clinical significance of this finding is unclear. A small clinical trial in females with SLE shows that taking vitamin D3 5000 IU daily for 12 weeks modestly improves overall disease activity, but not quality of life, when compared with placebo (109735).
• Thyroid cancer. It is unclear if oral vitamin D is beneficial in patients with thyroid cancer. Details: Observational research in patients undergoing thyroidectomy for differentiated thyroid cancer suggests that taking vitamin D daily for at least 6 months after surgery is associated with a 38% lower risk of all-cause mortality and a 33% lower risk of total cancer-related mortality when compared with no vitamin D supplementation at around 10 years' follow-up. However, vitamin D does not appear to be linked to a lower risk of thyroid cancer-related mortality in these patients (112018).
• Ulcerative colitis. Limited evidence suggests that vitamin D may be beneficial in patients with ulcerative colitis. Details: A meta-analysis of mainly small clinical trials in patients treated with mesalazine shows that taking vitamin D for up to 24 weeks modestly increases clinical efficacy and reduces disease score when compared with mesalazine alone (109044). Also, a meta-analysis of small, low-quality clinical studies in patients with IBD, including Crohn disease and ulcerative colitis, shows that taking high- or low-dose vitamin D for up to 1 year reduces the rate of relapse when compared with control (98915). These findings are limited because of the heterogeneity of the included studies.
• Upper respiratory tract infection (URTI). It is unclear if oral vitamin D is beneficial for dementia. Details: A large clinical trial shows that taking vitamin D 2800 IU daily, starting at gestational week 24 and continuing until one week after birth, reduces the risk of the child developing croup by 3 years of age by 40% when compared with olive oil as placebo. This risk reduction did not change after adjusting for the use of omega-3 fatty acids 2.4 grams daily, as well as for concomitant persistent wheeze and/or lower respiratory tract infections (109304).
• Urinary incontinence. Limited evidence suggests that vitamin D may be beneficial in middle-aged, but not older, adults with urinary incontinence. Details: Clinical research in middle-aged premenopausal females with stress urinary incontinence and low vitamin D status shows that taking vitamin D 5000 IU once weekly for 12 weeks has a moderate to large beneficial effect on the severity of incontinence and quality of life when compared with placebo. Kegel exercises were performed by all participants (109736). However, vitamin D supplementation does not seem to be beneficial for reducing urinary incontinence in older adults. In older females and males, a large clinical trial shows that vitamin D3 (cholecalciferol) 2000 IU daily for 5 years does not reduce the incidence or progression of urinary incontinence when compared with placebo (109738,109741). In older males with low vitamin D status, vitamin D supplementation may actually increase some types of incontinence (109738).
• Urinary tract infections (UTIs). It is unclear if oral vitamin D is beneficial for the prevention of UTIs in children. Details: A meta-analysis of 13 small observational studies in children suggests that lower levels of vitamin D are associated with 2.8-fold greater odds of UTI when compared with higher vitamin D levels. Further, this analysis shows that vitamin D deficiency in children is linked to 5.5-fold greater odds of UTI when compared with normal vitamin D levels (112030).
• Urticaria. It is unclear if oral vitamin D is beneficial for the prevention or treatment of urticaria. Details: A meta-analysis of population research has found that having urticaria is associated with a slightly lower vitamin D blood level and a greater likelihood of vitamin D deficiency when compared with individuals without urticaria. In addition, a meta-analysis of 6 clinical trials shows that taking high-dose vitamin D at an average daily dose of at least 4100 IU has a modest effect on the severity of urticaria symptoms (106115).
• Uterine fibroids. It is unclear if oral vitamin D is beneficial for preventing the recurrence of uterine fibroids. Details: A clinical study in patients with low vitamin D levels undergoing hysteroscopic myomectomy for uterine fibroids shows that taking vitamin D 1000 IU daily for 12 months has no effect on the rate of uterine fibroid recurrence when compared with placebo (108422).
• Vaginal atrophy. It is unclear if oral vitamin D is beneficial for vaginal atrophy. There is limited evidence on the topical use of vitamin D in vaginal atrophy in postmenopausal adults or patients taking tamoxifen. Details: A small cross-sectional study in postmenopausal adults has found that taking a vitamin D supplement for at least one year improves the maturation index of superficial vaginal wall cells when compared with those who do not take vitamin D. However, symptoms of vaginal atrophy were not different between groups (16879). Vitamin D has also been evaluated for vaginal atrophy due to tamoxifen. A small clinical trial in females with breast cancer using tamoxifen shows that receiving vitamin D 1000 IU vaginal suppositories daily for 8 weeks improves maturation index of vaginal walls and self-reported symptoms when compared with placebo (99773).
• Vertigo. Vitamin D with calcium might reduce positional vertigo. It is unclear if the benefit is from vitamin D, calcium, or the combination. Details: A large clinical study in adults with recurrent benign paroxysmal positional vertigo shows that taking vitamin D 400 IU and calcium 500 mg twice daily for one year reduces annual recurrence of vertigo by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 3.7 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination.
• Vitiligo. Although there is interest in using oral vitamin D for vitiligo, there is insufficient reliable information about the clinical effects of vitamin D for this condition.
• Warts. Although there is interest in using topical vitamin D derivatives for warts, there is insufficient reliable information about the clinical effects of vitamin D for this condition. More evidence is needed to rate vitamin D for these uses.

(Read more about VITAMIN D)

EFFECTIVE

• Zinc deficiency. Orally or intravenously, zinc is effective for treating and preventing zinc deficiency. Details: Taking zinc orally or intravenously prevents and treats zinc deficiency (2619). However, routine zinc supplementation is not recommended (403). Zinc deficiency requiring supplementation may occur in patients with severe diarrhea, malabsorption syndromes, liver cirrhosis, and alcoholism; after major surgery, renal failure, and dialysis; or during long-term administration of total parenteral nutrition (3900,24321). Zinc supplementation (136 mg of elemental zinc per day) in patients with cirrhosis and zinc deficiency seems to improve liver function and glucose tolerance, possibly by increasing insulin-like growth factor (8624,87520).

LIKELY EFFECTIVE

• Diarrhea. Oral zinc reduces duration and severity of acute diarrhea in malnourished children. Doses of 5-20 mg seem to be effective, while 5-10 mg daily is less likely to cause vomiting. Details: Most research, including meta-analyses and over 30 clinical trials, show that taking zinc orally reduces the duration and severity of acute and persistent diarrhea in malnourished or zinc-deficient children, but not in well-nourished children (87236,96074). Most studies have been conducted in Bangladesh and India, so it is unclear if these findings are generalizable to other geographic locations. The most comprehensive meta-analysis of clinical studies in children older than 6 months shows that zinc supplementation reduces the duration of acute diarrhea by about 11 hours and the duration of persistent diarrhea by about 16 hours when compared with placebo. However, zinc does not seem to reduce the duration of acute diarrhea in children younger than 6 months. Zinc supplementation seems to have the greatest benefit in children with clear malnutrition and diarrhea. In these children, zinc reduces diarrhea duration by about 26 hours and reduces the risk of diarrhea persisting through days 3, 5, and 7 by 18% to 24% when compared with placebo. There was no clear benefit of using zinc in a specific dose or salt form. The most common dose of zinc was 20 mg daily and salt forms included zinc sulfate, gluconate, and acetate (96074). Also, a large clinical trial in children with acute diarrhea shows that taking zinc 5 or 10 mg daily for 14 days is non-inferior to taking 20 mg. Furthermore, zinc 5 or 10 mg results in a respective 29% and 19% lower risk of vomiting within the first 30 minutes when compared with zinc 20 mg (104045). It's unclear whether zinc supplementation reduces mortality in children with diarrhea. A meta-analysis of clinical research in children under the age of five years shows that supplementation with zinc reduces the risk of mortality from diarrhea by 15% when compared with either placebo, other vitamin and/or mineral supplementation, or no supplementation (106239). However, many studies were conducted in hospitals where rates of mortality are low and were not adequately powered to determine whether zinc has an effect on mortality in children with acute diarrhea (87210,96074,106239).
• Wilson disease. Taking zinc orally improves symptoms of this condition. Details: Zinc acetate (Galzin) is an FDA-approved orphan drug for treating this condition. Zinc blocks copper absorption and increases copper elimination in the stool of people with Wilson disease (2692,2693,87327). Small clinical studies suggest that taking zinc after 8 weeks of treatment with tetrathiomolybdate alone can improve Kayser-Fleischer rings, urine copper levels, and neurological symptoms for up to 6 years post-treatment (63588,87491).

POSSIBLY EFFECTIVE

• Acne. Orally, zinc might help to reduce symptoms of acne. However, it's unclear how oral zinc compares to conventional acne treatments. Topical zinc doesn't seem to be beneficial if used alone. Details: Observational research has found that people with acne seem to have lower zinc levels in the serum and skin (104056). A meta-analysis of small, low quality clinical trials suggests that taking zinc sulfate or zinc gluconate 137-300 mg 2-3 times daily by mouth can modestly improve acne when compared with placebo (104056). However, not all individual trials show benefit (87002,104056). So far, it is not clear how oral zinc compares to other treatments. Trials comparing zinc sulfate with various tetracyclines have yielded conflicting results (6505,6506,86946,106233). One large open-label clinical trial shows that taking zinc sulfate 200 mg twice daily for 12 weeks is at least as effective as lymecycline 300 mg daily for reducing acne severity. Quality of life related to acne was modestly improved in the patients using zinc sulfate (106233). However, in another clinical trial, a 3-month treatment of oral zinc gluconate 30 mg daily reduced the number of acne lesions from baseline, but was not as effective as minocycline (86946). When applied topically, clinical research shows that zinc does not help treat acne when compared with placebo (87297,104056). However, when used in combination with erythromycin, topical zinc seems to result in improvement (819,820,2687,2688).
• Acrodermatitis enteropathica. Oral zinc seems to improve symptoms of this rare genetic disorder. Details: Multiple case reports have found that taking oral zinc seems to help improve symptoms of acrodermatitis enteropathica, a rare disorder (821,2689,2690,2691). One case report in a female with necrolytic acral erythema and hepatitis C suggests that adding oral zinc sulfate 225 mg twice daily to interferon alfa-2b for 6 months contributed to resolving all lesions. Necrolytic acral erythema is categorized in the family of necrolytic erythemas that includes acrodermatitis enteropathica (6192).
• Age-related macular degeneration (AMD). Oral zinc, especially in combination with antioxidant vitamins, seems to slow the progression of AMD. Details: Clinical research shows that taking elemental zinc 80 mg plus vitamin C 500 mg, vitamin E 400 IU, and beta-carotene 15 mg daily reduces the odds of progression to advanced AMD by 28%. In patients with more severe AMD, this combination reduced the odds of progression to advanced AMD by 34%. This combination also reduced the odds of visual acuity loss by 27% in patients with severe AMD (7303,11326). However, there is contradictory evidence about the effects of zinc plus antioxidants on visual acuity loss or the progression to advanced AMD in low-risk patients with AMD (6583,6584,7303). Some clinical evidence shows that, when taken without antioxidant vitamins, zinc supplementation does not slow the progression of existing AMD (6580,90069). However, a subgroup analysis of results from a large clinical trial that included patients with intermediate or advanced AMD suggests that the effect of zinc on AMD progression might vary depending on a patient's genetic predisposition. Complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) are two genes for which specific variations (i.e., risk alleles) have been associated with an increased risk of AMD. Results from the retrospective subgroup analysis suggest that zinc supplementation may DECREASE the progression of AMD in patients with ARMS2 risk alleles and INCREASE the progression of AMD in patients with CFH risk alleles (90193). However, some experts question the results from this analysis due to the retrospective nature of the study (93045). Another retrospective analysis of similar data found that only zinc plus antioxidants, but not zinc alone, was beneficial for slowing the progression of AMD, regardless of the patient's genotype (93046). Consequently, the American Academy of Ophthalmology does not currently recommend routine genetic screening to determine which patients would benefit from zinc, antioxidants, or the combination. Instead, patients with intermediate or advanced AMD are recommended to take an antioxidant and zinc supplement similar to those used in the Age-Related Eye Disease Study (AREDS) and the Age-Related Eye Disease Study 2 (AREDS2) (93047). Large scale population studies suggest that increasing dietary intake of zinc might reduce the risk of developing AMD (6579,14257).
• Child growth. Oral zinc seems to increase growth when taken by children and improve infant growth in the first year of life when taken by pregnant adults. Details: A meta-analysis of 8 clinical studies in healthy children over 2 years old shows that taking supplemental zinc 5-15 mg daily for 6-56 weeks modestly increases height and weight when compared with placebo. This analysis also shows that taking zinc may improve height for age, but not weight for age when compared with placebo (112474). Most of these studies were conducted in developing countries; results may not apply elsewhere. Another clinical study in pregnant adults in Peru shows that taking zinc 15 mg daily in addition to iron and folic acid, starting during the first or second trimester and continuing up to one month after delivery, modestly improves growth measures of infants at one year when compared with taking iron and folic acid alone. Improved growth measures include body weight, calf and chest circumference, and calf muscle area (87130).
• Common cold. Oral zinc seems to help treat cold symptoms in adults. However, it is unclear if zinc is beneficial for common cold prevention. Details: Using zinc oral lozenges seems to be beneficial in helping TREAT the common cold in adults. The majority of clinical trials and analyses of clinical research show a significant decrease in the duration of symptoms of the common cold when adults take zinc gluconate or zinc acetate lozenges providing 9-24 mg of elemental zinc per dose. It is recommended that lozenges be taken every 2 hours while awake, starting within 48 hours of symptom onset for a total daily dose of at least 75 mg in order to attain a mean cold duration reduction of 3 days (333,334,335,337,6703,6705,87501,92212,106902). However, not all studies have been positive (333,338,339,6522,6700,87512). The reasons for these different findings are not clear, but might be due to differences in zinc formulations and doses and study methodologies. In some cases, flavoring agents such as citric acid, mannitol, and sorbitol might chelate zinc and decrease zinc ionization. Since ionization is thought to be necessary for zinc activity, a decrease in zinc ionization could decrease effectiveness (300,340,6522). Some of the positive studies have also been criticized for inadequately blinding the unpleasant, distinctive taste of zinc (6522,6706). Allergy and smoking status do not appear to impact the efficacy of zinc acetate lozenges (92212). Overall, zinc products may be beneficial for modestly reducing the duration of symptoms of the common cold in adults, but adverse effects such as bad taste and nausea may limit their usefulness (18216). There is conflicting evidence for the use of oral zinc products to PREVENT colds. Some clinical research suggests that taking zinc prophylactically does not prevent the common cold in adults (10780,10784) or children (341). However, other clinical research suggests that administering zinc gluconate lozenges can reduce the incidence of colds in children and adolescents (10803,86972). In a meta-analysis of 28 randomized controlled trials with a total of 5446 participants, oral zinc prevented 5 viral upper respiratory tract infections per 100 person months of zinc use when compared with placebo, with a number needed to treat (NNT) of 20 (106902). Intranasal zinc is not recommended for the prevention or treatment of the common cold due to the risk for anosmia. See the Adverse Effects section for more information. Some research shows that zinc nasal spray (as a sulfate, gluconate emulsion, or gluconium gel) reduces the severity and duration of cold symptoms; however, other research has found no effect (6471,8628,8629,10247,87035). Zinc nasal spray does not seem to prevent experimentally-induced colds (8628).
• Coronavirus disease 2019 (COVID-19). While oral zinc does not seem to speed recovery from COVID-19 in non-hospitalized patients, an analysis of a small number of studies suggests that oral or intravenous zinc might reduce the risk of death in hospitalized patients with COVID-19. Details: A small observational study in patients with COVID-19 has found that lower serum zinc levels are associated with worse clinical outcomes, such as admission to the intensive care unit (ICU) and death, when compared with higher zinc levels (105681). Another small observational study has found that 96% of patients with confirmed COVID-19 were zinc-deficient based on plasma levels of zinc, and that these patients had lower plasma zinc levels than a group of individuals without COVID-19. However, plasma zinc concentrations were only weakly correlated with length of hospital stay and there was no correlation with morbidity or mortality (106236). One clinical study in adult outpatients with COVID-19 shows that taking zinc gluconate 50 mg daily at bedtime, alone or with vitamin C (ascorbic acid) 8000 mg daily, for 10 days does not reduce symptom severity when compared with standard care (104450). This study was terminated prior to complete enrollment due to a lack of effect with zinc and/or vitamin C supplementation. Limitations of this study include a lack of placebo control and blinding. Zinc supplementation also does not appear to enhance the clinical efficacy of hydroxychloroquine in patients with confirmed COVID-19 infection. Taking zinc sulfate 220 mg twice daily during a 6-day course of hydroxychloroquine does not improve the clinical recovery rate, reduce the mortality rate, or reduce the need for mechanical ventilation when compared with hydroxychloroquine alone (104818). Other research has evaluated zinc in hospitalized patients. Multiple meta-analyses of small and low-quality clinical studies, including randomized controlled trials and retrospective studies, involving hospitalized patients with COVID-19 shows that supplementation with oral or intravenous zinc is associated with a 29% to 43% reduction in the odds of in-hospital mortality when compared with control (109451,110631). However, in one meta-analysis, the odds of 30-day mortality were not different between groups (110631). These meta-analyses did not elevate the most effective form, dose, frequency, or duration of zinc supplementation (109451,110631). Additionally, a retrospective study in adults admitted to the ICU with COVID-19 has found that those who received oral zinc sulfate, 220 mg daily for a median of 11 days, had a lower 30-day mortality rate when compared with those who did not receive zinc. However, there was no difference in hospital length of stay or in-hospital mortality (106903).
• Depression. Oral zinc seems to be beneficial when used in combination with antidepressant treatments. Details: Population research has found that higher zinc levels and higher dietary intake of zinc are associated with a 28% lower incidence of depression (90227,97139,104057). Oral zinc seems to be beneficial as an adjunct therapy in depression. A meta-analysis of small, low-quality studies in patients with major depression shows that taking zinc in addition to antidepressant therapy is associated with modestly improved depression symptoms when compared with antidepressant therapy alone (104044). Clinical studies used zinc doses of 7-25 mg daily for up to 12 weeks (86985,90221,104044). One small clinical study also shows that adding zinc to imipramine therapy might improve depression that was previously resistant to antidepressant treatment (87158). One clinical guideline also provisionally recommends use of zinc 25 mg elemental orally daily to treat patients with depression based on low-quality evidence. This guideline recommends use of chelated or picolinate zinc products over other forms of zinc (110318).
• Diabetes. Oral zinc might modestly improve glycemic control in some patients. Details: A meta-analysis of 12 clinical studies in patients with diabetes shows that taking zinc supplements reduces fasting blood glucose by up to 20 mg/dL and glycated hemoglobin (HbA1c) by 0.35% when compared with control. However, when only high quality studies were included, the reduction in fasting blood glucose dropped to 12 mg/dL. Zinc seems to only have glycemic benefit in patients living in the Eastern hemisphere, and not the Western hemisphere. Also, glucose reduction seems to be higher with inorganic zinc formulations at doses of at least 30 mg daily taken for at least one month (104080). Zinc has also been evaluated for improving lipid parameters in patients with diabetes. A meta-analysis of nine studies in patients with diabetes shows that taking zinc reduces triglycerides by 17 mg/dL, but does not seem to affect low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol levels, when compared with placebo (104041). The findings from these meta-analyses are limited by the high heterogeneity and small size of the included studies. Zinc has also been studied for gestational diabetes. Some clinical research in patients with gestational diabetes shows that taking zinc gluconate for 6 weeks, starting at 24-28 weeks' gestation, reduces fasting plasma glucose levels by about 10% and improves insulin resistance by 14% when compared to baseline (96072). However, taking zinc gluconate does not reduce the need for caesarean section or insulin therapy, or improve infant outcomes, such as size or health at birth, in these patients (96073).
• Diaper rash. Topical and oral zinc seem to reduce the incidence and severity of diaper rash in infants. Details: Clinical research shows that administering oral zinc gluconate 10 mg daily for 4 months can reduce the incidence of diaper rash in infants when compared with placebo (87281). Other clinical research shows that applying 47% zinc oxide paste to affected areas for 5 days can improve the healing of diaper rash. However, the effect of zinc oxide paste is inferior to eosin 2% solution (86918).
• Gingivitis. Topical zinc seems to reduce the development of gingivitis. Details: While some clinical research shows that zinc, in combination with triclosan, does not prevent plaque and gingivitis (24093,87020), most clinical research shows that using zinc toothpaste or mouthwash, alone or in combination with triclosan, can prevent plaque accumulation, gingivitis, or the formation of calculus (6523,6524,6525,6526,6527,6528,6529,87418,87507). However, most studies used zinc citrate in combination with triclosan, which is not available in the US (6523). For treating existing plaque, calculus, and gingivitis, some clinical research suggests that using zinc citrate 0.5% toothpaste three times daily for 3 months reduces calculus scores by 14% when compared with placebo (87205). However, other evidence suggests that stannous fluoride 0.454% toothpaste is more effective than zinc citrate 0.75% toothpaste for reducing plaque levels (87136).
• Halitosis. Oral zinc seems to reduce halitosis when taken as a gum, mouth rinse, or candy. Details: Clinical research shows that chewing zinc-containing gum reduces volatile sulfur compounds and related odor levels when compared with placebo gum in patients with moderate to severe halitosis (87538). Clinical research also shows that using one of two mouth rinses (Halita, which contains 0.05% chlorhexidine and 0.14% zinc lactate, or Meridol, which contains 0.025% fluoride plus 0.2% zinc lactate) improves breath odor and volatile sulfur compounds by approximately two-fold when compared with mouth rinse containing only 0.05% fluoride or chlorhexidine 0.12% (90206). Additional clinical research shows that sucking a candy containing abrasive substances and zinc gluconate 0.5% or candy containing abrasive substances plus zinc 0.25% and propolis 1% improves breath malodor two- to three-fold when compared with sucking placebo candy (90196).
• Herpes labialis (cold sores). Topical zinc seems to reduce the severity and duration of cold sores. Details: Applying zinc topically seems to help treat herpes simplex infection (6538,6539,8623,11051). Zinc sulfate seems to reduce the severity and duration of symptoms in both orolabial and genital herpes (6538,6539). Zinc oxide (0.3%) in combination with glycine cream applied topically every 2 hours to facial and circumoral herpes seems to reduce symptoms such as blistering, soreness, itching, and tingling. It can also reduce the duration of lesions from 6.5 days to 5 days when treatment is begun within 24 hours of onset of symptoms (8623). A specific combination product containing zinc oxide and L-lysine plus 14 other ingredients (Super Lysine Plus +) also seems to help decrease symptoms and duration of herpes lesions when applied topically every 2 hours (11051). However, zinc may not be effective for recurrent herpes simplex infections. In one clinical study, applying zinc sulfate 0.0025% or 0.05% solution to affected areas did not reduce the frequency, severity, or duration of herpes episodes when compared with a placebo solution in patients experiencing more than five episodes per year (87330).
• Hypogeusia. Oral zinc might improve taste disturbance and taste acuity in people with hypogeusia of various etiologies. Details: A meta-analysis of low-quality studies in patients with taste disorders that are idiopathic or due to zinc deficiency shows that taking oral zinc modestly improves taste acuity when compared with placebo (104055). Studies tested zinc gluconate, zinc sulfate, zinc acetate, and zinc-carnosine as Polaprezinc (Promac, Zeria Pharmaceutical Co., Ltd.), containing 17-68 mg elemental zinc, daily for up to 12 weeks (104055). Zinc also might improve hypogeusia conditions unrelated to zinc deficiency, such as gustin/carbonic anhydrase VI deficiency, captopril-induced taste disturbances, hypogeusia due to chronic renal failure, and post-traumatic olfactory disorder (6543,6544,104055). It also seems be beneficial in radiation-induced dysgeusia. A meta-analysis of three small clinical trials shows that oral zinc reduces the risk of radiation-induced dysgeusia by 28%, but does not improve taste acuity when compared with placebo (104043). However, patients with hypogeusia from other causes may not benefit. Zinc supplementation does not seem to improve taste perception when compared with placebo in patients with acetazolamide-induced taste dysfunction or chemotherapy-induced taste dysfunction (87388,90214).
• Leishmania lesions. Oral zinc and intralesional injections of zinc might improve healing of these lesions. Details: Clinical research shows that taking zinc sulfate 2.5-10 mg/kg orally in three divided doses daily, improves the cure rate of cutaneous leishmania lesions after 45 days when compared with no treatment (86935). Other clinical research shows that intralesional injections of zinc sulfate 2% solution for 6 weeks improves cure rates of cutaneous leishmania lesions when compared with no treatment (6587). However, intralesional injections with zinc sulfate solution does not appear to be more effective than intralesional injections of meglumine antimoniate (Glucantime), hypertonic saline, or sodium stibogluconate (6587,86996,87008).
• Leprosy. Oral zinc seems to be beneficial when used in combination with anti-leprosy drugs. Details: Zinc levels appear to be reduced in people with leprosy. Early clinical research suggests that the addition of zinc improves tolerance of the anti-leprosy drug regimen and might allow for lowering or eliminating steroid doses in erythema nodosum leprosum, a severe form of leprosy (6534,6535,6536,6537).
• Low birth weight. Oral zinc supplementation seems to improve growth in low birth weight infants. Whether oral zinc can improve other outcomes, including mortality, is unclear. Taking oral zinc during pregnancy does not seem to reduce the risk of having a low birth weight infant. Details: While there is some mixed evidence regarding the effects of zinc supplementation on weight gain and length in infants born with low birth weight (87172,87452,90229), a meta-analysis of 14 clinical trials in preterm or low birth weight infants receiving breastmilk shows that zinc supplementation, typically 5-7 mg daily started at birth and continued for up to 12 months with or without other micronutrients, increases weight by around 380 grams, length by around 3 cm, and head circumference by around 0.6 cm when compared with control (109455). There is also mixed evidence regarding the effect of zinc supplementation on other outcomes in low birth weight infants. A large clinical trial in full-term, underweight infants aged 1-6 months in developing countries shows that adding zinc to nutritional supplementation reduces the risk of mortality by about 68% when compared with nutritional supplementation not containing zinc (8920). A small clinical trial in very low birth weight preterm infants born in an industrialized country shows that adding zinc to multivitamin supplementation appears to reduce the occurrence of necrotizing enterocolitis and mortality. However, adding zinc does not appear to prevent late-onset sepsis, bronchopulmonary dysplasia, or retinopathy of prematurity (90229). A meta-analysis of these trials and two other studies in low birth weight infants shows that supplementation with zinc reduces the risk of all-cause mortality by 52% when compared with either placebo, other vitamin and/or mineral supplementation, or no supplementation (106239). Another small clinical study in low birth weight and preterm infants born in a developing country shows that zinc supplementation seems to improve alertness and attention when compared with placebo (97140). However, a meta-analysis of 14 clinical trials in preterm or low birth weight infants receiving breastmilk shows that zinc supplementation, typically 5-7 mg daily started at birth and continued for up to 12 months with or without other micronutrients, does not improve mental or psychomotor development or reduce the risk of mortality, hospitalization, acute respiratory infection, or sepsis when compared with control (109455). Some of these discrepant findings may be due to differences in patient populations (hospitalized, non-hospitalized), milk sources (breastfed, formula-fed, or both), and duration of follow-up. The effect of zinc intake or supplementation during pregnancy has also been evaluated. Population research has found that low dietary intake of zinc during pregnancy is associated with low birth weight in infants; similarly, zinc supplementation is associated with increased infant weight at birth (87471,105678). However, a meta-analysis and a large clinical study show that zinc supplementation during pregnancy does not reduce the risk of having a low birth weight infant (97142,105679). Reasons for the discrepancies may be due to differing zinc status prior to supplementation. Also, numerous factors contribute to the risk of low birth weight, which may confound research on the use of zinc supplementation alone.
• Peptic ulcers. Oral zinc seems to treat and prevent peptic ulcers. Details: Taking zinc orally seems to help treat and prevent peptic ulcers (6588,6589,6591). Some clinical research shows that zinc acexamate improves peptic ulcers when compared with placebo (6589,87285), and seems to be as effective as H2-receptor antagonist drugs (6589,87533). It is not known if other zinc salts are effective.
• Pneumonia. Oral zinc might reduce the risk for pneumonia in children, but it doesn't seem to improve symptoms in children that already have pneumonia. Details: A meta-analysis of four clinical studies shows that giving zinc supplements to children, ages 3 months to 5 years living in developing countries, some of whom were undernourished, reduces the risk of pneumonia incidence by 21% when compared with placebo (104047). Another meta-analysis of clinical research in children under the age of five years shows that supplementation with zinc reduces the risk of pneumonia mortality by 21% when compared with either placebo, other vitamin and/or mineral supplementation, or no supplementation (106239). The research on TREATING existing pneumonia in children is inconsistent. Most meta-analyses and clinical studies in children ages 2 months to 5 years with severe pneumonia show that taking elemental zinc in addition to antibiotic therapy does not improve symptom resolution or the time to recovery when compared with antibiotic therapy alone. Zinc also does not seem to reduce mortality in these patients (87248,90197,96080,98131,104042). However, two clinical studies in children in the same age group with pneumonia suggest that adding zinc to standard antibiotic therapy improves symptom resolution and decreases hospital stay when compared with placebo (11052,87242). Reasons for these discrepancies are not clear, but may be related to zinc status prior to treatment.
• Prematurity. Analyses of clinical studies suggest that oral zinc improves growth in premature infants. Whether zinc improves development or reduces the risk of mortality in these patients is unclear. Details: A meta-analysis of small clinical trials in hospitalized infants born prematurely suggests that receiving enteral zinc supplementation at a dose of up to 10 mg daily reduces mortality and might improve short-term weight gain when compared with placebo (105687). Another meta-analysis of small clinical studies in preterm infants shows that adding zinc to formula or to a multivitamin seems to modestly increase infant weight and height and improve motor development when compared with control (105676). A larger meta-analysis of 14 clinical trials in preterm or low birth weight infants receiving breastmilk shows that zinc supplementation, typically 5-7 mg daily started at birth and continued for up to 12 months with or without other micronutrients, increases weight by around 380 grams, length by around 3 cm, and head circumference by around 0.6 cm when compared with control. However, zinc supplementation did not improve mental or psychomotor development or reduce the risk of mortality, hospitalization, acute respiratory infection, or sepsis when compared with control (109455). These analyses are limited by imprecision as well as a high risk of bias in some of the included studies. Some of the discrepant findings may be due to differences in patient populations (hospitalized, non-hospitalized), milk sources (breastfed, formula-fed, or both), and duration of follow-up.
• Pressure ulcers. Topical zinc paste seems to work as a skin barrier and improve pressure ulcer healing. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that applying zinc oxide paste to pressure ulcers daily for 8 weeks reduces necrotic tissue and decreases the surface area of skin pressure ulcers similarly to using a topical streptokinase-streptodornase product (Varidase) (87331). Other small clinical studies show that applying zinc oxide paste to pressure ulcers daily for 8-12 weeks improves healing similarly to a hydrocolloid dressing (Duoderm) (87181) or a specific barrier film product (Cavilon No Sting Barrier Film) (87017). Oral zinc has been evaluated in combination with other ingredients for the treatment of grade II-IV pressure ulcers. Two small clinical studies in hospitalized patients shows that administering an oral nutritional supplement enriched with zinc, L-arginine, and vitamin C improves ulcer healing when compared with a standard diet (31953,87173). Also, clinical research in patients living in long-term care facilities shows that taking an oral nutritional supplement enriched in protein, zinc, L-arginine, and vitamin C daily for 9 weeks reduces ulcer area and decreases oozing when compared to baseline (32045). The validity of this finding is limited by the lack of a comparator group.
• Sickle cell disease. Oral zinc seems to improve symptoms of sickle cell disease in patients with zinc deficiency. Details: Taking zinc orally seems to help reduce symptoms of sickle cell disease in people with zinc deficiency (6594,6595,6596,8626,87343). Taking zinc supplements also seems to decrease the occurrence rate of sickle-cell crises and infections (6594,6596,90228). Additionally, zinc might reduce the number of hospitalizations for sickle cell crises, although the severity of the crises that do develop is not necessarily decreased by taking zinc supplements (6594,6596). In prepubertal children and adolescents with homozygous sickle cell disease, taking zinc seems to improve growth, height, and weight gain (8626,87403).
• Warts. Oral and topical zinc seem to improve the cure rate of cutaneous warts. Details: A small clinical study suggests that applying zinc sulfate 10% solution three times daily for 4 weeks improves plane warts, but not common warts, when compared with distilled water (87094). Another small clinical study suggests that applying topical zinc oxide 20% ointment twice daily for up to 3 months seems to have a similar cure rate as ointment containing salicylic acid 15% with lactic acid 15% (87082). Taking zinc orally may also be effective in treating warts (87227). A meta-analysis of low quality clinical studies shows that taking zinc sulfate orally improves the odds of curing cutaneous warts nearly 17-fold when compared with respective controls (87227). Preliminary clinical research in adults treated with cryotherapy for anogenital warts shows that taking zinc gluconate 30 mg orally three times daily for 2 months does not reduce the number of warts when compared with placebo (111445).

POSSIBLY INEFFECTIVE

• Alopecia areata. Oral zinc does not seem to improve symptoms of this condition. Details: Although there is preliminary evidence that suggests zinc in combination with biotin might be helpful for alopecia areata (6932), most studies indicate that zinc is not effective for alopecia areata, alopecia totalis, or alopecia universalis (6931,6932).
• Cystic fibrosis. Oral zinc does not improve cystic fibrosis symptoms or progression. Details: Clinical research shows that taking supplements providing 30-90 mg of elemental zinc for 6 weeks to one year does not improve lung function when compared with placebo in children and adolescents with cystic fibrosis (87066,87113,96079). One clinical study also shows that taking elemental zinc for one year does not reduce the number of days requiring oral or intravenous antibiotics for pulmonary infections (96079). However, one study shows that taking zinc can reduce the number of days of oral antibiotic use when compared with placebo (87113).
• HIV/AIDS. Oral zinc does not seem to improve outcomes in patients with HIV. Details: Clinical research in adult HIV patients with normal or low zinc levels shows that taking elemental zinc 12-15 mg daily orally for 18 months along with antiretroviral therapy does not improve viral load, CD4/8 counts, or mortality when compared with placebo (87036,87216,105686). In children with HIV-1, clinical research shows that administering zinc sulfate, providing 10 mg elemental zinc, daily for 6 months does not improve mortality, viral load, or CD4 counts when compared with placebo (82377).
• HIV/AIDS-related pregnancy complications. Oral zinc does not prevent pregnancy complications related to HIV infection. Details: Adding zinc 25 mg orally during pregnancy does not seem to reduce parent-to-child vertical transmission of HIV, infant mortality, birth weight, or gestational period in HIV-infected females with low zinc levels (11054,87034). Also, one clinical study in HIV-1-infected pregnant patients suggests that supplemental zinc can increase the risk of wasting, as assessed by weight and mid-upper arm circumference, by 170% when compared with placebo (87034).
• HIV/AIDS-related wasting. Oral zinc does not seem to improve HIV-related wasting syndrome. Details: A clinical study in patients with HIV-related wasting syndrome shows that taking zinc orally in combination with vitamins and albendazole does not seem to improve diarrhea or mortality when compared with taking albendazole alone (6564).
• Infant development. Oral zinc does not seem to improve infant mental and psychomotor development. Details: Clinical research, including a meta-analysis of eight studies, shows that giving zinc to infants or children at high risk for zinc deficiency does not improve mental and psychomotor development when compared with placebo (87013,90209). In another meta-analysis of studies in children whose baseline zinc status was not specified, there was no beneficial effect of zinc supplementation on mental or psychomotor development at 6 or 12 months of age (104817).
• Inflammatory bowel disease (IBD). Oral zinc does not improve symptoms of IBD. Details: Some clinical research shows that taking zinc orally does not seem to help treat IBD (6913,6915,6916).
• Influenza. Oral zinc does not seem to reduce the risk for influenza. Details: Supplemental zinc seems to improve cell-mediated immune response in elderly people (824), but it does not seem to have a significant effect on antibody response and incidence of influenza infection after the vaccine (6553,6563). Additionally, zinc supplementation in patients on hemodialysis, who have a high risk of zinc deficiency, does not seem to improve response to influenza vaccine (10809). Taking zinc supplements orally is unlikely to improve immune function in people without risk factors for zinc deficiency (10789). However, there is preliminary evidence that suggests zinc along with selenium might reduce the incidence of infections in institutionalized older patients (8921).
• Otitis media. Oral zinc does not prevent otitis media in children. Details: A meta-analysis of clinical research shows that taking elemental zinc 3-70 mg daily for up to 24 months does not prevent the occurrence of ear infections in children from low- or middle-income countries (87258).
• Pre-eclampsia. Oral zinc taken prenatally does not seem to be beneficial for pre-eclampsia prevention. Details: A meta-analysis and a large clinical study show that zinc supplementation during pregnancy does not reduce the risk of pre-eclampsia when compared with placebo (97142,105679).
• Prostate cancer. Oral zinc does not reduce the risk for prostate cancer or prostate cancer-related mortality. Details: Some epidemiological research has found an inverse relationship between dietary zinc intake and prostate cancer (96075). Also some clinical research shows that taking zinc 20 mg in combination with vitamin C 120 mg, vitamin E (alpha-tocopherol) 30 mg, beta-carotene 6 mg, and selenium 100 mcg daily for an average of 8 years might reduce the risk of prostate cancer in men with normal PSA levels; however, it does not seem to be beneficial for reducing the risk of prostate cancer in patients with PSA levels above 3 mcg/L (14135). However, some evidence raises concern that zinc might actually INCREASE the risk of prostate cancer. A large-scale population study found that taking more than 100 mg of supplemental zinc daily or taking supplemental zinc for 10 or more years doubles the risk of developing prostate cancer (10306). Another large-scale population study shows that men who take a multivitamin more than seven times per week and who also take a separate zinc supplement have a significantly increased risk of prostate cancer-related mortality (15607). Despite these studies suggesting the potential for adverse effects of zinc, a meta-analysis of mainly population research has found that there is no association between zinc intake and the risk of prostate cancer (96075).
• Psoriasis. Oral zinc does not reduce the severity of psoriasis symptoms. Details: Zinc epidermal levels are reportedly lower in people with psoriasis (6509). However, taking zinc orally does not seem to help treat psoriasis (6513,6514,6912,87363). Zinc supplementation has no effect on the psoriasis area and severity index (6513,6514).
• Rheumatoid arthritis (RA). Oral zinc does not treat symptoms of RA. Details: Multiple clinical studies in patients with RA show that taking zinc orally does not improve function or symptoms when compared with baseline or control (6517,6518,6519,87406).
• Sexual dysfunction. Oral zinc does not improve sexual function in males with chronic kidney disease (CKD). Details: Clinical research shows that zinc supplementation does not improve sexual activity or libido when compared with placebo in males with sexual dysfunction secondary to CKD (6708,6568,87220,87386,87416). In fact, one clinical study shows that taking zinc can decrease the frequency of intercourse by 76% when compared with placebo in patients with CKD-related sexual dysfunction (87220).
• Tinnitus. Oral zinc does not improve severity of tinnitus or reduce tinnitus-related disability. Details: A meta-analysis of three small clinical trials in adults with tinnitus shows that taking elemental zinc 50 mg daily for up to 16 weeks does not improve tinnitus severity, or disability from tinnitus when compared with placebo (104051).

LIKELY INEFFECTIVE

• Malaria. Oral zinc does not prevent or treat malaria in undernourished children or pregnant adults in developing countries. Details: A meta-analysis of clinical research in children or pregnant adults shows that taking zinc orally, alone or in combination with other supplements, for does not reduce the risk of malaria parasitemia (111444). A large multi-country study in zinc-deficient preschool children with acute malaria shows that taking zinc supplements does not affect fever, parasitemia, or hemoglobin when compared with placebo (10246). An even larger clinical study of over 40,000 children with malaria aged 1-36 months shows that taking zinc 5-10 mg daily orally for approximately 17 months does not reduce mortality when compared with placebo (87078). Zinc supplements also do not appear to protect against infection by Plasmodium falciparum (8638,87235,86937). However, one small study in children with low and high levels of parasitemia shows that taking zinc 10 mg daily for 46 weeks may lower the incidence of fever episodes by 38% and 69%, respectively, when compared with placebo (86937).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral zinc is beneficial in patients with age-related cognitive decline. Details: An epidemiological study based on elderly adults enrolled in the National Health and Nutrition Examination Survey (NHANES) has found that taking zinc may improve cognition in a non-linear manner. Daily doses below 9 mg and 8 mg in males and females, respectively, showed a positive association with cognitive function, but doses above that level showed no association. Additionally, high intake of both zinc and selenium was associated with improved cognition in females, but not in males (108446). Dietary intake was collected from two patient-reported 24-hour recalls and cognition was only measured once, limiting the validity of these findings.
• Alcohol-related liver disease. It is unclear if oral zinc is beneficial in patients with alcoholic-related liver cirrhosis. Details: A small clinical study in patients with alcoholic liver cirrhosis shows that taking zinc sulfate 600 mg daily for 6 weeks improves liver function, based on increased alkaline phosphatase activity and reduced serum bilirubin, when compared to baseline (87325).
• Anorexia nervosa. Oral zinc seems to improve weight gain in people with anorexia nervosa. Details: Anorexia nervosa might be linked with zinc deficiency. Small clinical trials in adolescents and adults with anorexia nervosa show that oral zinc supplements might help increase weight gain and improve depressive symptoms when compared with placebo (6905,6906).
• Arsenic poisoning. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that taking zinc 4 mg in combination with spirulina extract 500 mg daily for 16 weeks can decrease skin manifestations and reduce arsenic levels in the urine and in hair of patients with chronic arsenic poisoning (18301).
• Asthenopia (eye strain). Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults without dry eye disease shows that taking a specific combination product containing zinc 10 mg, L-carnitine 50 mg, elderberry fruit extract 300 mg, currant 100 mg, and Eleutherococcus root 50 mg (Meramirt CM) orally once daily for 1 month improves measures of eye strain and contrast sensitivity when compared to baseline. Improvements in these measures were lacking in the control group (111295). Statistical comparison between the two groups was not reported. It is unclear if these effects are due to zinc, other ingredients, or the combination.
• Athletic performance. Although there is interest in using oral zinc for athletic performance, there is insufficient reliable information about the effects of zinc for this purpose.
• Atopic dermatitis (eczema). It is unclear if oral zinc is beneficial for alleviating eczema in children. Details: A small clinical study in children with eczema shows that taking zinc sulfate 185.4 mg orally daily for 8 weeks does not appear to improve the surface area affected and degree of erythema, symptom scores of itch and sleep disturbance, or topical steroid use when compared with placebo. Also, plasma zinc levels appear to be normal in children with eczema (6911).
• Attention deficit-hyperactivity disorder (ADHD). Oral zinc might improve certain symptoms in children with ADHD. Details: Observational research has found that lower serum zinc levels are both more prevalent in children with ADHD and are linked to worsened response to stimulant therapy (9965,9966,9967). Based on this evidence, there is some interest in using zinc to improve symptoms in children with ADHD. A meta-analysis of six small clinical trials shows that although taking zinc modestly improves overall symptoms of ADHD when compared with placebo, there is no effect on hyperactivity or inattention when these outcomes are examined separately. The sub-analyses conducted for these two separate outcomes included only 3 studies. Most, but not all, of the included studies were conducted in children also receiving methylphenidate treatment (106240). Elemental zinc, usually as sulfate, was typically used in doses of 10-40 mg daily for 6-12 weeks (11350,12060,106240). There is some evidence that zinc could be most helpful in children with a high body mass index (BMI), low zinc levels, and low free fatty acid levels (11350). It is unclear if zinc is beneficial in children who are not already taking stimulant medications. One clinical guideline also provisionally recommends against use of oral zinc to treat patient with ADHD based on low-quality evidence (110318).
• Autism spectrum disorder. It is unclear if oral zinc is beneficial in children with autism spectrum disorder. Details: One small clinical study conducted in children with autism spectrum disorder shows that taking zinc 15-30 mg orally, alone or as add-on therapy to amphetamine, does not improve attention deficit hyperactivity disorder (ADHD) symptoms when compared with placebo (98711). However, the optimal mg/kg dose of amphetamine was shown to be 37% lower for those children also taking zinc 15 mg twice daily when compared with those taking placebo (98711).
• Behcet disease. It is unclear if oral zinc is beneficial in patients with Behcet disease. Details: A small clinical trial in patients with Behcet disease shows that taking zinc gluconate 30 mg daily for 12 weeks does not improve disease activity scores, quality of life, or measures of inflammation when compared with placebo (109453).
• Benign prostatic hyperplasia (BPH). Although there is interest in using oral zinc for BPH, there is insufficient reliable information about the clinical effects of zinc for this condition.
• Beta-thalassemia. It is unclear if oral zinc is beneficial in patients with beta-thalassemia major. Details: A small clinical study in children recently diagnosed with beta-thalassemia major shows that initiating zinc sulfate in addition to standard blood transfusions increases linear growth rate when compared with transfusions alone (87329). Another small clinical study in adult and pediatric patients with thalassemia major and low bone mass shows that taking zinc 25 mg daily (as zinc sulfate) for 18 months improves whole-body bone mineral content, as well as hip and spine bone mineral density, by small amounts when compared with placebo (90208).
• Brain tumor. It is unclear if dietary zinc is beneficial for reducing the risk for brain cancer. Details: Population research has found that zinc intake is not associated with a reduced risk of developing brain cancer (87098).
• Breast cancer. It is unclear if increased dietary zinc intake is beneficial for reducing the risk for breast cancer. Details: Population research has found that neither zinc intake nor blood levels of zinc are associated with a reduced risk of breast cancer (106229).
• Bronchiolitis. It is unclear if oral zinc is beneficial for viral bronchiolitis in infants and children. Details: A small clinical study in children 2 years or younger with acute viral bronchiolitis shows that taking elemental zinc 10-20 mg as zinc sulfate for 5 days improves clinical recovery and reduces the duration of hospital stay by almost one day when compared with placebo. After 72 hours, 98% of infants and children taking zinc were considered fully recovered, compared to only 52% of infants taking placebo (96076).
• Burning mouth syndrome. Topical zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with burning mouth syndrome shows that taking zinc 15 mg and vitamin C 35 mg once daily, along with a vitamin B complex twice daily, for 30 days modestly decreases pain and burning when compared to baseline (105195). The validity of this finding is limited by the lack of a comparator group. Furthermore, it is unclear if the benefit is due to zinc, other vitamins, or the combination.
• Burns. Intravenous zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. The effects of oral zinc for burn healing are unclear. Details: Administering zinc intravenously in combination with other minerals seems to improve the outcomes of burn patients. Supplementation with zinc, copper, and selenium appears to improve wound healing, reduce pulmonary infections, and shorten intensive care unit stay in patients with serious burns (6520,87085). The effect of supplementation with zinc alone is unclear.
• Canker sores. It is unclear if oral zinc is beneficial in patients with canker sores. Details: Evidence for the use of zinc in canker sores is conflicting. A small clinical crossover study in patients with recurrent canker sores shows that taking zinc sulfate 660 mg daily for 3 months does not improve the size or frequency of canker sore ulcers when compared with control (6592). However, another clinical study in patients with recurrent sores and low or normal zinc levels shows that taking zinc sulfate 220 mg daily for 1 month reduces recurrence of sores when compared with placebo (86964). Reasons for conflicting results are unclear. Zinc might be beneficial when used in a muco-adhesive formulation. A small clinical study in patients with canker sores shows that taking a muco-adhesive zinc sulfate 5 mg tablet three times daily for 7 days reduces pain and speeds up healing when compared with placebo (104048).
• Cataracts. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking zinc orally in combination with antioxidant vitamins does not seem to help treat or prevent cataracts. Taking elemental zinc 80 mg plus vitamin C 500 mg, vitamin E 400 IU, and beta-carotene 15 mg daily does not seem to have any effect on the development or progression of age-related lens opacities (cataracts) or the need for cataract surgery in well-nourished people 55-80 years of age. However, it is unknown whether earlier intervention and/or a longer period of treatment with supplements would have any effect on cataracts (7304).
• Chemotherapy-induced acral erythema. It is unclear if oral zinc reduces the severity of acral erythema induced in patients treated with the vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) treatment regorafenib. Details: A small study in patients with metastatic colorectal cancer undergoing treatment with regorafenib shows that taking zinc gluconate 78 mg twice daily reduces the proportion of patients with more severe acral erythema when compared with control. Though there is no association in the zinc treatment group, lower serum zinc levels seem to correlate with more severe acral erythema in the control group, suggesting a possible role of zinc deficiency in the pathogenesis of acral erythema (112472). The validity of this study is limited by the lack of blinding.
• Chemotherapy-related fatigue. It is unclear if oral zinc improves symptoms in patients with fatigue due to chemotherapy. Details: A small clinical study in patients undergoing 4 or more cycles of chemotherapy for colorectal cancer shows that taking zinc 70 mg daily for 16 weeks does not improve fatigue or quality of life when compared with placebo (97141).
• Chronic fatigue syndrome (CFS). Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in females with CFS shows that taking zinc 10 mg as zinc sulfate plus melatonin 1 mg daily for 16 weeks modestly reduces self-reported symptoms of physical fatigue when compared with placebo. However, there was no effect on cognitive or psychological symptoms, sleep, or symptoms of anxiety or depression (106241). This study may not have been adequately powered to detect differences between groups.
• Cirrhosis. It is unclear if zinc is beneficial for reducing cirrhosis-related mortality. Details: A meta-analysis of four small clinical trials shows that zinc supplementation does not seem to reduce mortality in patients with cirrhosis when compared with control (104054). This finding is limited due to the heterogeneity and small size of the available studies.
• Cognitive function. It is unclear if zinc is beneficial for cognitive function. Details: A very small clinical study in adults with overweight and obesity shows that taking supplemental zinc 30 mg daily for 12 weeks improves some measures of cognitive function and executive processing but does not improve verbal fluency when compared with placebo (112471). Zinc has also been evaluated in combination with other ingredients. A small clinical trial in healthy adults shows that taking a specific product containing a combination of zinc 9 mg, Lactobacillus helveticus, Lactiplantibacillus plantarum, Bifidobacterium longum, and other ingredients (Puraflor, GSK Consumer Healthcare, Milano, Italy) orally daily for 4 weeks does not affect cognitive performance during acute stress when compared with placebo (110923).
• Colorectal adenoma. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study shows that taking a combination supplement containing zinc 30 mg, selenium 200 mcg (as l-selenomethionine), vitamin A 2 mg (as retinol), vitamin C 180 mg, and vitamin E 30 mg (as D-a-tocopherol acetate) by mouth daily for 5 years or until the recurrence of an adenoma reduces the risk of recurrent large-bowel adenomas by approximately 40% when compared with placebo (92903). It is not clear if the benefit is due to zinc, other supplements, or the combination.
• Colorectal cancer. It is unclear if oral zinc is beneficial for reducing colorectal cancer risk. Details: Population research has found that increased intake of zinc is associated with a 17% to 20% reduced risk of colorectal cancer (90213,90220).
• Congenital heart disease. It is unclear if oral zinc is beneficial for reducing the risk of congenital heart defects. Details: An observational study in pregnant adults has found that consuming the recommended nutritional intake of zinc may be associated with a lower risk of total congenital heart defects in infants, including atrial and ventricular septal defects, when compared with low zinc intake. This association appears to persist despite copper or selenium intake (108445).
• Critical illness (trauma). It is unclear if oral zinc is beneficial for critically ill patients. Details: A meta-analysis of two small randomized clinical trials in adults with head trauma shows that supplementing zinc, given as 120 mg elemental zinc orally daily or 12 mg elemental zinc intravenously daily for 15 days to 3 months, regardless of serum zinc levels, does not improve the risk of 30-day mortality when compared with control (111290). However, the study may have been inadequately powered to detect a difference between groups.
• Dementia. Although there is interest in using oral zinc for dementia, there is insufficient reliable information about the clinical effects of zinc for this condition.
• Diabetic foot ulcers. Although there is interest in using oral zinc for diabetic foot ulcers, there is insufficient reliable information about the clinical effects of zinc for this condition.
• Diabetic neuropathy. It is unclear if oral zinc is beneficial in patients with diabetic neuropathy. Details: A small clinical study in patients with poorly-controlled diabetic neuropathy shows that taking zinc sulfate 660 mg daily for 6 weeks improves motor nerve conduction velocity and reduces fasting and postprandial blood sugar when compared to baseline (86933). The validity of this finding is limited by the lack of statistical comparison to the control group.
• Down syndrome. It is unclear if oral zinc is beneficial for improving immune function in people with this condition. Details: A very small clinical study in Down syndrome patients with zinc deficiency shows that taking zinc sulfate 1 mg/kg daily for 2 months seems to improve immune function and reduce recurrent infections when compared with baseline (87289). The validity of this finding is limited by the lack of a control group. Another small clinical study in children with Down syndrome shows that zinc 25-50 mg daily for 6 months does not improve immune function when compared with placebo (87278). Reasons for the discrepancies may be related to the dose of zinc or zinc status at baseline.
• Dysmenorrhea. It is unclear if oral zinc is beneficial in patients with dysmenorrhea. Details: Preliminary clinical research in females aged 13 to 21 years with primary dysmenorrhea shows that taking zinc sulfate 40 mg orally daily for the first 3 days of menstruation for three cycles reduces mean pain scores by 51% when compared with placebo (111446).
• Epilepsy. There is limited evidence on the oral use of zinc in children with intractable seizures. Details: A small clinical study in children with intractable epilepsy shows that taking elemental zinc 1 mg/kg daily as zinc sulfate heptahydrate for 6 months reduces seizures when compared with placebo. About 31% of children taking zinc experienced a 50% decrease in seizure frequency, compared to only 5% of children taking placebo (96078).
• Esophageal cancer. It is unclear if oral zinc is beneficial for esophageal cancer prevention. Details: Population research in Chinese and Iranian patients has found that low intake of zinc is associated with an increased risk of esophageal squamous cell cancer (17205,87059). However, other population research in patients from America, Europe, or Asia has found that dietary zinc intake is not associated with esophageal cancer risk (90213).
• Fatigue. It is unclear if oral zinc is beneficial for reducing fatigue in older individuals. Details: A clinical study in adults 50 years and older, some with below-normal levels of zinc at baseline, shows that taking zinc 30 mg daily for 70 days improves subjective fatigue when compared with no intervention (105675). The validity of this finding is limited due to a lack of placebo control and potential performance bias. Additionally, it is unclear whether baseline zinc status alters the benefits of zinc supplementation.
• Fecal incontinence. Topical zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in females with fecal incontinence shows that topically applying an ointment containing zinc sulfate 1% and aluminum sulfate 5% to the anal canal mucosa three times daily for 4 weeks improves symptoms approximately twice as much as a placebo ointment. Quality of life related to the incontinence also improved (90219).
• Gastric cancer. It is unclear if dietary zinc is beneficial for gastric cancer prevention. Details: Population research has found that increased dietary zinc intake is not associated with a decreased risk of gastric cancer (90213).
• Head and neck cancer. It is unclear if oral zinc improves survival in patients with head and neck cancers. Details: Preliminary clinical research in patients with head and neck cancers shows that zinc supplementation does not improve disease-free or metastasis-free survival rates after 3 years when compared with placebo (87103).
• Hepatic encephalopathy. It is unclear if oral zinc is beneficial for reducing the severity of hepatic encephalopathy or preventing recurrence. Details: A meta-analysis of small clinical studies, as well as some individual clinical studies, show that short-term zinc supplementation improves cognitive function and possibly quality of life in patients with hepatic encephalopathy. These findings are based on results from the number connection test and other tests (87377,90202,106227). One study in patients with minimal hepatic encephalopathy used zinc bisglycinate 75 mg three times daily, providing elemental zinc 45 mg daily for 12 weeks (106227). However, other preliminary clinical research shows that short-term zinc supplementation does not improve hepatic encephalopathy severity when compared with placebo when assessed using Conn's index, which includes evaluation of mental state, asterixis (flapping tremor), number connection test, electroencephalogram (EEG) record, and plasma ammonia (87144). Also, a meta-analysis of clinical research shows that zinc sulfate supplementation does not reduce encephalopathy recurrence (90202). Based on these results, zinc supplementation may marginally improve cognitive function in hepatic encephalopathy patients, but it does not appear to improve disease severity or reduce the risk of recurrence.
• HIV/AIDS-related diarrhea. It is unclear if oral zinc is beneficial for preventing diarrhea in adult HIV patients. Details: Short-term zinc supplementation does not appear to TREAT diarrhea in adult HIV patients with persistent diarrhea. Clinical research shows that taking zinc 50 mg twice daily for 7 days does not reduce the duration of HIV-related diarrhea when compared with placebo (87055). However, zinc supplementation may help PREVENT HIV-related diarrhea when administered long-term. Clinical research shows that taking elemental zinc 12-15 mg daily for 18 months reduces the rate of diarrhea by about half when compared with placebo in adult HIV patients with zinc deficiency (87216). In HIV-infected children, clinical research shows that taking elemental zinc 10 mg daily for 6 months can reduce the occurrence of diarrhea by 49% when compared with placebo (82377). However, administering zinc in combination with vitamin A until 2 years of age does not reduce the occurrence of diarrhea when compared with vitamin A alone in HIV-infected children (82417).
• HIV/AIDS-related opportunistic infections. It is unclear if oral zinc is beneficial in opportunistic infections in patients with HIV/AIDs. Details: A small clinical study in patients with AIDS shows that taking zinc supplements orally in combination with zidovudine (AZT, Retrovir) might reduce opportunistic infections of Pneumocystis carinii and Candida when compared with taking zidovudine without zinc (6566).
• Human papillomavirus (HPV). It is unclear if oral zinc is beneficial for preventing relapse in patients with vulvar warts or for treating HPV infections and cervical lesions in patients with abnormal cervical cytology. Details: One small clinical study in patients with vulvar warts shows that taking zinc sulfate 400 mg daily for 8 weeks in addition to topical treatments including podophyllin 20%, imiquimod 5%, or cryotherapy, does not affect the duration of response, but does reduce the relapse rate by approximately 66% after 6 months, when compared with topical treatments alone (90190). Additionally, a small, open-label study in zinc-sufficient females with HPV shows that taking zinc sulfate 220 mg twice daily for 3 months reduces the odds of persistent HPV infection by 87% and improves the resolution of pre-existing cervical lesions when compared with no treatment (109456).
• Hypertension. It is unclear if oral zinc reduces blood pressure in normotensive or hypertensive patients. Details: A meta-analysis of small clinical trials shows that taking zinc reduces systolic blood pressure by about 1.5 mmHg, but does not reduce diastolic blood pressure, when compared with placebo. Response did not differ with the dosage of zinc or duration of supplementation. Only one study evaluated patients with hypertension; other patient populations included those with type 2 diabetes, diabetic retinopathy, pre-diabetes, obesity, polycystic ovary syndrome (PCOS), and patients on dialysis (104052). More research in patients with hypertension is needed to determine if zinc is beneficial in this population.
• Impaired glucose tolerance (prediabetes). While some conflicting evidence exists, several small clinical studies suggest that oral zinc may improve glycemic control in patients with prediabetes. Details: A meta-analysis of three low-quality studies in patients with prediabetes suggests that taking zinc sulfate 20-30 mg, alone or in combination with lysine and vitamin C, for 6-12 months reduces fasting blood glucose and postprandial glucose when compared with control (105682). Furthermore, a small clinical study in patients with prediabetes shows that taking zinc gluconate 30 mg daily for 90 days improves glycemic parameters when compared with placebo. All study participants were also instructed to increase physical activity and start a calorie-restricted diet (105391). However, another small clinical study in patients with prediabetes shows that taking zinc gluconate 30 mg daily for 12 months does not improve glycemic parameters when compared with placebo (109454). The available research has been conducted in Sri Lanka, Bangladesh, Iran, and Australia; it is unclear if these findings are generalizable to other geographic locations.
• Intestinal parasite infection. It is unclear if oral zinc is beneficial in patients with intestinal parasitic infections. Details: Zinc supplementation may help TREAT infection from Schistosoma mansoniin, but not other parasites, in children in developing countries. Results from one clinical study show that taking oral zinc sulfate 30-50 mg for 12 months reduces the intensity of Schistosoma mansoniin infection in children, as measured by number of eggs per gram in feces, when compared with placebo (87495). However, supplementation with zinc does not appear to reduce the intensity of Ascaris lumbricoides, Trichiuris trichura, nor Giardia lamblia infection in children (6586). Furthermore, preliminary clinical research suggests that supplementation with zinc may increase the duration of Entamoeba histolytica infection in children (87099). There are also inconsistent results regarding the effects of zinc in PREVENTING intestinal parasite infections. Some clinical research shows that taking zinc in combination with vitamin A reduces the incidence of Giardia lamblia infections when compared with placebo (87099). However, zinc supplementation does not appear to prevent intestinal infections by Ascaris lumbricoides, Schistosoma haematobium, nor Schistosoma mansoniin (87099,87495).
• Kidney failure. It is unclear if oral zinc is beneficial for patients on hemodialysis who have resistance to erythropoiesis-stimulating agents (ESAs). Details: Zinc deficiency is thought to play a role in ESA-resistant anemia in patients with kidney failure. A small clinical trial in patients on hemodialysis with low zinc levels shows that taking zinc acetate hydrate, usually 25mg or 50 mg daily, for 12 months increases plasma levels of zinc and modestly reduces the required weekly dose of ESAs when compared with placebo. However, there was no effect on hemoglobin levels (109781).
• Leukemia. It is unclear if oral zinc is beneficial for improving weight maintenance in children and adolescents with leukemia. Details: A small clinical study in children and adolescents with acute leukemia shows that taking zinc 2 mg/kg (as an amino acid salt) in two divided doses daily for 60 days doubles weight gain and reduces infection rate by approximately 60% when compared with placebo. However, zinc supplementation does not appear to improve nutritional status (90204).
• Liver cancer. It is unclear if oral zinc is beneficial for preventing hepatocellular carcinoma (HCC). Details: In patients treated for hepatitis C, the presence of hepatic fibrosis increases the risk for development of HCC, and is also associated with low plasma zinc levels. In a retrospective analysis of patients with a sustained virological response to hepatitis C therapy, those taking oral zinc supplements for at least 6 months had approximately half the risk of developing HCC when compared with those not taking zinc. Maintaining a serum zinc level above 90 mcg/dL seems to reduce the risk for HCC (106904).
• Lung cancer. It is unclear if increased dietary zinc intake is beneficial for reducing the risk of lung cancer. Details: Population research has found that the highest dietary intake of zinc is associated with a 32% reduced risk of lung cancer when compared with the lowest intake (106235).
• Male infertility. It is unclear if oral zinc is beneficial for infertility in males. Details: Some preliminary clinical research shows that taking zinc sulfate 66 mg daily increases sperm count, testosterone levels, and the incidence of pregnancy in idiopathic infertile men with low testosterone levels (9334,87430). Another clinical study shows that taking zinc sulfate 66 mg daily can improve sperm morphology by approximately 33% when compared to baseline in men with a grade III varicocele (90194). However, not all research agrees. One clinical study shows that taking elemental zinc 30 mg with folic acid 5 mg daily for 6 months does not improve sperm morphology or pregnancy rates when compared with placebo in infertile men (102085). It is possible the lower dose used in this study was insufficient to produce the beneficial effects observed in earlier research. Zinc supplementation has also been studied as part of combination therapy. A retrospective study in males with or without varicocele-related infertility has found that taking a specific combination product containing zinc 10 mg, L-carnitine fumarate 1725 mg, acetyl-L-carnitine 500 mg, vitamin C 90 mg, coenzyme Q10 20 mg, folic acid 0.2 mg, selenium 0.05 mg, and vitamin B12 0.015 mg (Proxeed Plus, Sigma-Tau) orally twice daily for 6 months improves sperm count, sperm concentration, and sperm motility when compared with baseline. Improvements in semen parameters were greatest in subjects with more severe varicoceles. The validity of this study is limited by the lack of a comparator group (111296). There is also interest in using zinc to improve results of in vitro fertilization (IVF). A small clinical study in couples undergoing IVF suggests that infertile male partners who take a specific combination product (Menevit) containing zinc and other antioxidants seem to have an increased rate of viable pregnancies when compared with placebo (87087). However, it's unclear if the benefit can be attributed to zinc, other antioxidants, or the combination.
• Melasma. It is unclear if topical zinc reduces melasma severity. Details: A small clinical study shows that applying a topical solution containing zinc sulfate 10% once daily for 2 months is less effective at reducing melasma severity when compared with hydroquinone 4% (90232).
• Menopausal symptoms. It is unclear if oral zinc improves sexual function after menopause. Details: A single clinical trial shows that taking zinc sulfate 110 mg daily for 6 weeks modestly improves testosterone levels and sexual function, including desire, arousal, satisfaction, and pain, after menopause when compared with placebo (106228).
• Migraine headache. It is unclear if oral zinc is beneficial in patients with migraine. Details: Two small clinical studies in patients with migraine show that taking zinc sulfate 200 mg or zinc gluconate 15 mg daily for 8-12 weeks modestly reduces migraine severity and frequency when compared with placebo (104040,105684). Both studies were conducted in Iran; it is unclear if these findings are generalizable to other geographic locations.
• Nasopharyngeal cancer. It is unclear if oral zinc is beneficial in patients with this type of cancer. Details: A small clinical study in patients with locally advanced nasopharyngeal cancer shows that zinc supplementation 75 mg daily for 2 months may improve disease-free survival rates after 5 years when compared with placebo (87163).
• Neonatal jaundice. It is unclear if oral zinc is beneficial for neonatal jaundice. Details: Two small clinical studies in infants with idiopathic neonatal hyperbilirubinemia show that receiving oral zinc sulfate 5 mg twice daily for 5-7 days does not affect levels of total bilirubin, the required duration of phototherapy, or the duration of hospitalization, when compared with placebo (90212,104814). A larger clinical trial suggests that this lack of effect may be due to the need for a longer treatment duration. In preterm infants receiving phototherapy and zinc 1.2 mg/kg daily as zinc sulfate heptahydrate, via either orogastric or nasogastric tube for 10 days, serum bilirubin levels were modestly decreased only on days 8-10 when compared with phototherapy alone (106242).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral zinc is beneficial in patients with NAFLD. Details: A small clinical study in patients with NAFLD shows that following a calorie-restricted diet and taking zinc 30 mg daily for 12 weeks reduces certain liver enzymes, but does not improve steatosis or reduce weight, when compared with taking placebo and following a calorie-restricted diet (104046).
• Non-Hodgkin lymphoma. It is unclear if oral zinc is beneficial for non-Hodgkin lymphoma prevention. Details: Population research has found that higher dietary intake of zinc is associated with a 42% decreased odds of developing non-Hodgkin lymphoma (87048).
• Obesity. Small studies suggest that oral zinc does not reduce weight or calorie intake in people with overweight or obesity. Details: A very small clinical study in adults with overweight or obesity shows that taking supplemental zinc 30 mg daily for 12 weeks does not reduce body weight, body mass index (BMI), calorie intake, or macronutrient intake when compared with placebo (112471). Additionally, clinical research in adults with overweight or obesity shows that taking zinc gluconate 25 mg and L-selenomethionine 200 mcg once daily for 8 weeks does not improve BMI, total body fat, or fat free mass when compared with placebo (111448).
• Obsessive-compulsive disorder (OCD). It is unclear if oral zinc reduces symptoms in patients with OCD. Details: A small clinical study in patients with OCD shows that taking zinc sulfate 200 mg twice daily with fluoxetine 20 mg daily for 8 weeks modestly reduces the severity of OCD symptoms when compared with taking placebo with fluoxetine (90223).
• Oral mucositis. It is unclear if oral or topical zinc prevents oral mucositis due to chemotherapy. Some small clinical studies suggest that oral zinc might prevent mucositis due to radiotherapy. Details: Two small clinical studies in adults with leukemia and other cancers shows that taking zinc sulfate 220 mg three times daily for 14 days or until the end of chemotherapy treatment reduces oral mucositis and pain intensity when compared with placebo (90191,98132). However, smaller doses have not shown benefit. A small clinical study in children and adolescents with leukemia shows that taking zinc 2 mg/kg daily (up to 60 mg daily) in two divided doses does not affect chemotherapy-induced mucositis when compared with placebo (90204). An unblinded clinical study in children and adolescents aged 8-16 years with recently diagnosed leukemia shows that taking zinc gluconate 50 mg (7 mg elemental zinc) daily does not significantly reduce the incidence or duration of oral mucositis when compared with a control group not receiving zinc (104816). Zinc also doesn't seem to be beneficial with high-dose chemotherapy. A small clinical study in adolescents and adults receiving high-dose chemotherapy prior to undergoing hematopoietic stem cell transplantation (HSCT) suggests that taking zinc sulfate 220 mg (50 mg elemental zinc) twice daily, beginning one day prior to the chemotherapy regimen and continuing for 3 weeks, does not affect the severity, duration, or onset of mucositis when compared with placebo (90215). Other preliminary clinical research in children aged 3-18 years receiving chemotherapy for leukemia or other cancer also shows that taking zinc 1 mg/kg orally daily for 14 days, beginning on the first day of chemotherapy, does not reduce the incidence or severity of mucositis when compared with placebo (111447). Topical zinc has also been investigated for radiation-induced or chemotherapy-induced oral mucositis. In two clinical studies, using 7.5 mL of a mouthwash containing zinc chloride 0.2% twice for 2 minutes every 8 hours for 3 weeks modestly reduces the incidence and severity of oral mucositis, and improves quality of life, when compared with a placebo mouthwash (106232,109690). In one study, the average patient weight was higher in the group using the mouthwash containing zinc (106232). Other preliminary clinical research in adults with head and neck cancer undergoing radiotherapy treatment, consisting of at least 30 Gy radiation exposure shows that using zinc sulfate 1% mouthwash, 5 mL three times daily for 6 weeks, beginning on the first day of radiation therapy, moderately improves oral mucositis severity and pain scores when compared with chlorhexidine 0.2% or placebo mouthwash (111291). Taking zinc orally might be beneficial in radiation-induced oral mucositis. A small clinical study in patients with head and neck tumors shows that taking zinc sulfate, providing 150 mg elemental zinc, daily starting at the first day of radiation therapy and ending at 6 weeks, reduces the severity of mucositis and prolongs the onset of mucositis when compared with placebo (86981). Another clinical study in patients with head and neck cancer shows that taking zinc sulfate 150 mg daily during and after chemoradiotherapy treatment, consisting of a total 69.5 Gy radiation exposure and cisplatin 40 mg/m2 weekly, is associated with less severe mucositis when compared with placebo (105677).
• Osteoporosis. It is unclear if oral zinc improves bone density in patients with osteoporosis. Details: Population research has found that reduced zinc intake and lower zinc serum levels seem to be associated with lower bone mineral density (BMD) (6920,14410). In elderly patients with at least marginal zinc deficiency who are taking standard therapy for osteoporosis, preliminary clinical research shows that taking zinc acetate dihydrate (Nobelzin, Nobelpharma) providing elemental zinc 25 mg twice daily for 12 months increases BMD when compared with baseline. Increases in serum zinc were associated with improvements in BMD. However, it is unclear if increases in BMD were significant when compared with placebo (106230). It is also unclear if zinc improves BMD in patients without zinc deficiency. A small clinical study in healthy postmenopausal adults suggests that taking zinc in combination with copper, manganese, and calcium might slow bone loss when compared with placebo (1994). It is not clear if this effect is due to zinc, other ingredients, or the combination.
• Overall mortality. It is unclear if oral zinc reduces overall mortality in young children. Details: A meta-analysis of clinical research in children under the age of five years shows that supplementation with zinc in daily doses of at least 10 mg reduces the risk of all-cause mortality by 16% when compared with either placebo, other vitamin and/or mineral supplementation, or no supplementation. The risk of mortality was reduced by 54% when children took zinc for up to one year, but overall mortality was not reduced in studies lasting at least one year (106239).
• Periodontitis. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with moderate or advanced periodontitis shows that taking a combination supplement containing zinc 3.75 mg, alpha-lipoic acid, coenzyme Q10, cranberry extract, grapeseed extract, selenium, vitamin C, and vitamin E twice daily for 8 weeks in addition to standard nonsurgical therapy does not reduce periodontal indices including bleeding on probing, gingival recession, plaque index, or inflammation when compared with placebo (111708).
• Pharyngitis. There is limited evidence on the oral use of zinc for reducing the risk of postoperative sore throat. Details: Clinical research shows that dissolving a lozenge containing zinc 40 mg as zinc sulfate in the mouth in the 30 minutes before surgery involving endotracheal intubation reduces the incidence of postoperative sore throat by 58% when compared with placebo lozenges. It also seems to reduce the severity of postoperative sore throat that does occur (97138).
• Polycystic ovary syndrome (PCOS). It is unclear if oral zinc is beneficial in patients with PCOS. Details: A small clinical study in adults taking metformin for PCOS shows that also taking zinc sulfate 220 mg (50 mg elemental zinc) daily for 8 weeks improves hair loss and facial growth, but not acne, when compared with placebo (96071).
• Postpartum depression. It is unclear if oral zinc prevents postpartum depression after a Cesarean section (C-section). Details: A small observational study in pregnant patients with anemia who underwent C-section has found that taking zinc sulfate 100 mg daily for 4 days after surgery is associated with a 75% reduction in the odds of developing postpartum depression when compared with no supplementation (109452).
• Premenstrual syndrome (PMS). It is unclear if oral zinc improves symptoms in patients with PMS. Details: A small clinical study in female college students shows that taking elemental zinc 30 mg daily for 3 months improves quality of life, but not quality of sleep, when compared with placebo (104049).
• Preterm labor. It is unclear if oral zinc reduces the risk of preterm labor. Details: Observational research has found that low dietary intake of zinc during pregnancy is associated with an increased likelihood of preterm deliveries (87471). Also, most meta-analyses of clinical research show that taking zinc supplements during pregnancy modestly reduces the risk of preterm birth (106231). However, one large meta-analysis of 22 clinical studies shows that zinc supplementation during pregnancy seems to have little or no benefit for reducing the risk of preterm birth when compared with control (105679). Zinc supplementation also does not seem to reduce the risk of stillbirth, neonatal death, spontaneous abortion, or premature rupture of membranes (97142,105679,106231).
• Prostatitis. It is unclear if oral zinc improves symptoms in men with chronic prostatitis. Details: A clinical study in men with chronic prostatitis shows that taking zinc sulfate 220 mg daily along with prazosin 2 mg daily for 12 weeks does not improve difficulty urinating or quality of life, but does seem to improve pain, when compared with prazosin alone (90210). The validity of this study was limited by a significant dropout rate.
• Pruritus. There is limited evidence on the oral use of zinc for reducing pruritis in hemodialysis patients. Details: A small clinical study in end-stage renal disease patients with hemodialysis-associated pruritus shows that taking zinc sulfate 220 mg twice daily for 2 months reduces pruritus severity when compared with placebo (90218).
• Psoriatic arthritis. It is unclear if oral zinc improves psoriatic arthritis symptoms. Details: Two small clinical trials in patients with psoriatic arthritis show that taking zinc orally, alone or in combination with nonsteroidal anti-inflammatory drugs (NSAIDs), does not seem to reduce pain or improve function when compared with control (6514,6515).
• Respiratory tract infections. It is unclear if oral zinc reduces respiratory tract infections in children. Details: An open-label study in children aged 6 months to 5 years with zinc deficiency shows that taking zinc sulfate 20 mg orally once daily for 2 weeks reduces the number of episodes and the mean duration of upper and lower respiratory tract infections over 6 months of follow-up when compared with the 6 months prior to zinc supplementation (104815). The validity of this finding is limited by the lack of a comparator group.
• Rosacea. It is unclear of oral zinc improves symptoms of rosacea or quality of life. Details: A small clinical trial shows that taking zinc sulfate 440 mg in two divided doses daily for 90 days does not improve quality of life or symptoms associated with rosacea when compared with placebo (90195).
• Seizures. It is unclear if oral zinc reduces recurrent febrile seizures in children. Details: Although some individual preliminary clinical research disagrees (96069), a meta-analysis of generally low-quality research in children under 5 years of age with a previous febrile seizure shows that taking zinc sulfate 1-2 mg/kg or 20 mg daily for 6-12 months does not reduce febrile seizure recurrence when compared with placebo (106237). Also, a small clinical study shows that taking zinc does not increase the time to first febrile seizure recurrence (96069).
• Sepsis. It is unclear if oral zinc is beneficial in sepsis of the newborn. Details: A meta-analysis of clinical research in children under the age of five years shows that supplementation with zinc reduces the risk of sepsis mortality by 57% when compared with either placebo, other vitamin and/or mineral supplementation, or no supplementation (106239). Also, a small clinical study in newborns with sepsis shows that giving zinc sulfate monohydrate 3 mg/kg twice daily for 10 days along with antibiotics reduces the likelihood of neurological abnormalities, such as those related to posture, behavior, and reflexes, by 70% when compared with antibiotics alone. Mortality and length of hospital stay were not improved, but the study may have been inadequately powered to detect a difference in these parameters (96077). Another study in preterm infants with late-onset sepsis (developing at least 72 hours after birth), shows that giving 1.4 mg/kg elemental zinc daily orally for 10 days in addition to antibiotics reduces the number of infants with unresolved sepsis at 10 days, and reduces C-reactive protein and procalcitonin levels, when compared with giving antibiotics alone (104819). A meta-analysis of small clinical studies in infants less than 4 months old shows that administering zinc 1-3 mg/kg daily for 1-18 weeks may reduce the rate of infant mortality and treatment failure when compared with placebo or control, but does not seem to prevent sepsis or improve sepsis-related mortality (108444).
• Shigellosis. It is unclear if oral zinc is beneficial in patients with acute shigellosis from food poisoning. Details: A small clinical study in malnourished children with acute shigellosis (food poisoning) shows that administering a multivitamin syrup containing elemental zinc 20 mg daily for 2 weeks, in addition to standard treatment, can improve recovery time and reduce the number of diarrhea episodes when compared with multivitamin syrup without elemental zinc (87088).
• Substance use disorder. It is unclear if oral zinc is beneficial for substance use disorder. Details: Preliminary clinical research in adults with opioid use disorder that were being treated with methadone shows that taking zinc sulfate, containing 12 mg zinc, orally daily for 3 months moderately improves relapse prevention scores, including drug use and drug craving scores, when compared with control. Taking zinc also modestly improved stress and anxiety scores (111293).
• Traumatic brain injury (TBI). There is limited evidence on the parenteral use of zinc for closed head injury. Details: A small clinical study shows that administering zinc parenterally immediately following severe closed head injury seems to improve the rate of neurological recovery when compared with standard therapy (2696).
• Tuberculosis. It is unclear if oral zinc can improve outcomes in patients receiving tuberculosis treatment. Details: Low levels of zinc are common in patients with tuberculosis. In patients newly diagnosed with tuberculosis and using anti-tuberculosis treatment, some clinical research shows that taking zinc 50 mg daily as zinc sulfate for 6 months increases the number of patients with negative sputum smears by 50% to 80% within the first 6 weeks of treatment when compared with placebo. However, there were no differences in the number of patients with negative smears after this time point. There were also improvements in some liver function enzyme levels after 2 months, but not 6 months, when compared with placebo (106238). However, other clinical research shows that taking zinc 15-90 mg daily for 2-6 months does not improve cure rates or sputum smear conversions when compared with placebo. However, when combined with vitamin A, serum levels of vitamin A, zinc, and hemoglobin were modestly improved and there was a modest increase in sputum smear conversions (109754).
• Urinary tract infections (UTIs). It is unclear if oral zinc is beneficial in children with UTI. Details: A low-quality, clinical study in children aged 3-12 years hospitalized for a UTI and receiving intravenous antibiotic treatment shows that taking zinc 1 mg/kg daily for 14 days reduces the duration of dysuria, urinary frequency, and urgency when compared with intravenous antibiotics alone. Zinc does not improve fever or the time to negative urine culture (96081). However, this study did not demonstrate that treatment groups were equal at baseline.
• Venous leg ulcers. It is unclear if oral or topical zinc is beneficial for leg ulcer healing. Details: Two small studies in elderly patients with leg ulcers suggest that using a zinc saline solution on a wound dressing or applying zinc oxide to a dressing might improve healing of leg ulcers (2694,6901). However, oral zinc supplementation does not seem to be beneficial. A meta-analysis of four small clinical trials in patients with venous leg ulcers shows that taking zinc orally does not improve healing when compared with placebo (104079).
• Vertigo. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with benign paroxysmal positional vertigo with serum 25-hydroxyvitamin D levels less than 20 ng/mL shows that taking a specific combination product containing zinc 7.5 mg, alpha-lipoic acid 600 mg, L-carnosine 165 mg, curcumin 100 mg, piperine 1 mg, cholecalciferol 800 units, vitamin B2 0.8 mg, and vitamin B6 1 mg (Vertistop D, Difass) orally daily for 6 months moderately reduces the number of vertigo relapse episodes when compared with control. However, in patients with serum 25-hydroxyvitamin D levels greater than 20 ng/mL that took a specific combination product containing zinc 7.5 mg, alanine 600 mg, L-carnosine 165 mg, curcumin 100 mg and piperine 1 mg (Vertistop L, Difass) orally daily for 6 months there was no difference in relapse episodes when compared with control (111294). It is unclear if this effect is due to zinc, other ingredients, or the combination.
• Water warts. It is unclear if oral zinc is beneficial for the treatment of water warts in children. Details: In children with water warts, preliminary clinical research shows that taking zinc sulfate heptahydrate (as Zinco syrup) for 2 months results in lesion resolution in 70% of patients when compared with baseline. Lesion resolution occurred in an additional 13% of patients in the month after treatment completion, with no recurrence in any of these children over the next 9 months. Zinc 3 mg daily was used in children up to 3 years of age, and 5 mg daily was used in older children (106234). Due to the lack of a comparator group, it is unclear if these outcomes are due to zinc or the natural resolution of the condition.
• Wound healing. Topical zinc might be beneficial for the healing of uncomplicated wounds. Details: A small clinical study shows that applying zinc chloride solution, standardized to contain zinc 20 mcg/mL, twice daily improves wound healing when compared with saline solution in patients with uncomplicated, skin wounds. However, when zinc is administered as a component of an insulin product (Humulin, Eli Lilly and Company), it seems to be more effective than zinc chloride alone (90192).
• Wrinkled skin. Topical zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A topical preparation containing 10% vitamin C as L-ascorbic acid and acetyl tyrosine, zinc sulfate, sodium hyaluronate, and bioflavonoids (Cellex-C High Potency Serum) applied to photo-aged facial skin for 3 months seems to improve fine and coarse wrinkling, yellowing and sallowness, roughness, and skin tone when compared with placebo (6155). More evidence is needed to rate zinc for these uses.

(Read more about ZINC)

POSSIBLY SAFE ...when used orally and appropriately, short-term. L-theanine has been used safely in clinical research in doses of up to 900 mg daily for 8 weeks (12188,36439,96331,96332,96334,96341,97923,101986,104976). There is insufficient reliable information available about the safety of L-theanine when used long-term.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. A specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg twice daily has been used safely in males aged 8-12 years for up to 6 weeks (91744).

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

(Read more about THEANINE)

LIKELY SAFE ...when used orally, topically, intramuscularly, or intravenously and appropriately. Vitamin C is safe when taken orally in doses below the tolerable upper intake level (UL). Tell patients not to exceed the UL of 2000 mg daily (1959,4713,4714,4844). ...when used intravenously or intramuscularly and appropriately. Injectable vitamin C is an FDA-approved prescription product (15).

POSSIBLY UNSAFE ...when used orally in excessive doses. Doses greater than the tolerable upper intake level (UL) of 2000 mg daily can significantly increase the risk of adverse effects such as osmotic diarrhea and gastrointestinal upset (4844).

CHILDREN: LIKELY SAFE
when used orally and appropriately (4844,10352,14443).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive amounts. Tell patients not to use doses above the tolerable upper intake level (UL) of 400 mg daily for children ages 1 to 3 years, 650 mg daily for children 4 to 8 years, 1200 mg daily for children 9 to 13 years, and 1800 mg daily for adolescents 14 to 18 years. Higher doses can cause osmotic diarrhea and gastrointestinal upset (4844).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (4844).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. Tell patients over age 19 not to use doses exceeding the UL of 2000 mg daily when pregnant or breast-feeding and for those 14-18 years of age not to use doses exceeding 1800 mg daily when pregnant or breast-feeding. Higher doses can cause osmotic diarrhea and gastrointestinal upset. Large doses of vitamin C during pregnancy can also cause newborn scurvy (4844); avoid using.

(Read more about VITAMIN C)

LIKELY SAFE ...when used orally or intramuscularly and appropriately. Vitamin D has been safely used in a wide range of doses (7555,16888,16891,17476,95913,98186,104619,105209,109059). When used orally long-term, doses should not exceed the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily for adults (17506,99773); however, much higher doses such as 50,000 IU (1250 mcg) weekly orally for 6-12 weeks are often needed for the short-term treatment of vitamin D deficiency (16891,17476). Monthly oral doses of up to 60,000 IU (1500 mcg) have also been safely used for up to 5 years (105726). Toxicity usually does not occur until plasma levels exceed 150 ng/mL (17476).

POSSIBLY UNSAFE ...when used orally in excessive doses, long-term. Taking doses greater than the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily for long periods can increase the risk of hypercalcemia (17506); however, much higher doses are often needed for short-term treatment of vitamin D deficiency. Toxicity typically occurs when levels exceed 150 ng/mL (17476).

CHILDREN: LIKELY SAFE
when used orally and appropriately. When used long-term, doses should not exceed the tolerable upper intake level (UL) of 1000 IU (25 mcg) daily for those 0-6 months of age, 1500 IU (37.5 mcg) daily for those 6-12 months of age, 2500 IU (62.5 mcg) daily for those 1-3 years of age, 3000 IU (75 mcg) daily for those 4-8 years of age, and 4000 IU (100 mcg) daily for those 9 years and older (17506); however, much higher doses are often needed for the short-term treatment of vitamin D deficiency. Some research shows that giving vitamin D 14,000 IU (350 mcg) weekly for a year in children aged 10-17 years is safe (16875). A meta-analysis of clinical studies shows that 1000 IU (25 mcg) daily in those up to a year of age and greater than 2000 IU (50 mcg) daily in those aged 1-6 years does not increase the risk of serious adverse events (108424).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses for longer than one year. Taking doses greater than the tolerable upper intake level (UL) long-term can increase the risk of hypercalcemia (17506).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. Vitamin D is safe when used in doses below the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily (17506,95910).

PREGNANCY: POSSIBLY UNSAFE
when used orally in excessive amounts. Tell patients not to use doses above the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily. Hypercalcemia during pregnancy due to excessive vitamin D intake can lead to several fetal adverse effects, including suppression of parathyroid hormone, hypocalcemia, tetany, seizures, aortic valve stenosis, retinopathy, and mental and/or physical developmental delay (17506).

LACTATION: LIKELY SAFE
when used orally and appropriately. Vitamin D is safe when used in doses below the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily (17506).

LACTATION: POSSIBLY UNSAFE
when used orally in excessive amounts. Tell patients not to use doses above the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily (17506).

(Read more about VITAMIN D)

LIKELY SAFE ...when used orally and appropriately. Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 40 mg daily (7135). ...when used topically and appropriately (2688,6538,6539,7135,8623,11051,111291).

POSSIBLY SAFE ...when used orally and appropriately in doses higher than the tolerable upper intake level (UL). Because the UL of zinc is based on regular daily intake, short-term excursions above 40 mg daily are not likely to be harmful. In fact, there is some evidence that doses of elemental zinc as high as 80 mg daily in combination with copper 2 mg can be used safely for approximately 6 years without significant adverse effects (7303,8622,92212). However, there is some concern that doses higher than the UL of 40 mg daily might decrease copper absorption and result in anemia (7135).

POSSIBLY UNSAFE ...when used intranasally. Case reports and animal research suggest that intranasal zinc might cause permanent anosmia or loss of sense of smell (11155,11156,11703,11704,11705,11706,11707,16800,16801,17083). Several hundred reports of anosmia have been submitted to the US Food and Drug Administration (FDA) and the manufacturer of some intranasal zinc products (Zicam) (16800,16801). Advise patients not to use intranasal zinc products.

LIKELY UNSAFE ...when taken orally in excessive amounts. Ingestion of 10-30 grams of zinc sulfate can be lethal in adults (7135). Chronic intake of 450-1600 mg daily can cause multiple forms of anemia, copper deficiency, and myeloneuropathies (7135,17092,17093,112473). This has been reported with use of zinc-containing denture adhesives in amounts exceeding the labeled directions, such as several times a day for several years (17092,17093). Advise patients to follow the label directions on denture adhesives that contain zinc.

CHILDREN: LIKELY SAFE
when used orally and appropriately (7135). Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL). The UL for children is based on age: 4 mg daily for 0-6 months, 5 mg daily for 7-12 months, 7 mg daily for 1-3 years, 12 mg daily for 4-8 years, 23 mg daily for 9-13 years, and 34 mg daily for 14-18 years (7135,97140).

CHILDREN: POSSIBLY UNSAFE
when used orally in high doses. Taking amounts greater than the UL can cause sideroblastic anemia and copper deficiency (7135). ...when used topically on damaged skin. An infant treated with 10% zinc oxide ointment for severe diaper rash with perianal erosions developed hyperzincemia. Absorption seemed to occur mainly via the erosions; plasma levels dropped after the erosions healed despite continued use of the ointment (106905).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 34 mg daily during pregnancy in those 14-18 years of age and 40 mg daily in those 19-50 years of age (7135).

PREGNANCY: LIKELY UNSAFE
when used orally in doses exceeding the UL (7135).

LACTATION: LIKELY SAFE
when used orally and appropriately. Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 34 mg daily during lactation in those 14-18 years of age, and 40 mg daily for those 19-50 years of age (7135).

LACTATION: POSSIBLY UNSAFE
when used orally in doses exceeding the UL. Higher doses can cause zinc-induced copper deficiency in nursing infants (7135).

(Read more about ZINC)

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theanine might lower blood pressure, potentiating the effects of antihypertensive drugs.  Details Animal research shows that theanine can lower blood pressure in spontaneously hypertensive animals (7687,77354). Theoretically, concomitant use of theanine and antihypertensive drugs might potentiate the antihypertensive activity.

CNS DEPRESSANTS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, theanine might have additive sedative effects when used in conjunction with CNS depressants. However, it is unclear if this concern is clinically relevant.  Details Theoretically, theanine may compete with glutamate and/or increase plasma gamma-aminobutyric acid (GABA) levels, which could cause CNS depression (96334). In one clinical study, some subjects taking oral theanine reported drowsiness (96331).

(Read more about THEANINE)

ACETAMINOPHEN (Tylenol, others) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Probable •  Level of Evidence = B High-dose vitamin C might slightly prolong the clearance of acetaminophen.  Details A small pharmacokinetic study in healthy volunteers shows that taking high-dose vitamin C (3 grams) 1.5 hours after taking acetaminophen 1 gram slightly increases the apparent half-life of acetaminophen from around 2.3 hours to 3.1 hours. Ascorbic acid competitively inhibits sulfate conjugation of acetaminophen. However, to compensate, elimination of acetaminophen glucuronide and unconjugated acetaminophen increases (6451). This effect is not likely to be clinically significant.

ALKYLATING AGENTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, antioxidant effects of vitamin C might reduce the effectiveness of alkylating agents.  Details The use of antioxidants like vitamin C during chemotherapy is controversial. There is concern that antioxidants could reduce the activity of chemotherapy drugs that generate free radicals, such as cyclophosphamide, chlorambucil, carmustine, busulfan, and thiotepa (391). In contrast, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that could interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin C have on chemotherapy.

ALUMINUM Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Vitamin C can increase the amount of aluminum absorbed from aluminum compounds.  Details Research in animals and humans shows that vitamin C increases aluminum absorption, theoretically by chelating aluminum and keeping it in solution where it is available for absorption (10549,10550,10551,21556). In people with normal renal function, urinary excretion of aluminum will likely increase, making aluminum retention and toxicity unlikely (10549). Patients with renal failure who take aluminum-containing compounds such as phosphate binders should avoid vitamin C supplements in doses above the recommended dietary allowances.

ANTITUMOR ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, the antioxidant effects of vitamin C might reduce the effectiveness of antitumor antibiotics.  Details The use of antioxidants like vitamin C during chemotherapy is controversial. There is concern that antioxidants could reduce the activity of chemotherapy drugs which generate free radicals, such as doxorubicin (391). In contrast, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that could interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effects, if any, antioxidants such as vitamin C have on chemotherapy.

ASPIRIN Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Acidification of the urine by vitamin C might increase aspirin levels.  Details It has been suggested that acidification of the urine by vitamin C could increase reabsorption of salicylates by the renal tubules, and increase plasma salicylate levels (3046). However, short-term use of up to 6 grams daily of vitamin C does not seem to affect urinary pH or salicylate excretion (10588,10589), suggesting this interaction is not clinically significant.

CHOLINE MAGNESIUM TRISALICYLATE (Trilisate) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Acidification of the urine by vitamin C might increase choline magnesium trisalicylate levels.  Details It has been suggested that acidification of the urine by vitamin C could increase reabsorption of salicylates by the renal tubules, and increase plasma salicylate levels (3046,4531). However, short-term use of up to 6 grams daily of vitamin C does not seem to affect urinary pH or salicylate excretion (10588,10589), suggesting this interaction probably is not clinically significant.

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Vitamin C might increase blood levels of estrogens.  Details Increases in plasma estrogen levels of up to 55% occur under some circumstances when vitamin C is taken concurrently with oral contraceptives or hormone replacement therapy, including topical products (129,130,11161). It is suggested that vitamin C prevents oxidation of estrogen in the tissues, regenerates oxidized estrogen, and reduces sulfate conjugation of estrogen in the gut wall (129,11161). When tissue levels of vitamin C are high, these processes are already maximized and supplemental vitamin C does not have any effect on estrogen levels. Increases in plasma estrogen levels may occur when patients who are deficient in vitamin C take supplements (11161). Monitor these patients for estrogen-related side effects.

FLUPHENAZINE (Prolixin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, vitamin C might decrease levels of fluphenazine.  Details In one patient there was a clinically significant decrease in fluphenazine levels when vitamin C (500 mg twice daily) was started (11017). The mechanism is not known, and there is no further data to confirm this interaction.

INDINAVIR (Crixivan) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Vitamin C can modestly reduce indinavir levels.  Details One pharmacokinetic study shows that taking vitamin C 1 gram orally once daily along with indinavir 800 mg orally three times daily reduces the area under the concentration-time curve of indinavir by 14%. The mechanism of this interaction is unknown, but it is unlikely to be clinically significant in most patients. The effect of higher doses of vitamin C on indinavir levels is unknown (11300,93578).

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Vitamin C can increase levothyroxine absorption.  Details Two clinical studies in adults with poorly controlled hypothyroidism show that swallowing levothyroxine with a glass of water containing vitamin C 500-1000 mg in solution reduces thyroid stimulating hormone (TSH) levels and increases thyroxine (T4) levels when compared with taking levothyroxine alone. This suggests that vitamin C increases the oral absorption of levothyroxine, possibly due to a reduction in pH (102978).

NIACIN Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = A Vitamin C might decrease the beneficial effects of niacin on high-density lipoprotein (HDL) cholesterol levels.  Details A combination of niacin and simvastatin (Zocor) effectively raises HDL cholesterol levels in patients with coronary disease and low HDL levels. Clinical research shows that taking a combination of antioxidants (vitamin C, vitamin E, beta-carotene, and selenium) along with niacin and simvastatin (Zocor) attenuates this rise in HDL, specifically the HDL-2 and apolipoprotein A1 fractions, by more than 50% in patients with coronary disease (7388,11537). It is not known whether this adverse effect is due to a single antioxidant such as vitamin C, or to the combination. It also is not known whether it will occur in other patient populations.

SALSALATE (Disalcid) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Acidification of the urine by vitamin C might increase salsalate levels.  Details It has been suggested that acidification of the urine by vitamin C could increase reabsorption of salicylates by the renal tubules, and increase plasma salicylate levels (3046). However, short-term use of up to 6 grams/day vitamin C does not seem to affect urinary pH or salicylate excretion (10588,10589), suggesting this interaction probably is not clinically significant.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D High-dose vitamin C might reduce the levels and effectiveness of warfarin.  Details Vitamin C in high doses may cause diarrhea and possibly reduce warfarin absorption (11566). There are reports of two people who took up to 16 grams daily of vitamin C and had a reduction in prothrombin time (9804,9806). Lower doses of 5-10 grams daily can also reduce warfarin absorption. In many cases, this does not seem to be clinically significant (9805,9806,11566,11567). However, a case of warfarin resistance has been reported for a patient who took vitamin C 500 mg twice daily. Cessation of vitamin C supplementation resulted in a rapid increase in international normalized ratio (INR) (90942). Tell patients taking warfarin to avoid taking vitamin C in excessively high doses (greater than 10 grams daily). Lower doses may be safe, but the anticoagulation activity of warfarin should be monitored. Patients who are stabilized on warfarin while taking vitamin C should avoid adjusting vitamin C dosage to prevent the possibility of warfarin resistance.

(Read more about VITAMIN C)

ALUMINUM Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Vitamin D might increase aluminum absorption and toxicity, but this has only been reported in people with renal failure.  Details The protein that transports calcium across the intestinal wall can also bind and transport aluminum. This protein is stimulated by vitamin D, which may therefore increase aluminum absorption (11595,11597,22916). This mechanism may contribute to increased aluminum levels and toxicity in people with renal failure, when they take vitamin D and aluminum-containing phosphate binders chronically (11529,11596,11597).

ATORVASTATIN (Lipitor) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Vitamin D might reduce absorption of atorvastatin.  Details A small, low-quality clinical study shows that taking vitamin D reduces levels of atorvastatin and its active metabolites by up to 55%. However, while atorvastatin levels decreased, total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels did not substantially change (16828). Atorvastatin is metabolized in the gut by CYP3A4 enzymes, and researchers theorized that vitamin D might induce CYP3A4, causing reduced levels of atorvastatin. However, this proposed mechanism was not specifically studied.

CALCIPOTRIENE (Dovonex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Taking calcipotriene with vitamin D increases the risk for hypercalcemia.  Details Calcipotriene is a vitamin D analog used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia (15). Theoretically, combining calcipotriene with vitamin D supplements might increase the risk of hypercalcemia.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Vitamin D might induce CYP3A4 enzymes and reduce the bioavailability of CYP3A4 substrates.  Details There is some concern that vitamin D might induce CYP3A4. In vitro research suggests that vitamin D induces CYP3A4 transcription. Additionally, observational research has found that increased UV light exposure and serum vitamin D levels are associated with decreased serum levels of CYP3A4 substrates such as tacrolimus and sirolimus, while no association between UV light exposure or vitamin D levels and levels of mycophenolic acid, a non-CYP3A4 substrate, was found (110539). A small, low-quality clinical study shows that taking vitamin D reduces levels of the CYP3A4 substrate atorvastatin and its active metabolites by up to 55%; however, the clinical effects of atorvastatin were not reduced (16828). While researchers theorized that vitamin D might induce CYP3A4, this proposed mechanism was not specifically studied.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, hypercalcemia induced by high-dose vitamin D can increase the risk of arrhythmia from digoxin.  Details High doses of vitamin D can cause hypercalcemia. Hypercalcemia increases the risk of fatal cardiac arrhythmias with digoxin (15). Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and digoxin concurrently.

DILTIAZEM (Cardizem, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, hypercalcemia induced by high-dose vitamin D can reduce the therapeutic effects of diltiazem for arrhythmia.  Details High doses of vitamin D can cause hypercalcemia. Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically this could also occur with diltiazem. Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and diltiazem concurrently.

THIAZIDE DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking thiazide diuretics and high-dose vitamin D can increase the risk of hypercalcemia.  Details Thiazide diuretics decrease urinary calcium excretion, which could lead to hypercalcemia if vitamin D supplements are taken concurrently (3072,11541,69580). This has been reported in people being treated with vitamin D for hypoparathyroidism, and also in elderly people with normal parathyroid function who were taking a thiazide, vitamin D, and calcium-containing antacids daily (11539,11540).

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Hypercalcemia induced by high-dose vitamin D can reduce the therapeutic effects of verapamil for arrhythmia.  Details Hypercalcemia due to high doses of vitamin D can reduce the effectiveness of verapamil in atrial fibrillation (10574). Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and verapamil concurrently.

(Read more about VITAMIN D)

AMILORIDE (Midamor) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Probable •  Level of Evidence = B Amiloride can modestly reduce zinc excretion and increase zinc levels.  Details Clinical research shows that amiloride can reduce urinary zinc excretion, especially at doses of 10 mg per day or more. This zinc-sparing effect can help to counteract zinc losses caused by thiazide diuretics, but it is unlikely to cause zinc toxicity at usual amiloride doses (830,11626,11627,11634). The other potassium-sparing diuretics, spironolactone (Aldactone) and triamterene (Dyrenium), do not seem to have a zinc-sparing effect.

ATAZANAVIR (Reyataz) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Probable •  Level of Evidence = B Zinc modestly reduces levels of atazanavir, although this effect does not seem to be clinically significant.  Details Clinical research shows that zinc might decrease serum atazanavir levels by chelating with atazanavir in the gut and preventing its absorption (93578). Although a single dose of zinc sulfate (Solvazinc tablets) 125 mg orally does not affect atazanavir concentrations in patients being treated with atazanavir/ritonavir, co-administration of zinc sulfate 125 mg daily for 2 weeks reduces plasma levels of atazanavir by about 22% in these patients. However, despite this decrease, atazanavir levels still remain at high enough concentrations for the prevention of HIV virus replication (90216).

CEPHALEXIN (Keflex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Zinc might decrease cephalexin levels by chelating with cephalexin in the gut and preventing its absorption.  Details A pharmacokinetic study shows that zinc sulfate 250 mg taken concomitantly with cephalexin 500 mg decreases peak levels of cephalexin by 31% and reduces the exposure to cephalexin by 27%. Also, taking zinc sulfate 3 hours before cephalexin decreases peak levels of cephalexin by 11% and reduces the exposure to cephalexin by 18%. By decreasing cephalexin levels, zinc might increase the risk of treatment failure. This effect does not occur when zinc is taken 3 hours after the cephalexin dose (94163). To avoid an interaction, advise patients take zinc sulfate 3 hours after taking cephalexin.

CISPLATIN (Platinol-AQ) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, zinc might interfere with the therapeutic effects of cisplatin.  Details Animal research suggests that zinc stimulates tumor cell production of the protein metallothionein, which binds and inactivates cisplatin (11624,11625). It is not known whether zinc supplements or high dietary zinc intake can cause clinically significant interference with cisplatin therapy. Cisplatin might also increase zinc excretion.

INTEGRASE INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking zinc along with integrase inhibitors might decrease the levels and clinical effects of these drugs.  Details Zinc is a divalent cation. Pharmacokinetic studies have shown that other divalent cations such as calcium and iron can decrease blood levels of the integrase inhibitor dolutegravir through chelation (93578,93579).

PENICILLAMINE (Cuprimine, Depen) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Zinc might reduce the levels and clinical effects of penicillamine.  Details By forming an insoluble complex with penicillamine, zinc interferes with penicillamine absorption and activity. Zinc supplements reduce the efficacy of low-dose penicillamine (0.5-1 gram/day), but do not seem to affect higher doses (1-2.75 gram/day), provided dosing times are separated (2678,4534,11605). Advise patients to take zinc and penicillamine at least 2 hours apart.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Zinc can decrease the levels and clinical effects of quinolones antibiotics.  Details Quinolones form complexes with zinc in the gastrointestinal tract, reducing absorption of both the quinolone and zinc if taken at the same time (828,2682,3046,11600). Advise patients to take these drugs at least 2 hours before, or 4-6 hours after, zinc supplements.

RITONAVIR (Norvir) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Zinc modestly reduces levels of ritonavir.  Details Clinical research shows that zinc might reduce serum ritonavir levels by chelating with ritonavir in the gut and preventing its absorption (93578). In patients with HIV, ritonavir is taken with atazanavir to prevent the metabolism and increase the effects of atazanavir. A pharmacokinetic study shows that, in patients being treated with atazanavir/ritonavir, co-administration of zinc sulfate (Solvazinc tablets) 125 mg as a single dose or as multiple daily doses for 2 weeks reduces plasma levels of ritonavir by about 16% (90216). However, atazanavir levels still remains high enough to prevent HIV virus replication. Therefore, the decrease in ritonavir levels is not likely to be clinically significant.

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Zinc might reduce levels of tetracycline antibiotics.  Details Tetracyclines form complexes with zinc in the gastrointestinal tract, which can reduce absorption of both the tetracycline and zinc when taken at the same time (3046,4945). Taking zinc sulfate 200 mg with tetracycline reduces absorption of the antibiotic by 30% to 40% (11615). Demeclocycline and minocycline cause a similar interaction (4945). However, doxycycline does not seem to interact significantly with zinc (11615). Advise patients to take tetracyclines at least 2 hours before, or 4-6 hours after, zinc supplements to avoid any interactions.

(Read more about ZINC)

General ...Orally, L-theanine seems to be well tolerated.
Most Common Adverse Effects:
Orally: Drowsiness, headaches.

Neurologic/CNS ...Orally, L-theanine may cause headaches (36439). Patients have also reported drowsiness, increased duration of sleep, and increased dream activity after oral L-theanine use (96331).
A case of subtle facial tic starting within 4 days of taking L-theanine 400 mg daily has been reported for a pediatric patient. Although the tics reportedly ceased once theanine was discontinued, the child had exhibited tics in the past. Therefore, the adverse effect was not thought to be related to L-theanine (91744).

(Read more about THEANINE)

General ...Orally, intravenously, and topically, vitamin C is well-tolerated.
Most Common Adverse Effects:
Orally: Abdominal cramps, esophagitis, heartburn, headache, osmotic diarrhea, nausea, vomiting. Kidney stones have been reported in those prone to kidney stones. Adverse effects are more likely to occur at doses above the tolerable upper intake level of 2 grams daily.
Topically: Irritation and tingling.
Serious Adverse Effects (Rare):
Orally: There have been rare case reports of carotid inner wall thickening after large doses of vitamin C.
Intravenously: There have been case reports of hyperoxalosis and oxalate nephropathy following high-dose infusions of vitamin C.

Cardiovascular ...Evidence from population research has found that high doses of supplemental vitamin C might not be safe for some people. In postmenopausal adults with diabetes, supplemental vitamin C intake in doses greater than 300 mg per day is associated with increased risk of cardiovascular mortality. However, dietary intake of vitamin C is not associated with this risk. Also, vitamin C intake is not associated with an increased risk of cardiovascular mortality in patients without diabetes (12498).
Oral supplementation with vitamin C has also been associated with an increased rate of carotid inner wall thickening in men. There is preliminary evidence that supplemental intake of vitamin C 500 mg daily for 18 months can cause a 2.5-fold increased rate of carotid inner wall thickening in non-smoking men and a 5-fold increased rate in men who smoked. The men in this study were 40-60 years old (1355). This effect was not associated with vitamin C from dietary sources (1355).
There is also some concern that vitamin C may increase the risk of hypertension in some patients. A meta-analysis of clinical research suggests that, in pregnant patients at risk of pre-eclampsia, oral intake of vitamin C along with vitamin E increases the risk of gestational hypertension (83450). Other clinical research shows that oral intake of vitamin C along with grape seed polyphenols can increase both systolic and diastolic blood pressure in hypertensive patients (13162).

Dental ...Orally, vitamin C, particularly chewable tablets, has been associated with dental erosion (83484).

Dermatologic ...Topically, vitamin C might cause tingling or irritation at the site of application (6166). A liquid containing vitamin C 20%, red raspberry leaf cell culture extract 0.0005%, and vitamin E 1% (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) has been reported to cause mild tingling and skin tightness (102355). It is unclear if these effects are due to vitamin C, the other ingredients, or the combination.

Gastrointestinal ...Orally, the adverse effects of vitamin C are dose-related and include nausea, vomiting, esophagitis, heartburn, abdominal cramps, gastrointestinal obstruction, and diarrhea. Doses greater than the tolerable upper intake level (UL) of 2000 mg per day can increase the risk of adverse effects such as osmotic diarrhea and severe gastrointestinal upset (3042,4844,96707,104450). Mineral forms of vitamin C, such as calcium ascorbate (Ester-C), seem to cause fewer gastrointestinal adverse effects than regular vitamin C (83358). In a case report, high dose intravenous vitamin C was associated with increased thirst (96709).

Genitourinary ...Orally, vitamin C may cause precipitation of urate, oxalate, or cysteine stones or drugs in the urinary tract (10356). Hyperoxaluria, hyperuricosuria, hematuria, and crystalluria have occurred in people taking 1 gram or more per day (3042,90943). Supplemental vitamin C over 250 mg daily has been associated with higher risk for kidney stones in males. There was no clear association found in females, but the analysis might not have been adequately powered to evaluate this outcome (104029). In people with a history of oxalate kidney stones, supplemental vitamin C 1 gram per day appears to increase kidney stone risk by 40% (12653). A case of hematuria, high urine oxalate excretion, and the presence of a ureteral stone has been reported for a 9-year-old male who had taken about 3 grams of vitamin C daily since 3 years of age. The condition resolved with cessation of vitamin C intake (90936).

Hematologic ...Prolonged use of large amounts of vitamin C can result in increased metabolism of vitamin C; subsequent reduction in vitamin C intake may precipitate the development of scurvy (15). In one case, a patient with septic shock and a large intraperitoneal hematoma developed moderate hemolysis and increased methemoglobin 12 hours after a high-dose vitamin C infusion. The patient received a blood transfusion and the hemolysis resolved spontaneously over 48 hours (112479).

Neurologic/CNS ...Orally, the adverse effects of vitamin C are dose-related and include fatigue, headache, insomnia, and sleepiness (3042,4844,83475,83476).

Renal ...Hyperoxalosis and oxalate nephropathy have been reported following high-dose infusions of vitamin C. Hyperoxalosis and acute kidney failure contributed to the death of a 76-year-old patient with metastatic adenocarcinoma of the lung who received 10 courses of intravenous infusions containing vitamins, including vitamin C and other supplements over a period of 1 month. Dosages of vitamin C were not specified but were presumed to be high-dose (106618). In another case, a 34-year-old patient with a history of kidney transplant and cerebral palsy was found unresponsive during outpatient treatment for a respiratory tract infection. The patient was intubated for acute hypoxemic respiratory failure, initiated on vasopressors, hydrocortisone, and antibacterial therapy, and received 16 doses of vitamin C 1.5 grams. Serum creatinine level peaked at greater than 3 times baseline and the patient required hemodialysis for oliguria and uncontrolled acidosis. Kidney biopsy revealed oxalate nephropathy with concomitant drug-induced interstitial nephritis (106625). In another case, a 41-year-old patient with a history of kidney transplant presented with fever, nausea, and decreased urine output 4 days after receiving intravenous vitamin C 7 grams for urothelial carcinoma. Serum creatinine levels increased from 1.7 mg/dL to 7.3 mg/dL over those 4 days, and hemodialysis was initiated 3 days after admission due to anuria. Renal biopsy confirmed the diagnosis of acute oxalate nephropathy (109962).

Other ...Intravenously, hypernatremia and falsely elevated ketone levels is reported in a patient with septic shock and chronic kidney disease after a high-dose vitamin C infusion. The hypernatremia resolved over 24 hours after cessation of the infusion (112479).

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General ...Orally or intramuscularly, vitamin D is well tolerated.
Serious Adverse Effects (Rare):
Orally or intramuscularly: Excessive doses can lead to vitamin D toxicity with symptoms of hypercalcemia, and also sometimes azotemia and anemia.

Cardiovascular ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Rarely, people develop hypertension (10142). An analysis of clinical research suggests that, when taken orally, vitamin D might modestly increase levels of low-density lipoprotein (LDL)-cholesterol. However, it is not clear if this increase is clinically significant (84642).

Gastrointestinal ...Orally, vitamin D may cause dry mouth. In clinical research, intake of vitamin D 50,000 IU weekly for 4 weeks followed by 50,000 IU monthly for 5 months thereafter was associated with a 3.7-fold increase in reports of dry mouth compared with placebo (91348).Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Symptoms of vitamin D toxicity include pancreatitis (10142,84433). Vomiting occurred in one patient given a single dose of 200,000 IU (104624).

Genitourinary ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Advanced symptoms may include decreased libido (10142). Vaginal discharge and itching have been reported in a clinical trial following oral use (91348).

Hematologic ...Lab values of urinary and blood calcium, phosphate, albumin, blood urea nitrogen, serum cholesterol, aspartate aminotransferase, and alanine aminotransferase concentrations might increase with vitamin D use, especially with high doses (10142,91349,93943).
A case of elevated international normalized ration (INR) has been reported for an 84 year-old patient who took vitamin D 50,000 IU daily for 2 months. The patient's serum levels of vitamin D increased from <7 ng/mL to 100 ng/mL over 6 months. To resolve symptoms, vitamin D supplementation was discontinued (84433).

Musculoskeletal ...Vitamin D intoxication can occur when vitamin D supplements are taken in excessive doses (10142,17506). Symptoms of vitamin D toxicity include osteoporosis in adults and decreased growth in children (10142).

Ocular/Otic ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses (10142,17506). Symptoms of vitamin D toxicity include calcific conjunctivitis and photophobia (10142).

Psychiatric ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses (10142,17506). In rare cases, symptoms of vitamin D toxicity include psychosis (10142,93002).

Pulmonary/Respiratory ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Advanced symptoms of vitamin D toxicity may include runny nose (10142,17506,93002).

Renal ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Symptoms of vitamin D toxicity include azotemia. Vitamin D may also cause hypercalcemia, with advanced symptoms including kidney stones or kidney insufficiency due to precipitation of calcium phosphate in the tubules. Symptoms of renal impairment include frequency, nighttime awakening to urinate, thirst, inability to concentrate urine, and proteinuria. Renal impairment is usually reversible with discontinuation of vitamin D supplements (10142,93002,93943,110831,110833).

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General ...Orally, zinc is well tolerated in doses below the tolerable upper intake level (UL), which is 40 mg daily for adults. Topically, zinc is well tolerated.
Most Common Adverse Effects:
Orally: Abdominal cramps, diarrhea, metallic taste, nausea and vomiting (dose-related).
Topically: Burning, discoloration, itching, stinging, and tingling when applied to irritated tissue.
Intranasally: Bad taste, dry mouth, headache, irritation, reduced sense of smell.
Serious Adverse Effects (Rare):
Orally: There have been cases of acute renal tubular necrosis, interstitial nephritis, neurological complications, severe vomiting, and sideroblastic anemia after zinc overdose.
Intranasally: There have been cases where intranasal zinc caused permanent loss of smell (anosmia).

Dermatologic ...Topically, zinc can cause burning, stinging, itching, and tingling when applied to inflamed tissue (6911,8623,87297). Zinc oxide can be deposited in the submucosal tissue and cause dark discoloration of the skin. This can occur with prolonged topical application to intact skin, application to eroded or ulcerated skin, or penetrating traumatic exposure, and also parenteral administration (8618).
In rare cases, oral zinc has resulted in worsened acne (104056), skin sensitivity (6592), a leishmanial reaction with a macular rash that occurred on exposed parts of the body (86935), eczema (104055), systemic contact dermatitis (109457), and the development of severe seborrheic dermatitis (86946).

Gastrointestinal ...Orally, zinc can cause nausea (338,2663,2681,6592,6700,18216,106230,106233,106227), vomiting (2663,2681,6519,6592,96069,96074), a metallic or objectionable taste in the mouth (336,338,6700,11350,18216,106902), abdominal cramping (6592,96069), indigestion (87227), heartburn (96069), dry mouth (87533), and mouth irritation (336,2619). When used orally in amounts above the tolerable upper intake level, zinc may cause irritation and corrosion of the gastrointestinal tract (331,86982,87315,106902), watery diarrhea (1352), epigastric pain (2663,2681), and severe vomiting (2663,2681).
Intranasally, zinc can cause bad taste, dry mouth, and burning and irritation of the throat (8628,8629).
When used topically as a mouth rinse, zinc may cause tooth staining (90206).

Hematologic ...There is concern that high daily doses of zinc, above the tolerable upper intake level (UL) of 40 mg per day, might increase the risk of copper deficiency, potentially leading to anemia and leukopenia (7135,112473). To prevent copper deficiency, some clinicians give a small dose of copper when zinc is used in high doses, long-term (7303).

Hepatic ...There are two cases of liver deterioration in patients with Wilson disease following initiation of treatment with zinc 50-200 mg three times daily. The mechanism of action is not understood, and the event is extremely uncommon (86927,87470).

Immunologic ...Daily doses of 300 mg of supplemental zinc for 6 weeks appear to impair immune response (7135). A case of erythematosus-like syndrome, including symptoms such as fever, leg ulcers, and rash, has been reported following intake of effervescent tablets (Solvezink) containing zinc 45 mg (87506). In another case, severe neutropenia was reported after taking supplemental zinc 900 mg daily for an unknown duration (112473).

Neurologic/CNS ...Zinc-containing denture adhesives can cause toxicity if used more frequently than recommended for several years. Case reports describe hyperzincemia, low copper levels, blood dyscrasias, and neurological problems, including sensory disturbances, numbness, tingling, limb weakness, and difficulty walking in patients applying denture adhesive multiple times daily for several years (17092,17093,90205,90233). Due to reports of zinc toxicity associated with use of excessive amounts of zinc-containing denture adhesives for several years, GlaxoSmithKline has reformulated Polygrip products to remove their zinc content (17092,17093).
Intranasally (8628) and orally (87534), zinc can cause headache. When used orally in amounts above the tolerable upper intake level (UL), zinc may cause central nervous system (CNS) symptoms including lethargy, fatigue, neuropathy, dizziness, and paresthesia (2663,2681,87369,87470,87533,87534,112473).

Oncologic ...There is concern that zinc might worsen prostate disease. For example, some preliminary evidence suggests that higher dietary zinc intake increases the risk for benign prostatic hyperplasia (6908). Epidemiological evidence suggests that taking more than 100 mg of supplemental zinc daily or taking supplemental zinc for 10 or more years doubles the risk of developing prostate cancer (10306). Another large-scale population study also suggests that men who take a multivitamin more than 7 times per week and who also take a separate zinc supplement have a significantly increased risk of prostate cancer-related mortality (15607). However, a large analysis of population research suggests that there is no association between zinc intake and the risk of prostate cancer (96075).

Pulmonary/Respiratory ...There are several hundred reports of complete loss of sense of smell (anosmia) that may be permanent with use of zinc gluconate nasal gel, such as Zicam (11306,11155,11707,16800,16801,17083,86999,87535). Loss of sense of smell is thought to be dose related but has also been reported following a single application (11306,11155,11707,16800). Patients often report having sniffed deeply when applying the gel, then experiencing an immediate burning sensation, and noticing anosmia within 48 hours (17083). On June 16, 2009, the US Food and Drug Administration (FDA) advised patients not to use a specific line of commercial zinc nasal products (Zicam) after receiving 130 reports of loss of smell (16800). The manufacturer of these products had also received several hundred reports of loss of smell related to its intranasal zinc products (16801). Zinc sulfate nasal spray was used unsuccessfully for polio prophylaxis before the polio vaccine was developed. It caused loss of smell and/or taste, which was sometimes permanent (11713). Animal studies suggest that zinc sulfate negatively affects smell, possibly by damaging the olfactory epithelium and neurons (11156,11703,11704,11705,11706). Zinc gluconate nasal spray has not been tested for safety in animals or humans. The clinical studies of intranasal zinc have not described anosmia as an adverse effect, but testing was not done to see if zinc use adversely affected sense of smell (6471,8628,8629,10247). Also, these clinical studies reported tingling or burning sensation in the nostril, dry nose, nose pain, and nosebleeds.
When used in amounts above the tolerable upper intake level (UL), zinc may cause flu-like symptoms including coughing (2663).

Renal ...In overdose, zinc can cause acute renal tubular necrosis and interstitial nephritis (331,1352,87338).

Other ...Occupational inhalation of zinc oxide fumes can cause metal fume fever with symptoms including fatigue, chills, fever, myalgias, cough, dyspnea, leukocytosis, thirst, metallic taste, and salivation (331).

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