Alive! Fruit Source Vitamin C [Discontinued] by Nature's Way

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). It is unclear if oral goji berry reduces the risk of developing AMD. Details: A small, unblinded clinical study in healthy adults aged 45 to 65 years shows that consuming goji berries 28 grams five times a week for 90 days improves macular pigment optical density, which is a marker for AMD, when compared to baseline (110767). The validity of this finding is limited by the lack of statistical comparison to the other study group that received a supplement containing lutein and zeaxanthin.
• Cancer. Although there is interest in using oral goji for cancer, there is insufficient reliable information about the clinical effects of goji for this condition.
• Cardiovascular disease (CVD). It is unclear if oral goji improves risk factors for CVD. Details: A meta-analysis of 6 mostly small clinical studies of adults in China shows that consuming goji as polysaccharide extract or juice for 1-3 months modestly improves triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and fasting blood glucose but does not impact total cholesterol when compared with no treatment or placebo (110765). Another meta-analysis of 4 small clinical studies in adults also shows that consuming goji polysaccharide extract or goji berries for 1-4 months modestly improves triglycerides and HDL but does not impact total or LDL cholesterol when compared with placebo or healthy eating. Goji also had no impact on systolic or diastolic blood pressure, or markers of oxidative stress (110768). However, the interpretation of the findings from these meta-analyses is limited by the use of variable goji forms and doses, as well as inclusion of studies in heterogeneous patients, including healthy people, patients with diabetes, and patients with metabolic syndrome. Furthermore, most studies were conducted in China; it is unclear if these benefits can be extrapolated to other geographic locations.
• Cognitive function. It is unclear if oral goji berry improves cognition in healthy young individuals. Details: A small clinical crossover study in healthy participants 14-24 years of age shows that taking goji berry fruit water extract (BIOMIX Company) 3600 mg in 3 divided doses daily for 4 weeks might improve certain cognitive measures such as verbal learning, short-term memory, and attention when compared with baseline (105488). The validity of these findings are limited due to incomplete outcome reporting and a lack of statistical comparisons between the treatment and placebo groups.
• Cough. Although there is interest in using oral goji for cough, there is insufficient reliable information about the clinical effects of goji for this purpose.
• Depression. It is unclear if oral goji berry polysaccharide is beneficial for adolescents with subthreshold depression. Details: A small clinical study in adolescents aged approximately 15 years with subthreshold depression in China shows that taking goji berry polysaccharide extract 300 mg daily for 6 weeks modestly improves clinician-assessed depression scores (i.e. Hamilton Depression Scale, HAMD-24) but does not improve self-reported depression scores (i.e. Beck Depression Inventory) or scores assessing sleep quality, psychological distress, or anxiety when compared with placebo (110769). However, these results are from an interim analysis, which limits the interpretation of these findings. Furthermore, it is unclear if results can be extrapolated to patients in other geographic locations.
• Diabetes. It is unclear if oral goji berry polysaccharides improve glycemic control in patients with diabetes. Details: One small clinical study in patients with type 2 diabetes shows that taking goji fruit polysaccharide powder 150 mg twice daily for 3 months results in a slightly lower postprandial glucose area under the curve (AUC), but does not seem to affect insulin levels or insulin resistance, when compared with placebo. A subgroup of patients who were not taking antidiabetes medications had a greater reduction in postprandial blood glucose (92117).
• Dry eye. Although there is interest in using oral goji for dry eye, there is insufficient reliable information about the clinical effects of goji for this purpose.
• Erectile dysfunction (ED). Although there is interest in using oral goji for ED, there is insufficient reliable information about the clinical effects of goji for this condition.
• Hypertension. Although there is interest in using oral goji root bark for hypertension, there is insufficient reliable information about the clinical effects of goji for this condition.
• Obesity. It is unclear if oral goji berry juice improves weight loss. Details: Preliminary clinical research in healthy, overweight adults shows that drinking a specific goji fruit juice (GoChi, FreeLife International LLC) 120 mL daily for 14 days while following a weight loss diet and participating in an exercise program decreases waist circumference by about 4.7 cm more than exercise and diet alone. However, drinking goji berry juice along with diet and exercise does not improve body weight, body mass index, or body fat when compared with diet and exercise alone (52536).
• Quality of life. Small clinical studies suggest that oral goji berry juice may modestly improve quality of life in healthy adults. Details: Small clinical studies in healthy adults suggest that taking a specific standardized goji fruit juice (GoChi, FreeLife International LLC) 120 mL daily for 14-30 days improves subjective measures of energy levels, athletic performance, sleep quality, mental acuity, calmness, feelings of well-being, and gastrointestinal regularity when compared with placebo (17082,52532,52542). These studies were funded by the juice manufacturer.
• Sunburn. It is unclear if oral goji extract can prevent sunburn. Details: A small clinical study in healthy Japanese adults shows that taking goji extract 900 mg daily for 8 weeks reduces and accelerates resolution of erythema after exposure to a standard dose of UVB irradiation when compared with placebo (110770). All study participants were highly UV-sensitive; it is unclear whether these results can be extrapolated to individuals less sensitive to UV irradiation.
• Tinnitus. Although there is interest in using oral goji for tinnitus, there is insufficient reliable information about the clinical effects of goji for this purpose. More evidence is needed to rate goji for these uses.

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POSSIBLY EFFECTIVE

• Dyslipidemia. Oral Indian gooseberry seems to be beneficial for dyslipidemia. Details: Meta-analyses of 12 small clinical studies in healthy adults or patients with dyslipidemia, diabetes, hypertension, or metabolic syndrome show that taking Indian gooseberry fruit extract or powder 0.5-3 grams daily or Indian gooseberry fruit 12 grams daily for 2-12 weeks reduces total cholesterol by around 39 mg/dL, low-density lipoprotein (LDL) cholesterol by around 15-34 mg/dL, and triglycerides by around 22-52 mg/dL when compared with control groups. Results are conflicting whether Indian gooseberry increases high-density lipoprotein (HDL) cholesterol (111567,111568). Subgroup analysis suggests that Indian gooseberry is more effective at doses greater than 1 gram daily and in adults with triglycerides above 150 mg/dL (111568). Clinical research in patients with dyslipidemia shows that taking Indian gooseberry whole fruit extract (Tri-low, Arjuna Natural Ltd.) 500 mg twice daily for 12 weeks reduces triglyceride and low-density lipoprotein (LDL) cholesterol levels by 34% and 20%, respectively, compared with 15% and 5%, respectively, in patients taking placebo (99238).
• Gastroesophageal reflux disease (GERD). Oral Indian gooseberry seems to be beneficial for reducing symptoms of GERD. Details: Clinical research in adults who have had non-erosive symptoms of GERD for at least 3 months shows that taking Indian gooseberry fruit extract 1000 mg twice daily for 4 weeks reduces the frequency and severity of heartburn and regurgitation by about 63% and 50%, respectively, compared with reductions of 24% and 5%, respectively, in patients taking placebo (99240).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Oral Indian gooseberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in healthy, middle-aged females shows that drinking 50 mL of a juice containing Indian gooseberry extract 30-60 mg and lingonberry extract 25-50 mg daily for 12 weeks improves skin elasticity, thickness, wrinkles, and hydration when compared with placebo (102856). It is unclear if these effects are due to Indian gooseberry, lingonberry, or the combination. Another small clinical study in healthy, middle-aged females shows that applying a topical emulsion containing extracts of Indian gooseberry 3% and gotu kola 3% twice daily for 60 days improves skin hydration, some measures of skin wrinkles, and elasticity of the cheek but not the eye when compared with placebo (111571). It is unclear if these effects are due to Indian gooseberry, gotu kola, or the combination.
• Androgenic alopecia. Topical Indian gooseberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In individuals with self-perceived hair loss, preliminary clinical research shows that applying a hair product containing Indian gooseberry modestly improves hair growth rate and density, as well as hair thinning, when compared with baseline. Patients used a leave-in product containing Indian gooseberry (Saberry), coconut water solids (Cococin), gamma-L-glutamyl-selenomethionine (Peptiselect), and other ingredients as 3.5 mL in females and 2 mL in males, once daily for 3 months (105353).
• Cancer. Although there is interest in using oral Indian gooseberry for cancer, there is insufficient reliable information about the clinical effects of Indian gooseberry for this purpose.
• Cardiovascular disease (CVD). It is unclear if oral Indian gooseberry is beneficial for the prevention of CVD. Details: A meta-analysis of 9 small clinical studies in adults who are healthy or have CVD risk factors shows that taking Indian gooseberry fruit extract or powder 500-1500 mg daily for 2-12 weeks reduces low-density lipoprotein (LDL) cholesterol by around 15 mg/dL, very low-density lipoprotein (VLDL) cholesterol by around 5 mg/dL, triglycerides by around 22 mg/dL, and high-sensitivity C-reactive protein when compared with control groups. However, the meta-analysis suggests that Indian gooseberry does not improve high-density lipoprotein (HDL) cholesterol, systolic blood pressure, or diastolic blood pressure (111567). The validity of these findings is limited by small sample sizes and considerable heterogeneity among the included studies.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral Indian gooseberry is beneficial for the treatment of COVID-19 in hospitalized adults. Details: A small clinical trial in adults hospitalized with COVID-19 shows that receiving Indian gooseberry powder 2 grams twice daily for 10 days does not impact RT-PCR positivity rate at day 10 when compared with placebo. Additionally, there were no clear trends in clinical improvement in patients receiving Indian gooseberry when compared with placebo. All patients in this study also received oral hydroxychloroquine and lopinavir/ritonavir (110012).
• Diabetes. Several small or limited-quality clinical studies suggest that oral Indian gooseberry may modestly improve glycemic control and blood lipid levels in patients with type 2 diabetes. Details: A moderate-sized, open-label study in adults with newly-diagnosed type 2 diabetes and dyslipidemia shows that taking Indian gooseberry extract, standardized to 10% beta-glucogallin, 2 grams daily for 90 days reduces glycated hemoglobin (HbA1c), fasting blood glucose, and postprandial blood glucose when compared to baseline, with superior effects on fasting blood glucose and postprandial blood glucose when compared with metformin 500 mg (111569). A smaller clinical study in patients with type 2 diabetes on stable doses of metformin shows that taking Indian gooseberry fruit extract (Capros, Natreon Inc) 500 mg twice daily for 12 weeks reduces HbA1c by around 0.5% and improves low-density lipoprotein (LDL) cholesterol, triglyceride, and high-density lipoprotein (HDL) levels when compared with placebo. Taking a lower dose, 250 mg twice daily, does not seem to improve HbA1c but has a modest effect on lipid levels (105356). Another small clinical study in patients with type 2 diabetes using various antidiabetes drugs shows that taking powdered Indian gooseberry fruit 1 gram, 2 grams, or 3 grams daily for 3 weeks modestly reduces fasting and 2-hour postprandial blood glucose levels and improves lipid levels when compared to baseline (105355). The validity of these findings is limited by the lack of a comparator group.
• Hangover. It is unclear if oral Indian gooseberry is beneficial for hangover prevention. Details: A small clinical trial shows that taking Indian gooseberry leaf extract (Phyllpro) 750 mg daily for 10 days prior to alcohol intoxication modestly reduces some hangover symptoms 10 hours later, including nausea, headache, lack of appetite, and dizziness, when compared with placebo. Blood alcohol levels after 12 hours were also reduced. However, the overall hangover score was not significantly different between groups (99846).
• Hepatitis B. Although there is interest in using oral Indian gooseberry for hepatitis B, there is insufficient reliable information about the clinical effects of Indian gooseberry for this condition.
• Hypercholesterolemia. Small studies suggest that oral Indian gooseberry might help to reduce low-density lipoprotein (LDL) cholesterol levels. Details: Preliminary clinical research shows that taking Indian gooseberry might reduce levels of LDL cholesterol in patients with hypercholesterolemia. One preliminary clinical study shows that taking Indian gooseberry 50 grams for 4 weeks decreases LDL cholesterol by 15% when compared to baseline (2077). Other preliminary clinical research shows that taking Indian gooseberry fruit extract (Amlamax, Arjuna Natural Ltd.) 500 mg or 1000 mg daily for 6 months reduces levels of LDL cholesterol by about 13% when compared with baseline (99241). Also, one small study shows that taking an Indian gooseberry fruit juice powder 500 mg daily for 6 weeks modestly decreases LDL cholesterol and triglyceride levels when compared with baseline (99242). Some preliminary clinical research also shows that Indian gooseberry reduces LDL cholesterol in obese individuals. One small study shows that taking Indian gooseberry fruit extract (Capros, Natreon Inc.) 500 mg twice daily for 12 weeks reduces LDL cholesterol by 16 mg/dL in this population when compared to baseline (92515). However, the validity of these studies is limited by the lack of comparator groups.
• Hypertension. It is unclear if oral Indian gooseberry is beneficial for hypertension. Details: In patients with uncontrolled hypertension using standard therapies, clinical research shows that taking Indian gooseberry dried fruit powder 500 mg three times daily for 8 weeks reduces systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 16% and 12%, respectively, from baseline, which is significantly greater than reductions seen with placebo. The frequency of response to treatment, based on a reduction in SBP or DBP of at least 10 mmHg or 5 mmHg, respectively, was also increased from up to 50% to at least 83% of patients (105352). However, other clinical research in adults with cardiovascular risk factors shows that taking Indian gooseberry 500-1500 mg twice daily for 2-12 weeks does not reduce SBP or DBP more than placebo (105354,111567).
• Irritable bowel syndrome (IBS). Indian gooseberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, open-label study of adults with IBS shows that taking 7 grams of an Unani medicinal product called Jawarish Shahi, containing Indian gooseberry, terminalia, coriander, cardamom, and willow bark, twice daily for 45 days reduces the severity of IBS, as measured by improvements in abdominal pain and distension, bowel habits, and quality of life, when compared to baseline (111570). The validity of these findings is limited by insufficient blinding and the lack of a comparator group. It is unclear if these effects are due to Indian gooseberry, other ingredients, or the combination.
• Metabolic syndrome. It is unclear if oral Indian gooseberry is beneficial for metabolic syndrome. Details: Preliminary clinical research in adults with metabolic syndrome shows that taking a specific Indian gooseberry extract (Capros, Natreon Inc.) 250 mg twice daily for 12 weeks reduces total cholesterol by nearly 10%, low-density lipoprotein (LDL) cholesterol by 15%, and triglycerides by 10%, and increases high-density lipoprotein (HDL) cholesterol by about 7% when compared with placebo. Additionally, taking this product as 500 mg twice daily reduces total cholesterol by 14%, LDL cholesterol by 26%, and triglycerides by 19%, and increases HDL cholesterol by 22% when compared with placebo. Both doses also seem to improve markers of endothelial function, oxidative stress, and systemic inflammation (102857).
• Obesity. It is unclear if oral Indian gooseberry is beneficial for improving weight loss or metabolic parameters in adults with obesity. Details: Preliminary clinical research in overweight or obese individuals shows that taking Indian gooseberry fruit extract (Capros, Natreon Inc.) 500 mg twice daily for 12 weeks reduces low-density lipoprotein (LDL) cholesterol by 16 mg/dL when compared to baseline. However, there was no effect on other lipids or on blood pressure, body weight, or body mass index (92515). The validity of these findings is limited by the lack of a comparator group.
• Oral mucositis. It is unclear if oral Indian gooseberry is beneficial in patients with radiation-induced mucositis. Details: A retrospective observational study in patients with head and neck cancer receiving radiotherapy suggests that rinsing the mouth with Indian gooseberry 1% and povidone-iodine twice daily is associated with delayed development of mucositis and intolerable mucositis and a decreased incidence of intolerable mucositis when compared with povidone-iodine alone (111566). The validity of these findings is limited by the retrospective study design.
• Osteoarthritis. Oral Indian gooseberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with knee osteoarthritis suggests that specific Ayurvedic formulas containing Indian gooseberry may be equivalent to glucosamine sulfate 2 grams daily or celecoxib 200 mg daily for reducing pain. Two capsules containing Indian gooseberry 166.66 mg/capsule, ginger 33.33 mg/capsule, and Tinospora cordifolia 73.33 mg/capsule, with or without Boswellia serrata 100 mg/capsule, taken three times daily for 24 weeks, were used. All four treatments reduced active pain by about 28% to 38%, functional pain by 19% to 29%, and functional difficulty by 18% to 25%, with no significant between-group differences in the observed improvements (89557). It is not clear if these effects are due to Indian gooseberry, the other ingredients, or the combination.
• Periodontitis. It is unclear if subgingival Indian gooseberry is beneficial for periodontitis. Details: Clinical research in patients with chronic periodontitis shows that the subgingival application of a sustained-release Indian gooseberry fruit 10% gel following scaling and root planing does not affect plaque or gingivitis development over 2-3 months when compared with placebo. However, there was a modest benefit on periodontal destruction based on probing pocket depth (105358).
• Vitiligo. Oral Indian gooseberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with vitiligo shows that taking 1 tablet containing Indian gooseberry 100 mg, vitamin E 10 mg, and carotenoids 4.7 mg orally 3 times daily for 6 months, in combination with conventional topical therapy and/or phototherapy, increases re-pigmentation in the head, neck, and trunk and decreases signs of inflammation when compared with conventional treatment alone (92513). More evidence is needed to rate Indian gooseberry 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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POSSIBLY SAFE ...when goji fruit preparations are used orally and appropriately, short-term. Goji berry whole fruit, boiled or steamed, has been used with apparent safety at a dose of 15 grams daily for 16 weeks (105489). Other goji berry products have also been used with apparent safety in clinical research, including a specific goji fruit juice (GoChi, FreeLife International) 120 mL daily for 30 days (52532), a goji fruit polysaccharide 300 mg daily for 3 months (92117), and a specific milk-based formulation of goji berry (Lacto-Wolfberry, Nestlé Research Center) for 3 months (52539). There has been some concern about the atropine content of goji; however, most analyses show that levels of atropine in goji berries from China and Thailand are far below potentially toxic levels (52524,94667). There is insufficient reliable information available about the safety of oral use of other parts of the goji plant.

PREGNANCY AND LACTATION:
Insufficient reliable information available. Some animal research shows that goji fruit may stimulate the uterus (12). However, this has not been reported in humans. Until more is known, avoid using during pregnancy or lactation.

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LIKELY SAFE ...when consumed in amounts commonly found in foods (6,2076).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Indian gooseberry fruit extract has been used safely in doses of up to 1000 mg daily for up to 6 months, 1500 mg daily for up to 8 weeks, or 2000 mg daily for up to 4 weeks (92515,99238,99240,99241,102855,102857,105352,105354,105356). Indian gooseberry leaf extract has been used with apparent safety at a dose of 750 mg daily for 10 days (99846). ...when used topically and appropriately. An emulsion containing Indian gooseberry extract 3% and other ingredients has been applied safely to the skin twice daily for up to 60 days (111571).

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

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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.

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ANTIDIABETES DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of goji fruit polysaccharides or goji root bark with antidiabetes drugs might have additive effects.  Details Animal and in vitro research show that goji root bark and fruit polysaccharides might have hypoglycemic effects (7126,92118,94667). However, clinical research has only shown that taking goji fruit polysaccharides with or without antidiabetes drugs modestly reduces postprandial glucose when compared with control, with no reports of hypoglycemia (92117).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of goji root bark, but not goji fruit, with antihypertensive drugs might have additive effects.  Details Animal and in vitro research suggest that goji root bark has hypotensive effects (7126,94667). However, goji fruit juice does not appear to reduce systolic or diastolic blood pressure in humans (17082).

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goji berry might inhibit CYP2C19 and reduce metabolism of CYP2C19 substrates.  Details In vitro research shows that goji berry tincture and juice inhibit CYP2C19 enzymes (105486). Concomitant use with goji may decrease metabolism and increase levels of CYP2C19 substrates. However, this has not been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goji berry might inhibit CYP2C9 and reduce metabolism of CYP2C9 substrates.  Details In vitro research shows that goji berry tincture and juice inhibit CYP2C9 enzymes (105486). Additionally, multiple case reports suggest that goji berry concentrated tea and juice inhibit the metabolism of warfarin, a CYP2C9 substrate (7158,105462). Concomitant use with goji may decrease metabolism and increase levels of CYP2C9 substrates.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goji berry might inhibit CYP2D6 and reduce metabolism of CYP2D6 substrates.  Details In vitro research shows that goji berry juice inhibits CYP2D6 enzymes (105486). Concomitant use with goji may decrease metabolism and increase levels of CYP2D6 substrates. However, this has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goji berry might inhibit CYP3A4 and reduce metabolism of CYP3A4 substrates.  Details In vitro research shows that goji berry juice inhibits CYP3A4 enzymes (105486). Concomitant use with goji may decrease metabolism and increase levels of CYP3A4 substrates. However, this has not been reported in humans.

FLECAINIDE (Tambocor) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, goji berry might increase the levels and clinical effects of flecainide.  Details In one case report, a 75-year-old patient stable on flecainide and warfarin presented to the emergency room with fainting and pleomorphic arrhythmia caused by flecainide toxicity. Flecainide toxicity was attributed to drinking 1-2 glasses of concentrated goji tea daily for 2 weeks. Theoretically, goji may have inhibited the cytochrome P450 2D6 (CYP2D6) metabolism of flecainide (105462).

WARFARIN (Coumadin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Goji can increase the effects of warfarin and possibly increase the risk of bleeding.  Details There are at least 5 case reports of increased international normalized ratio (INR) in patients stabilized on warfarin who began drinking goji juice, concentrated goji tea, or goji wine (7158,16529,23896,105462,105487). Goji may inhibit the metabolism of warfarin by cytochrome P450 2C9 (CYP2C9) (7158).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, Indian gooseberry may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs; however, research is conflicting.  Details Clinical research shows that taking Indian gooseberry 500 mg as a single dose or twice daily for 10 days reduces platelet aggregation by about 24% to 36%, increases bleeding time by about 3.8-5.9 seconds, and increases clotting time by about 9.8-12.7 seconds when compared to baseline. However, taking Indian gooseberry 500 mg along with clopidogrel 75 mg or ecosprin 75 mg, as a single dose or for 10 days, does not significantly reduce platelet aggregation or increase bleeding time or clotting time when compared with clopidogrel 75 mg or ecosprin 75 mg alone (92514). Until more is known, use caution when taking Indian gooseberry in combination with anticoagulant/antiplatelet drugs.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Taking Indian gooseberry with antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical research shows that taking Indian gooseberry fruit or fruit extract alone or in conjunction with antidiabetes medications can lower blood glucose levels (31025,105355,105356,111569). Dose adjustments to diabetes medications might be necessary.

ASPIRIN Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, Indian gooseberry may increase the risk of bleeding if used with aspirin; however, research is conflicting.  Details Clinical research shows that taking Indian gooseberry 500 mg as a single dose or twice daily for 10 days reduces platelet aggregation by about 24% to 36%, increases bleeding time by about 3.8-5.9 seconds, and increases clotting time by about 9.8-12.7 seconds when compared to baseline. However, taking a single dose of Indian gooseberry 500 mg along with ecosprin 75 mg, or taking a combination of Indian gooseberry 500 mg twice daily plus ecosprin 75 mg once daily for 10 days, does not significantly reduce platelet aggregation or increase bleeding time or clotting time when compared with ecosprin 75 mg alone (92514).

CLOPIDOGREL (Plavix) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, Indian gooseberry may increase the risk of bleeding if used with clopidogrel; however, research is conflicting.  Details Clinical research shows that taking Indian gooseberry 500 mg as a single dose or twice daily for 10 days reduces platelet aggregation by about 24% to 36%, increases bleeding time by about 3.8-5.9 seconds, and increases clotting time by about 9.8-12.7 seconds when compared to baseline. However, taking a single dose of Indian gooseberry 500 mg along with clopidogrel 75 mg, or taking a combination of Indian gooseberry 500 mg twice daily plus clopidogrel 75 mg once daily for 10 days, does not significantly reduce platelet aggregation or increase bleeding time or clotting time when compared with clopidogrel 75 mg alone (92514).

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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.

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General ...Orally, goji fruit seems to be well tolerated.
Serious Adverse Effects (Rare):
Orally: Allergic reactions including anaphylaxis.

Dermatologic ...A case of photosensitivity secondary to consumption of goji berries has been reported. The patient presented with a pruriginous eruption that had lasted for 2 weeks. The patient had been taking goji berries for 5 months and cat's claw for 3 months. Upon testing, it was revealed that the patient tested positive to goji berries in a photoprovocation test, but not to cat's claw (40263).

Hepatic ...Orally, consumption of goji berries has been associated with a single case report of autoimmune hepatitis (52541). A case of acute hepatitis has also been reported in a female who consumed 2 ounces of a specific combination product (Euforia, Nuverus International) containing goji berry, pomegranate, curcumin, green tea, noni, acai berry, aloe vera, blueberry, resveratrol, mangosteen, and black seed, daily for one month. It is unclear whether the liver injury was caused by goji berry, other ingredients, or the combination (90125).

Immunologic ...Several cases of allergic reactions secondary to consumption of goji berries have been reported. Symptoms included facial angioedema with dyspnea, pharyngeal itching, itching in the mouth, ears, and axilla, labial angioedema, and perioral skin rash (92116). Anaphylaxis has also been reported (52538).

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General ...Orally, Indian gooseberry seems to be well tolerated.

Dermatologic ...Orally, itching has been reported by one individual in a clinical trial (105354).

Gastrointestinal ...Orally, epigastric discomfort or dyspepsia have been reported by up to four individuals in clinical trials (105354,105356).

Hepatic ...In clinical research, increased serum glutamic pyruvic transaminase (SGPT) levels, with otherwise normal liver function, occurred in patients taking Ayurvedic formulations containing ginger, Tinospora cordifolia, and Indian gooseberry, with or without Boswellia serrata. The SGPT levels normalized after discontinuing the treatments (89557). It is unclear if these hepatic effects were due to Indian gooseberry or other ingredients contained in the formulations.

Musculoskeletal ...Orally, musculoskeletal pain has been reported by three individuals in a clinical trial (105354).

Neurologic/CNS ...Orally, fatigue has been reported by one individual in a clinical trial (105354).

Pulmonary/Respiratory ...Orally, breathlessness has been reported by one individual in a clinical trial (105354).

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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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