Vitality by Legion

POSSIBLY INEFFECTIVE

• Night vision. Most research suggests that oral bilberry does not improve night vision in healthy individuals. Details: There is contradictory evidence about the effectiveness of bilberry for improving night vision; however, much of the research is of poor quality. In general, the most rigorous research shows that bilberry is not effective for improving night vision in healthy individuals (8139,9739,14280,35446). Whether bilberry can improve night vision in patients with night blindness is unclear.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study of elderly Norwegian males with subjective cognitive impairment shows that drinking 330 mL of bilberry and red grape juice twice daily for 9 weeks does not improve measures of memory or motor skills when compared with placebo (110641).
• Age-related macular degeneration (AMD). Although there has been interest in using oral bilberry for AMD, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Asthenopia (eye strain). Small clinical studies suggest that oral bilberry fruit extract may improve objective measures of asthenopia, but it is unclear if oral bilberry improves subjective symptoms of asthenopia. Details: Two small clinical studies in adults who report general eye strain or those who look at computer or other display screens at work for long periods of time show that taking bilberry-derived anthocyanins 43.2 mg daily for 6 weeks or bilberry extract 240 mg daily for 12 weeks improves objective measures of eye strain after staring at computer screens when compared with placebo (103190,104195). However, bilberry extract did not improve subjective measures of eye strain in the study that evaluated these outcomes (104195). This study may have been underpowered to detect significant differences between groups. Bilberry has also been evaluated in combination with other ingredients for improving eye strain. A small clinical trial in patients with eye strain shows that a combination of fish oil, lutein, and bilberry extract containing bilberry anthocyanidins 59 mg, taken daily for 4 weeks, reduces dry eye, lower back pain, shoulder stiffness, and stuffy head when compared with placebo (35470). It is unclear if these effects are due to bilberry, other ingredients, or the combination.
• Atherosclerosis. Although there has been interest in using oral bilberry for atherosclerosis, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Cataracts. Although there has been interest in using oral bilberry for cataracts, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Chronic venous insufficiency (CVI). It is unclear if oral bilberry is beneficial in patients with CVI. Details: One small clinical study in patients with CVI shows that taking bilberry extract containing anthocyanins 173 mg daily for 30 days reduces symptoms of CVI when compared with placebo (35510).
• Diabetes. It is unclear if oral bilberry is beneficial in patients with diabetes. Details: One small clinical trial in patients with type 2 diabetes shows that taking a specific extract of bilberry fruit (Mirtoselect, Indena S.p.A) 470 mg once, prior to taking an oral glucose tolerance test, lowers plasma glucose levels when compared with placebo (91507). However, a small crossover trial in Chinese patients with type 2 diabetes shows that taking bilberry fruit extract 700 mg twice daily for 4 weeks does not improve glycated hemoglobin (HbA1c), body weight, blood pressure, or lipid levels when compared with placebo (104194). The validity of the HbA1c-related findings is limited due to the short study duration.
• Diabetic retinopathy. It is unclear if oral bilberry is beneficial in patients with diabetic retinopathy. Details: One small clinical trial in adults with diabetic and hypertensive retinopathy shows that taking bilberry fruit extract 160 mg daily for 6 months, in addition to standard management, improves edema and measures of retinal circulatory health when compared with standard management alone. Bilberry in the form of a generic, commercially available product appears to produce less dramatic improvements than a branded formulation (Mirtoselect, Indena S.p.A.) containing matching anthocyanin content. This specific product also reduced flow velocity in those with high-flow, diabetic retinopathy when compared with either the generic bilberry extract or standard management alone (97032).
• Dry eye. Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with severe dry eye symptoms suggests that taking bilberry extract 600 mg and docosahexaenoic fish oil 240 mg once daily for 3 months may modestly improve measures of tear quality and patient-reported scores for dry eye symptoms when compared with control (112415). However, the validity of these results is limited by the lack of a statistical comparison between groups. Additionally, it is unclear if these effects are due to bilberry, fish oil, or the combination.
• Dysmenorrhea. It is unclear if oral bilberry is beneficial in patients with dysmenorrhea. Details: One small clinical study in patients with dysmenorrhea shows that a specific bilberry product (Tegens) containing bilberry anthocyanoside 160 mg, taken twice daily beginning 3 days prior to menses and continuing for 8 days, reduces pelvic pain, lumbosacral pain, breast pain, nausea, vomiting, and headache when compared with placebo (35512).
• Exercise-induced muscle soreness. It is unclear if oral bilberry is beneficial for reducing exercise-induced muscle soreness. Details: A small clinical study in trained athletes shows that drinking 200 mL of bilberry juice, containing about 744 mg phenols and 80 mg anthocyanins, twice daily for 5 days prior to running a half-marathon modestly worsens muscle soreness immediately after the run when compared with placebo. There was no longer a difference in muscle soreness between groups within 1-2 days after the run (99540).
• Glaucoma. Small clinical studies suggest that oral bilberry fruit extract, when taken with maritime pine extract, may lower intraocular pressure in patients with glaucoma. It is unclear if oral bilberry alone is beneficial in patients with glaucoma. Details: One small, uncontrolled clinical trial in Japanese patients with open-angle glaucoma shows that taking a specific product (Sante Glagenox, Saten Pharmaceutical Co. Ltd.) containing bilberry fruit extract 90 mg and maritime pine extract 40 mg daily for 4 weeks reduces intraocular pressure by 8.7% when compared to baseline (104192). Another small clinical study in patients with high intraocular pressure shows that taking a specific product (Mirtogenol) containing bilberry fruit extract (Mirtoselect, Indena S.p.A.) 80 mg and maritime pine extract (Pycnogenol, Horphag Research) 40 mg twice daily for 6 months lowers intraocular pressure and improves intraocular blood flow when compared with no treatment (35456). It is unclear if these findings are due to bilberry, maritime pine, or the combination. A retrospective chart review of patients with normal tension glaucoma has found that taking bilberry anthocyanin 60 mg twice daily for at least 12 months is associated with improvements in visual function when compared to pretreatment (35472).
• Hemorrhoids. Although there has been interest in using oral bilberry for hemorrhoids, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Hyperlipidemia. It is unclear if oral bilberry is beneficial in patients with hyperlipidemia. Details: A small clinical study in adults with hyperlipidemia shows that taking bilberry-derived anthocyanins 320 mg daily for 4 weeks does not improve total cholesterol, low-density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, or triglyceride levels. Further, no improvements in other biomarkers of cardiovascular disease were reported (110640). The validity of this study is limited by its short duration.
• Hypertension. Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in adults with hypertension shows that consuming 500 mL of a juice containing bilberry, red grape, and chokeberry, with or without black currant (MANA Blue, TINE SA), daily for 12 weeks does not improve blood pressure when compared with placebo (92371).
• Hypertensive retinopathy. It is unclear if oral bilberry is beneficial in patients with hypertensive retinopathy. Details: One small clinical trial in adults with diabetic and hypertensive retinopathy shows that taking bilberry fruit extract 160 mg daily for 6 months, in addition to standard management, improves edema and measures of retinal circulatory health when compared with standard management alone. Bilberry in the form of a generic, commercially available product appears to produce less dramatic improvements than a branded formulation (Mirtoselect, Indena S.p.A.) containing matching anthocyanin content. This specific product also increased flow velocity for those with ischemic, hypertensive retinopathy when compared with either the generic bilberry extract or standard management alone (97032).
• Impaired glucose tolerance (prediabetes). Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with impaired glucose tolerance and two markers of metabolic syndrome shows that consuming a diet high in whole grain products, fatty fish, and bilberries three times daily for 12 weeks reduces levels of plasma glucose when compared to baseline (35468). However, it is unclear if these findings are due to bilberry, another component of the diet, or the combination.
• Irritable bowel syndrome (IBS). Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial in adults with IBS shows that consuming a formula containing powdered bilberry fruit, aerial agrimony parts, cinnamon quills, and slippery elm bark modestly improves bowel movement frequency and reduces symptoms such as abdominal pain, bloating, flatulence, and straining when compared to baseline (35462). It is unclear if these findings are due to bilberry, other ingredients, or the combination.
• Metabolic syndrome. It is unclear if oral bilberry is beneficial in patients with metabolic syndrome. Details: One small clinical study in patients with metabolic syndrome shows that consuming a diet containing 400 grams of fresh bilberries daily does not affect body weight, glucose metabolism, or lipid metabolism when compared with a control diet (35473).
• Myopia. It is unclear if oral bilberry is beneficial in patients with myopia. Details: One small clinical trial in adults with myopia shows that a specific fermented bilberry fruit extract (Fermented Blueberry, Ajinomoto, Co., Inc.) 200 mg, taken twice daily for 4 weeks, improves night vision as well as the eye's ability to adjust focus when compared with placebo. The amplitude of accommodation was also significantly increased from 4.62 to 5.33 (91505).
• Obesity. It is unclear if oral bilberry is beneficial in patients with obesity. Details: One small clinical study in obese and overweight females shows that consuming 100 grams of frozen, whole bilberries daily for 33-35 days decreases weight and waist circumference when compared to baseline (35463). The validity of these findings is limited by the lack of a comparator group.
• Osteoarthritis. Although there has been interest in using oral bilberry for osteoarthritis, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Ulcerative colitis. It is unclear if oral bilberry is beneficial in patients with ulcerative colitis. Details: One small, open-label clinical study in adults with mild-to-moderate ulcerative colitis shows that consuming sieved bilberries and concentrated bilberry juice (Symrise GmbH & Co) 160 grams daily for 6 weeks induces remission in 46% of patients. Furthermore, 91% of patients achieved remission at the end of treatment, and 72% of patients achieved remission at the end of the study (91506). The validity of these findings is limited by the lack of a comparator group.
• Urinary tract infections (UTIs). Although there has been interest in using oral bilberry for UTIs, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Varicose veins. Although there has been interest in using oral bilberry for varicose veins, there is insufficient reliable information about the clinical effects of bilberry for this purpose. More evidence is needed to rate bilberry for these uses.

(Read more about BILBERRY)

LIKELY EFFECTIVE

• Vaginal atrophy. Intravaginal DHEA can reduce pain during intercourse and improve vaginal health in patients with this condition. Details: Clinical research shows that ovules or suppositories containing DHEA 0.25% to 1%, inserted vaginally once daily for 12 weeks, can reverse vaginal thinning, restore vaginal pH, and reduce pain during sexual intercourse by up to 15% when compared with placebo in patients with vaginal atrophy (21320,21429,21430,94576). A specific vaginal insert containing DHEA 0.5% (Intrarosa, Endoceutics Inc.) is an FDA approved drug used for reducing pain during sexual intercourse in patients with vaginal atrophy (94573,94576). Other clinical research shows that applying DHEA 10% cream (Diosynth) to the inner thighs daily for 12 months might improve vaginal atrophy by stimulating maturation of the vaginal epithelium in postmenopausal patients. It might also increase bone mineral density in these patients (4242).

POSSIBLY EFFECTIVE

• Aging skin. Oral and topical DHEA have been evaluated for treating aging skin, with promising results. Details: Some clinical research shows that taking DHEA 50 mg daily for 12 months increases epidermal thickness, sebum production, and skin hydration, and decreases facial skin pigmentation in elderly patients (6446). Other preliminary clinical research shows that applying 1% DHEA daily for 4 months improves the appearance of paper-like skin when compared with placebo in postmenopausal patients. It also improves sebum production, skin wrinkling, and skin appearance when compared with baseline (21428).
• Depression. Oral DHEA 30-500 mg daily for up to 8 weeks seems to improve symptoms of depression and dysthymia in patients with depression. Details: Canadian clinical practice guidelines recommend DHEA as a third-line treatment for depression (95691). Most clinical research shows that taking DHEA 30-500 mg daily for around 6-8 weeks improves symptoms of depression and dysthymia when compared with placebo (3270,3864,3892,4233,21404,21405). Additionally, a pooled analysis of these and 9 other clinical studies shows that DHEA can improve depressive symptoms when compared with placebo, although most of the trials evaluated in the analysis included patients without clinically diagnosed depression (104161). Other preliminary clinical research using lower doses of 5-20 mg daily over 3 weeks shows no improvement in depressive symptoms in psychotic patients (21406).
• Infertility. Oral DHEA appears to improve fertility outcomes, including pregnancy and live birth rates, in females undergoing assisted reproduction. However, it is unclear if oral DHEA can reduce the risk for miscarriage after in vitro fertilization (IVF) or intra-cytoplasmic sperm injection (ICSI). Details: Meta-analyses of clinical research show that taking DHEA, typically at a dose of 75 mg daily, improves fertility outcomes for females undergoing assisted reproduction (96819,96820,96821,111227). One meta-analysis limited to randomized controlled trials in patients considered poor responders to standard IVF found that taking DHEA prior to IVF or ICSI treatments increases the clinical pregnancy rate by 34% and the rate of live births or ongoing pregnancy by 88% when compared with placebo or no treatment (96820). Another meta-analysis consisting of 16 studies, including both randomized controlled trials and observational research, in patients with diminished ovarian reserve (DOR) or poor ovarian response (POR) undergoing IVF or ICSI shows that taking DHEA 50-90 mg daily is associated with increases in oocyte yields, fertilized oocytes, top-quality embryos, clinical pregnancy rates, and ongoing pregnancy rates when compared with control groups. However, DHEA supplementation was not linked to improvements in live birth rates (111227). In females with various conditions of compromised fertility, some preliminary clinical research shows that taking DHEA 50-75 mg daily for at least 4 months may aid with natural conception, insemination-induced conception, and IVF pregnancy outcomes (21362). Some observational research in older females with DOR has also found that taking DHEA 30 mg three times daily for 12 weeks before IVF cycles is associated with a greater number of retrieved oocytes, improved oocyte quality, and increased cumulative pregnancy rates (103185). Inclusion of lower quality research also supports these findings (21413,21414,88493,96819,96821,99923). However, other research conflicts with findings that show a benefit of DHEA for infertility. (21415,88726,90304,111226). A large clinical study shows that pretreatment with DHEA in infertile females with POR prior to IVF and embryo transfer does not improve the number of retrieved oocytes and the rates of clinical pregnancy, pregnancy loss, and cumulative live births when compared with placebo (111226). Observational research in older patients with DOR suggests that DHEA supplementation is not linked to improved clinical pregnancy or live birth rates when compared with a control group (103185). Other clinical research in females with primary ovarian insufficiency shows that taking DHEA 75 mg daily for 16 weeks might not improve follicle size when compared with placebo (21364). The effect of DHEA pretreatment on miscarriage rates after IVF or ICSI is not clear. A meta-analysis of randomized clinical research does not support the use of DHEA pretreatment for preventing miscarriage (96820). However, when lower quality research is considered, use of DHEA seems to reduce the risk of miscarriage by up to 50% (21418,96819).

POSSIBLY INEFFECTIVE

• Aging. Oral DHEA, taken for up to 2 years, does not appear to improve bone health, quality of life, or sexual function in older adults. Details: Clinical research shows that DHEA, taken as 75 mg daily in males or 50 mg daily in females, for 2 years does not seem to improve body composition, bone mineral density (BMD), insulin sensitivity, or quality of life in people aged 60 years or older who have low DHEA-S levels (15027). Additionally, a pooled analysis of clinical trials shows that taking DHEA 50-1600 mg daily for up to 2 years does not improve body composition, bone health, sexual function, lipid and glycemic parameters, or quality of life in elderly males (88434).
• Muscle strength. Oral DHEA does not seem to improve muscle strength in adults. Details: While some clinical research shows that adults who take DHEA have increased muscle strength when measured by grip strength, leg press, chest press, and other measures, most clinical evidence shows that DHEA provides no benefit to muscle strength in younger and older adults (1365,10406,17617,21392,21419,21420,21421,47198).
• Physical performance. Oral DHEA does not seem to improve physical performance in elderly patients. Details: Most clinical research and a meta-analysis show that older adults who take DHEA do not have increased physical function or performance as measured by oxygen uptake, duration of exercise, balance, and ability to rise from a chair (17617,21420,21421). However, one clinical study shows that taking DHEA 50 mg daily for 6 months improves lower body strength and function by a small amount when compared with placebo in elderly frail females (21392). More research is needed to determine if DHEA is beneficial in specific populations.

LIKELY INEFFECTIVE

• Cognitive function. Oral DHEA does not improve cognitive function or prevent cognitive decline in most populations. Details: In the majority of clinical research, taking DHEA orally does not seem to improve cognitive function or decrease cognitive decline in healthy people over the age of 50 (3893,11334,14862,21333,21445), in peri- or post-menopausal women (6011,21397,21445), in patients with HIV (47435), or in young healthy adults when given as an acute dose (21399). However, preliminary clinical research shows that taking DHEA 50 mg daily for 4 weeks may improve certain measures of visual spatial performance and memory when compared with placebo in middle aged and elderly females (21396,21398).
• Sjogren syndrome. Oral DHEA does not appear to improve symptoms with this condition. Details: Clinical research shows that taking DHEA 50-200 mg daily for 4-12 months does not benefit symptoms of primary Sjogren syndrome when compared with placebo (21354,21358,21363,21365).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Addison disease. It is unclear if oral DHEA is beneficial in patients with this condition. Details: Some preliminary clinical research shows that taking DHEA up to 50 mg daily for up to 12 months improves symptoms of Addison disease, including reversing the loss of bone mineral density (BMD) and lean mass, but without improving cognitive function (8595,21387). However, taking DHEA 50 mg daily for 12 weeks does not appear to improve cognitive or sexual function, body composition, or BMD, although it may improve mood and fatigue (7614,21330,21356).
• Adrenal insufficiency. It is unclear if oral DHEA is beneficial in patients with primary or secondary adrenal insufficiency. Details: Some clinical research shows that taking low-dose DHEA, 20-50 mg daily, improves feelings of well-being, skin and hair, pubic hair growth, and sexuality in females with adrenal insufficiency or androgen deficiency due to hypopituitarism (3231,8593,17218,21317,21370,21385). However, other clinical research shows that taking low-dose DHEA for 3-12 months has little to no effect on quality of life, body composition, physical performance, cardiac function, depression, anxiety, and sexual arousal in patients with primary or secondary adrenal insufficiency (17218,21351,21357,21360,21386,21388,21389). Also, there is contradictory evidence about the effects of DHEA on plasma lipid levels in patients with adrenal insufficiency (21348,21351).
• Athletic performance. It is unclear if oral DHEA can improve sprint performance. Details: Preliminary clinical research in female recreationally trained athletes shows that taking DHEA 100 mg daily for 4 weeks does not improve sprint performance when compared with placebo (99925).
• Cardiovascular disease (CVD). Observational research has found that low DHEA levels are linked to a greater risk for CVD, but it is unclear if supplementation with oral DHEA is beneficial. Details: A meta-analysis of population research shows that patients with CVD and lower blood levels of DHEA-S have a worse overall prognosis when compared with patients with higher levels. Patients with the lowest levels have a 47% increased risk of future mortality events, including a 58% increased risk of fatal cardiovascular events. There was also a 42% increased risk of nonfatal cardiovascular events (96817). In elderly males, population research also shows that low serum levels of DHEA and DHEA-S are associated with an increased risk of coronary heart disease (CHD) but not cerebrovascular disease (90303).
• Cervical dysplasia. It is unclear if intravaginal DHEA is beneficial in patients with cervical dysplasia. Details: Preliminary clinical research shows that DHEA 150 mg intravaginally for up to 6 months reverses dysplasia in 83% of treated females with low-grade cervical dysplasia when compared to baseline (21426). The validity of these findings is limited by the lack of a comparator group.
• Chronic fatigue syndrome (CFS). It is unclear if oral DHEA is beneficial in patients with CFS. Details: Preliminary clinical research shows that oral DHEA 25-100 mg daily for 6 months improves symptoms of CFS by 8.5% to 26% when compared to baseline (7559). The validity of these findings is limited by the lack of a comparator group.
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral DHEA is beneficial in patients with COPD. Details: A small clinical study shows that taking DHEA 200 mg daily for 3 months increases walking distance and improves lung function in patients with COPD when compared to baseline (21395). The validity of these findings is limited by the lack of a comparator group.
• Cocaine dependence. It is unclear if oral DHEA is beneficial for reducing cocaine cravings. Details: A small clinical study shows that taking DHEA 100 mg daily for 12 weeks, in addition to cognitive-behavioral group counseling, does not reduce cocaine craving when compared with counseling alone in cocaine-dependent participants (21411).
• Crohn disease. It is unclear if oral DHEA is beneficial for inducing Crohn disease remission. Details: A small clinical study shows that taking DHEA 200 mg daily for 8 weeks reduces symptoms in some patients with Crohn disease when compared to baseline. Remission occurred in 6 of 7 Crohn patients (21416). The validity of these findings is limited by the small study size and lack of a comparator group.
• Diabetes. Although there has been interest in using oral DHEA for diabetes, there is insufficient reliable information available about the clinical effects of DHEA for this purpose.
• Erectile dysfunction (ED). It is unclear if oral DHEA is beneficial in patients with ED. Details: Preliminary clinical research shows that taking DHEA orally for 24 weeks improves erectile function, orgasmic function, sexual desire, and overall sexual satisfaction in patients with ED. DHEA seems to be beneficial for idiopathic ED or ED secondary to hypertension, but doesn't seem to provide benefit for ED related to diabetes or neurological disorders (793,8596).
• Exercise-induced muscle damage. It is unclear if oral DHEA is beneficial for reducing muscle damage from exercise. Details: Preliminary clinical research shows that taking DHEA 50 mg twice daily for 5 days improves delayed-onset muscle soreness and reduces post-training blood creatinine kinase levels when compared with placebo in young males completing a 5-day exercise training program (88375).
• Fibromyalgia. It is unclear if oral DHEA is beneficial for improving fibromyalgia symptoms. Details: Preliminary clinical research shows that taking DHEA 50 mg daily for 3 months does not reduce fibromyalgia symptoms when compared with placebo in postmenopausal patients with fibromyalgia (21355).
• HIV/AIDS. Small clinical studies suggest that oral DHEA may improve mental health and quality of life in patients with HIV/AIDS, but DHEA does not seem to improve CD4 counts or body composition. Details: Population research shows that levels of DHEA seem to be lower in patients with more severe HIV/AIDS, suggesting that DHEA could be a marker for disease severity. Some evidence suggests that lower DHEA levels are associated with an increased risk of disease progression and AIDS (8598,14278,14279). Some clinical research shows that taking DHEA 50-500 mg daily for 2-4 months might improve mental health and quality of life when compared with placebo (3864,8598,14277,21390). However, taking DHEA in doses up to 2.25 grams daily does not appear to improve CD4 counts, muscle mass, or bone mass when compared with placebo (3865,14277,21390).
• Menopausal symptoms. Oral DHEA might reduce hot flashes and intravaginal DHEA might improve vaginal atrophy and sexual activity; however, oral DHEA does not seem to improve psychological symptoms associated with menopause. Details: Some research shows that taking DHEA 10-25 mg daily for 12 months improves subjective vasomotor symptoms such as hot flashes, as well as psychological symptoms and sexuality (11464,21417). Also, administering a daily ovule containing DHEA (Vaginorm, Recipharm) 3.5-13 mg intravaginally for 12 weeks appears to reverse vaginal atrophy and improve sexual activity in postmenopausal patients with vaginal atrophy (21442). However, other clinical research shows that taking DHEA 50 mg daily for up to 26 weeks does not improve mood, fatigue, cognition, sexual function, or sense of well-being in post- or peri-menopausal patients when compared with placebo (6011,21361). Additionally, a pooled analysis of clinical research shows that DHEA taken orally does not improve psychological symptoms related to menopause (88492).
• Metabolic syndrome. It is unclear if oral DHEA is beneficial for reducing risk for metabolic syndrome. Details: Preliminary clinical research shows that taking DHEA 50 mg daily for 6 months or 100 mg daily for 3 months decreases weight, abdominal fat, and blood pressure and reduces cholesterol, glucose, and insulin levels when compared with placebo in overweight elderly patients (12215,21350).
• Muscular dystrophy. It is unclear if oral DHEA is beneficial in patients with myotonic dystrophy type I. Details: Taking DHEA 100 or 400 mg daily for 12 weeks might not affect muscle strength in patients with myotonic dystrophy type I when compared with placebo (21334). However, intravenous DHEA-S 200 mg daily for 8 weeks appears to improve daily function, muscle strength, and heart function compared with baseline (21434). The validity of this finding is limited by the lack of a control group.
• Obesity. It is unclear if oral DHEA is beneficial for reducing body weight in patients who are obese or overweight. Details: Preliminary clinical research shows that taking DHEA 40 mg sublingually twice daily for 8 weeks, or 1600 mg by mouth for 28 days, does not affect body weight or body composition when compared with placebo in obese adults (21410,21427). Also, preliminary clinical research shows that taking DHEA 50-100 mg daily for 3-12 months does not affect central adiposity in older individuals when compared with placebo (21349).
• Opioid withdrawal. It is unclear if oral DHEA is beneficial in patients with heroin withdrawal. Details: Preliminary clinical research shows that taking DHEA 100 mg daily as adjunct to standard therapy for 12 months does not improve drug withdrawal symptoms in heroin addicts when compared with standard therapy alone (21412).
• Osteoporosis. It is unclear if oral DHEA is beneficial in patients with osteoporosis; any benefit may depend on individual patient characteristics. Details: There is contradictory evidence about the effectiveness of DHEA 50-100 mg daily for improved bone mineral density (BMD) in older adults with osteoporosis or osteopenia (12563,12564,21392), as well as the effectiveness of DHEA for improved BMD in females with anorexia nervosa (12562,21393). One pooled analysis shows that DHEA does not improve BMD in postmenopausal patients (88492), while another shows that DHEA can increase hip BMD in healthy older females, but not males (103186). The reason for these discrepant findings is unclear, but may relate to different patient populations, durations of therapy, and DHEA doses assessed in the included studies. Additionally, most of the studies included in these analyses were of low quality and inadequate statistical power.
• Parkinson disease. Although there has been interest in using oral DHEA for Parkinson disease, there is insufficient reliable information available about the clinical effects of DHEA for this purpose.
• Partial androgen deficiency. It is unclear if oral DHEA is beneficial for symptom improvement in patients with this condition. Details: Preliminary clinical research shows that taking DHEA 25 mg daily for one year might clinically improve mood, fatigue, and joint pain in older males with partial androgen deficiency when compared to baseline (21331). Other preliminary clinical research shows that taking DHEA 50 mg twice daily for 4 months does not improve erectile or sexual function when compared with placebo in hypoandrogenic males (21424).
• Parturition. Intravenous DHEA before the onset of labor may shorten the time to labor onset and shorten labor duration. Details: Clinical research shows that intravenous DHEA-S 100 mg daily for 3 days, or given twice weekly until the onset of labor starting after 38 weeks of gestation, increases cervical ripening and shortens the time to onset of labor and the duration of labor when compared with a control in nulliparous women (21384,21431). Also, intravenous DHEA 50-200 mg given multiple times until the onset of labor starting after 37 weeks of gestation appears to shorten the time to delivery in primiparous and multiparous women (21432,21433). It is unclear if oral DHEA is beneficial for this purpose.
• Rheumatoid arthritis (RA). It is unclear if oral DHEA is beneficial in patients with RA. Details: Preliminary clinical research shows that taking oral DHEA 200 mg for 16 weeks does not reduce symptoms of RA in elderly patients (21422). However, other clinical research in a small number of premenopausal females with RA shows that taking DHEA 50 mg daily for 12 weeks improves quality of life, but not disease activity, when compared with placebo (104159).
• Schizophrenia. It is unclear if oral DHEA is beneficial in patients with schizophrenia. Details: Some research shows that taking DHEA orally improves both negative and positive symptoms in patients with schizophrenia. It may be more effective in females (9692). However, other clinical research shows no benefit (21423).
• Sexual dysfunction. It is unclear if oral or intravaginal DHEA is beneficial for improving sexual dysfunction in males or females. Details: DHEA may be modestly beneficial in some postmenopausal patients with decreased libido or dyspareunia. Preliminary clinical research shows that taking DHEA 50-100 mg daily, or a single dose of DHEA 300 mg, improves sexual desire when compared to baseline (9906,21443). Additional clinical research shows that use of intravaginal DHEA (Vaginorm, Recipharm) at concentrations of 0.25% to 1% daily for 12 weeks might improve sexual function when compared with placebo (47361). However, a pooled analysis shows that DHEA is not associated with improvements in libido or sexual function (88414,88492). DHEA has also been evaluated in other patient populations. Small clinical studies show that taking DHEA doesn't seem to influence response to sexual stimuli in sexually functional premenopausal women (8594) or improve libido in individuals age 40-70 years (21449). Preliminary clinical research in males with hypoactive sexual desire disorder (HSDD) shows that taking DHEA 50 mg twice daily for 6 weeks does not improve erectile or sexual function when compared with placebo (88414). In adults with midlife-onset or HIV-associated depression, preliminary clinical research shows that taking DHEA 90-500 mg daily for 3-8 weeks may improve sexual function and libido when compared with placebo (3864,21405).
• Systemic lupus erythematosus (SLE). Most small clinical studies suggest that oral DHEA may modestly improve symptoms in patients with SLE, but some conflicting research exists. Details: Some clinical research shows that taking DHEA has little to no effect on disease activity in patients with mild to moderate SLE (21425,21447). However, small clinical studies and a meta-analysis of these studies show that taking DHEA in conjunction with conventional treatment may help improve frequency of flare-ups, muscle ache, oral ulcers, and quality of life, reduce corticosteroid doses needed (2113,2114,2136,6068,6447,12561,12574,21346,21447), and improve bone mineral density (6068,6097,6447,21394).
• Ulcerative colitis. It is unclear if oral DHEA is beneficial for inducing ulcerative colitis remission. Details: A small clinical study shows that taking DHEA 200 mg daily for 8 weeks reduces symptoms of ulcerative colitis when compared to baseline in some patients with ulcerative colitis. Remission occurred in 6 of 13 ulcerative colitis patients (21416). The validity of these findings is limited by the small study size and the lack of a comparator group. More evidence is needed to rate DHEA for these uses.

(Read more about DHEA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about RHODIOLA)

EFFECTIVE

• Imerslund-Grasbeck disease. Intramuscular vitamin B12 is effective for patients with this condition. Details: Administering intramuscular vitamin B12 (hydroxocobalamin) 1 mg daily for 10 days, followed by monthly injections for the remainder of a patient's life, is effective for treating familial selective vitamin B12 malabsorption (Imerslund-Grasbeck disease) (15,82862).
• Vitamin B12 deficiency. Administering vitamin B12 orally, intramuscularly, or intranasally is effective for preventing and treating vitamin B12 deficiency. Details: Vitamin B12 deficiency has varying definitions but is often defined as vitamin B12 (cobalamin) levels less than 180-200 pmol/L (or 240 pg/mL). Some believe that only intramuscular vitamin B12 is effective for treating vitamin B12 deficiency. However, clinical research shows that oral therapy increases cobalamin levels similarly to intramuscular administration, even in patients with pernicious anemia or malabsorption, if a high enough dose is given (2909,2911,2915,9335,82832) (82836,82949,82860,103976,103972,107141,107144). Some evidence suggests that the most effective oral dose is between 647-1032 mcg daily (13106). However, in certain situations, intramuscular treatment might be more appropriate. Guidelines by the British Committee for Standards in Hematology recommend only intramuscular vitamin B12 for initial treatment of severe vitamin B12 deficiency in patients with pernicious anemia, malabsorption disorders, or neurological involvement (94722). Intramuscular vitamin B12 is also appropriate in patients with diarrhea or vomiting and those likely to be nonadherent (103972). Vitamin B12 deficiency is especially common in older adults, primarily due to lack of intrinsic factor and malabsorption (2915,2919,9335). Daily supplementation with vitamin B12 50-100 mcg might be needed to correct deficiency (10126), while daily doses of 25-37.5 mcg help to maintain normal levels over time (9335). In addition to supplements, foods such as milk and bread fortified with vitamin B12 can be used and are approximately 55% to 60% absorbed by people over 60 years of age (10124). Vitamin B12 deficiency is also common in patients that have had gastric surgery, including gastrectomy and bariatric surgery (107144,107145). Taking vitamin B12 in the doses found in multivitamins or generic vitamin B supplements does not seem to prevent vitamin B12 deficiency following bariatric surgery (107145). However, taking methylcobalamin 500 mcg daily is beneficial for treating vitamin B12 deficiency associated with a total gastrectomy and taking cyanocobalamin 5000 mcg daily is beneficial for preventing vitamin B12 deficiency following gastric bypass (107144). Other people at risk for vitamin B12 deficiency include strict vegetarians who eat no animal products (vegans) and people with increased vitamin B12 requirements associated with pregnancy, thyrotoxicosis, hemolytic anemia, hemorrhage, malignancy, and hepatic and kidney disease. Moderate consumption of animal products may not be sufficient to restore and maintain vitamin B12 levels, especially in adolescents who had consumed macrobiotic (vegan type) diets for the first 6 years of life. High dietary intake of vitamin B12 or supplements is usually needed in order to restore and maintain optimal vitamin B12 levels in these adolescents (10125).

LIKELY EFFECTIVE

• Cyanide poisoning. Intravenous hydroxocobalamin (Cyanokit) is likely effective as an antidote for patients with suspected or known cyanide toxicity due to inhalation, ingestion, or skin exposure. Details: Treatment of cyanide poisoning with hydroxocobalamin (Cyanokit) up to 10 grams has been approved by the US Food and Drug Administration (FDA) and recommended by the Australian Resuscitation Council (82870,82905,82906). Hydroxocobalamin is also FDA-approved for treating cyanide toxicity during pregnancy (82904).

POSSIBLY EFFECTIVE

• Canker sores. Sublingual or topical vitamin B12 seems to reduce canker sore symptoms. Details: Clinical research in patients with canker sores shows that applying a topical ointment containing vitamin B12 500 mcg in four divided doses daily for 2 days reduces pain levels by 80% when compared with a control ointment not containing vitamin B12 (96176). Other preliminary clinical research shows that taking vitamin B12 1000 mcg sublingually daily for 6 months reduces the duration of canker sore outbreaks, the number of ulcers, and level of pain when compared with placebo in patients with normal vitamin B12 levels (17242).
• Hyperhomocysteinemia. Oral vitamin B12 in combination with folic acid, and sometimes with vitamin B6, reduces homocysteine levels. Details: While folic acid 0.5-5 mg daily lowers fasting homocysteine levels by an average of 25%, adding vitamin B12 0.5 mg daily produces an additional decrease of about 7% on average (6883,9400,9401,9405,9409,50145,107136). Vitamin B12 in combination with folic acid and other vitamins also reduces homocysteine levels in patients with kidney failure, sickle cell disease, and those receiving nitrous oxide general anesthesia (1489,6883,6884,7289,7881,9324,9414,9415,9416,9481,82941). Some researchers recommend routine use of vitamin B12 with homocysteine-lowering regimens to avoid the risk of neuropathy in people with undetected vitamin B12 deficiency (9405). Using vitamin B12 alone has a limited effect on homocysteine levels, and probably only in those people with vitamin B12 deficiency (2147,9410,9512). Hyperhomocysteinemia is considered by some to be an independent risk factor for atherosclerosis, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, and ischemic stroke (1899,2147,3323,9402,9405,9408,9409). Clinical research suggests that supplementation with folic acid, pyridoxine, and vitamin B12 decreases homocysteine levels and reduces the atherosclerosis progression in patients at risk for atherosclerosis when compared with placebo (50133,50056,82806). However, other research suggests that elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). A 5 µmol/L increase in plasma homocysteine increases the risk of cerebrovascular disease by 50%, and the odds of coronary heart disease by 60% and 80% in males and females, respectively (9407,9411). However, it is not clear if reducing homocysteine levels results in reduced cardiovascular morbidity and mortality (1489,6883,6884,9400,9405,9409,96417). Folic acid, vitamin B6, and vitamin B12 supplementation can reduce total homocysteine from 13.4 to 11 µmol/L. However, this reduction does not seem improve endothelial function or help with secondary prevention of death or myocardial infarction, and some research even suggests an increase in cardiovascular disease (CVD) risk (11387,13482,50373,50314,97619). There is also some debate about whether supplementation with homocysteine-lowering B vitamins can reduce the risk of stroke. A number of large clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with CVD or impaired kidney function (11387,13482,50423,83050,96150). However, a more recent meta-analysis of 10 clinical trials including over 44,000 patients shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo in patients at risk or with a history of CVD (97619). Also, a meta-analysis in adults with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and vascular death by 11% when compared with placebo (107136).
• Postherpetic neuralgia. Subcutaneous injections of vitamin B12 seem to reduce postherpetic neuralgia symptoms. Details: Clinical research in patients with subacute herpetic neuralgia shows that subcutaneous injection of vitamin B12 (methylcobalamin) 1000 mcg six times weekly for 4 weeks reduces pain when compared with oral vitamin B12 or subcutaneous lidocaine (90394). Another clinical study shows that administering local subcutaneous injections of methylcobalamin 1000 mcg plus lidocaine up to 20 mg daily for 12 injections over 14 days, starting within 7 days of the onset of subacute ophthalmic herpetic neuralgia, decreases the mean pain score by 63% to 79% when compared with intravenous lidocaine and intramuscular methylcobalamin. Less than 2 patients need to be treated to achieve a pain reduction to ≤3 out of 10. Healing of rash, itching, numbness, and tingling were also improved (96175). Additional clinical research in patients with postherpetic pain and itching shows that this same dosing regimen of subcutaneous vitamin B12 reduces pain and analgesic requirements when compared to baseline (90396).

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Oral vitamin B12 does not seem to improve cognitive function in older adults when used alone or in combination with other B vitamins. Details: Taking vitamin B12 100-1000 mcg plus folic acid 400-2000 mcg, with or without vitamin B6 3-50 mg, daily for up to about 2 years does not seem to improve tests of cognitive function in adults aged 65 or older, most of whom do not report cognitive impairment at baseline (14392,50225,50510,90392,107140). Also, supplementation with vitamin B12 does not seem to improve cognitive function in elderly individuals with low vitamin B12 levels (12305).
• Alzheimer disease. Oral vitamin B12, when used in combination with other B vitamins, does not seem to improve cognitive function in patients with Alzheimer disease. Details: Clinical research in patients with probable Alzheimer disease using routine medication shows that taking vitamin B12 1 mg, folic acid 5 mg, and vitamin B6 25 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo. In this study, all patients were consuming a folate-fortified diet (50319). Also, a meta-analysis of clinical research in elderly adults with mild cognitive impairment or dementia shows that taking vitamin B12, usually with other B vitamins, does not improve cognitive function (50510). Observational research has also found that higher vitamin B12 intake over 3 years in a population consuming a folate-fortified diet is not associated with a decreased risk of developing Alzheimer disease (15270). In contrast, preliminary clinical research in patients with probable Alzheimer disease who are not consuming a folate-fortified diet shows that taking vitamin B12 50 mcg daily plus folic acid 1.2 mg daily for 6 months modestly improves some measures of cognitive performance and decreases levels of homocysteine when compared with placebo (107150). More research is needed to determine if any changes in this latter study are clinically relevant.
• Cataracts. Oral vitamin B12 does not seem to reduce cataract development. Details: Clinical research in women with existing cardiovascular disease (CVD) or at increased risk of CVD shows that taking a combination of folic acid 2.5 mg daily, vitamin B6 50 mg daily, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of cataracts and seems to increase the risk of cataract extraction by 28% when compared with placebo (96149).
• Circadian rhythm sleep disorders. Oral vitamin B12 does not seem to improve sleep disorders. Details: Oral vitamin B12 (methylcobalamin) does not seem to be effective for treating delayed sleep phase syndrome. Methylcobalamin 0.5-1 mg three times daily, with or without bright light therapy, also does not seem to help people with primary circadian rhythm sleep disorders (1344,1345,1346,1347,1348).
• Cognitive impairment. Oral vitamin B12 does not seem to be beneficial for older adults with cognitive impairment. Details: A meta-analysis of clinical research in elderly adults with mild cognitive impairment or dementia shows that taking vitamin B12, usually with other B vitamins, does not improve cognitive function (50510). One clinical trial in elderly people with memory complaints shows that taking a combination of B vitamins, including folic acid 0.8 mg, vitamin B12 0.5 mg, and vitamin B6 (form not specified) 20 mg daily for 24 months reduces cerebral atrophy in the gray matter regions associated with Alzheimer disease by up to seven-fold when compared with placebo. However, this protection does not occur in patients with the lowest average blood levels of homocysteine (90374).
• Fall prevention. Oral vitamin B12 does not seem to reduce the risk of falls. Details: Clinical research shows that taking B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg, daily for 2 years does not prevent falls when compared with placebo in elderly individuals also taking vitamin D (96148).
• Osteoporosis. Oral vitamin B12 does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in elderly patients or patients with a history of cerebrovascular disease shows that taking vitamin B12 500 mcg and folic acid 0.4-2 mg, with or without vitamin B6 25 mg, daily for 2-3 years does not seem to reduce the risk for osteoporotic fractures when compared with placebo (90377,90393). A 5-7 year follow-up of this research has also found no benefit (103981).
• Physical performance. Oral vitamin B12 does not seem to improve physical performance in older adults. Details: Clinical research shows that taking B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg, daily for 2 years does not increase hand strength or improve performance such as walking when compared with placebo in elderly individuals also taking vitamin D (96148).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking vitamin B12 1000 mcg, folic acid 2.5 mg, and vitamin B6 50 mg daily, reduces the risk of developing AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or at least three risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to vitamin B12, other ingredients, or the combination.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if high-dose intramuscular vitamin B12 improves the prognosis of ALS. Details: A clinical study in patients with ALS symptoms for 3 years or less shows that intramuscular vitamin B12 (methylcobalamin) 25-50 mg twice weekly for 3.5 years does not slow functional decline or increase the time until ventilation or death when compared with placebo. However, other clinical research in patients with early-stage ALS shows that intramuscular methylcobalamin 50 mg twice weekly for 16 weeks is associated with slower functional decline and a longer period of time until death or full ventilation when compared with placebo (104947,111556). These effects seem to be particularly notable in fine and gross motor skills, but not bulbar or respiratory functions. Furthermore, vitamin B12 and riluzole slowed clinical progression of ALS more than riluzole alone (111556).
• Angioplasty. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that vitamin B12 400 mcg, folic acid 1 mg, and vitamin B6 10 mg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412,34540). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, pyridoxine, and vitamin B12 followed by oral administration of folic acid 1.2 mg, pyridoxine 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151,34540). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151). It is unclear if any effects are due to vitamin B12, other ingredients, or the combination.
• Anxiety. Although there is interest in using oral vitamin B12 for anxiety and panic attacks, there is insufficient reliable information about the clinical effects of vitamin B12 for these uses.
• Asthma. Although there is interest in using oral vitamin B12 for asthma, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Atherosclerosis. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with intermediate risk for coronary heart disease shows that taking vitamin B12 100 mcg, aged garlic extract 250 mg, folic acid 300 mcg, vitamin B6 12.5 mg, and L-arginine 100 mg daily for 12 months reduces coronary artery calcium progression when compared with placebo (88385). It is unclear if this effect is due to vitamin B12, other ingredients, or the combination.
• Atopic dermatitis (eczema). It is unclear if topical vitamin B12 reduces the severity of eczema. Details: Preliminary clinical research shows that applying a specific topical vitamin B12 0.07% cream (Regividerm) twice daily reduces the extent and severity of atopic dermatitis when compared with placebo (15765).
• Attention. Although there is interest in using oral vitamin B12 for improving attention and focus, there is insufficient reliable information about the clinical effects of vitamin B12 for this use.
• Cancer. It is unclear if oral vitamin B12 reduces overall cancer risk when used in combination with other B vitamins. Details: An ancillary clinical study in middle-aged and elderly adults with cardiovascular disease shows that taking a combination of vitamin B12 (cyanocobalamin) 0.02 mg, folic acid 0.56 mg, and vitamin B6 3 mg, with or without eicosapentaenoic acid (EPA) 400 mg plus docosahexaenoic acid (DHA) 200 mg, for a median of 4.7 years does not reduce the risk of cancer when compared with placebo (90666). An additional secondary analysis of clinical research in patients recovering from stroke or transient ischemic attack shows that taking vitamin B12 500 mcg, folic acid 2 mg, and vitamin B6 25 mg daily for around 3.4 years does not reduce the risk of cancer when compared with placebo (90378). The validity of these findings is limited because the studies were not designed nor adequately powered to test for cancer risk.
• Cardiovascular disease (CVD). Oral vitamin B12, taken along with other B vitamins, does not seem to improve secondary prevention of death or myocardial infarction in patients with CVD. However, it might slightly reduce the risk of stroke. Details: Overall evidence from clinical research and meta-analyses shows that taking vitamin B12 in combination with folic acid and/or vitamin B6 does not seem to reduce the risk for secondary death or myocardial infarction in patients with or at risk for CVD (11387,13482,34540,50423,83050,90379,97619). In fact, some research suggests that long-term supplementation with vitamin B6, folic acid, and vitamin B12 for secondary prevention increases the risk of CVD by 20% despite lowering homocysteine levels by 30% (13482). However, other research shows that taking vitamin B12 in combination with other B vitamins modestly reduces the risk of stroke, although results are conflicting (11387,13482,50423,83050,96150,96165,97619,107136). It is unclear which specific combination of B vitamins, if any, might be optimal for reducing stroke risk and which patients are most likely to benefit. In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368).
• Cervical cancer. It is unclear if oral vitamin B12 reduces cervical cancer risk. Details: Some epidemiological evidence has found that increasing vitamin B12 intake from dietary and supplement sources, along with folic acid, thiamine, and riboflavin, might decrease the risk of precancerous cervical lesions (11074). Also, an analysis of two case control studies has found that increased intake of vitamin B12 is associated with a 75% reduced odds of cervical cancer (34609).
• Chemotherapy-induced peripheral neuropathy. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients receiving chemotherapy shows that a combination of B vitamins that includes vitamin B12 (cyanocobalamin) 1000 mcg, taken daily starting one week prior to treatment and finishing 12 weeks after treatment is completed, does not prevent peripheral neuropathy when compared with placebo (96173).
• Child development. It is unclear if oral vitamin B12 is beneficial for child development. Details: Population research has found that daily dietary intake of less than 2.26 mcg vitamin B12 in the third trimester of pregnancy is associated with an increased risk of poorer outcomes in the offspring for some measures of speech and mathematics ability, including vocabulary at 24 months, combining words at 38 months, speech intelligibility at 6 years, and math comprehension between ages 8-11 years, when compared with dietary intakes of at least 2.26 mcg daily. There was no association between prenatal vitamin B12 intake and reading or spelling abilities, vocabulary at other ages, or full-scale Intelligence Quotient (IQ) at ages 8 or 15 (107143).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral vitamin B12 reduces the risk of COPD. Details: Clinical research in patients with COPD shows that taking vitamin B12 500 mg daily for 8 weeks modestly improves endurance on the cycle ergometer, but does not improve oxygen consumption, when compared with placebo (96172).
• Cognitive function. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy, middle-aged adults shows that taking a combination product containing vitamin B12, other B vitamins, bacopa, and gingko biloba twice daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo (111554).
• Colorectal cancer. It is unclear if oral vitamin B12 reduces colorectal cancer risk. Details: Some epidemiological evidence has found that increased dietary intake of vitamin B12 is associated with a reduced risk of developing colorectal cancer (90383). However, preliminary clinical research shows that taking vitamin B12 1 mg, folic acid 2.5 mg, and vitamin B6 50 mg daily for up to 7.3 years does not reduce the risk of colorectal adenoma in females at high risk for cardiovascular disease (90389). Furthermore, a secondary analysis of clinical research in elderly patients suggests that taking vitamin B12 500 mcg and folic acid 400 mcg daily for 2 years might increase the risk of colorectal cancer when compared with placebo (90393).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral vitamin B12 is beneficial for patients with COVID-19. Details: A small observational study in hospitalized patients with COVID-19 pneumonia has found that higher plasma vitamin B12 levels may be associated with an increased risk of transfer to intensive care or death than lower plasma levels. However, when multivariate regression was conducted, only patient age was associated with worsened outcomes. Additionally, the total study population was small, with only nine of 49 patients experiencing the worsened outcomes (107138).
• Dementia. It is unclear if oral vitamin B12 reduces the risk of developing dementia. Details: A large cohort of Danish adults has found that vitamin B12 levels or intake does not seem to impact the risk of developing Alzheimer disease or other dementias (104922). However, vitamin B12 might be beneficial in specific patient populations. A small observational study in patients with Parkinson disease has found that higher vitamin B12 levels (648.5 ng/L) are associated with a lower risk of developing dementia when compared with lower vitamin B12 levels (452 ng/L) (103975). It is not yet known if supplementation with vitamin B12 reduces the risk for dementia in these patients.
• Depression. It is unclear if oral vitamin B12 is beneficial for reducing depression risk. Details: A meta-analysis of epidemiological research has found that the highest dietary intake of vitamin B12 is associated with a 14% reduced risk of depression. However, in a sub-analysis, this association was not significant in males (107133). In contrast, one epidemiological study in older males included in the analysis has found that daily dietary intake of at least 4.79 mcg vitamin B12 is linked with a 58% lower risk of depression when compared with daily intake of less than 3.16 mcg. In this study, this inverse association was not observed in females (96168). Other observational research has found that low-normal serum vitamin B12 levels are associated with a 3.8 times increased risk for depression during pregnancy when compared with normal vitamin B12 levels (102384). It is unclear if increased intake of vitamin B12 through the diet or supplements reduces the risk for depression or is beneficial for treating symptoms of depression in any population. However, a meta-analysis of clinical research in elderly populations shows that supplementation with vitamin B12 100-1000 mcg daily, usually in combination with folic acid 400-2000 mcg daily, does not reduce symptoms of depression. Most individuals in these studies were not specifically diagnosed with depression (107140).
• Diabetes. It is unclear if oral vitamin B12 improves glycemic indices or prevents loss of skeletal muscle in patients with diabetes. Details: A small clinical study in patients with diabetes in India who are stabilized on metformin and/or a sulfonylurea shows that taking vitamin B12 (methylcobalamin) 500 mcg with or without folic acid 5 mg daily for 8 weeks seems to reduce glycated hemoglobin (HbA1C) by 1.3% to 1.5%, compared with a 0.3% increase with placebo (104917). This study is limited due its small sample size and lack of blinding. In elderly adults with type 2 diabetes, population research has found a lower dietary intake of vitamin B12 (average of 11.2 mcg daily) in individuals with a loss of skeletal muscle mass of at least 1.2%, compared with an average intake of 13.4 mcg daily in those with a skeletal muscle mass loss of less than 1.2%. However, further analysis determined that any relationship between vitamin B12 intake and loss of skeletal muscle mass was only significant in individuals with insufficient energy intake overall (107151).
• Diabetic neuropathy. Small clinical studies suggest that oral vitamin B12 may modestly improve pain in patients with diabetic neuropathy. Details: Two small clinical studies in patients with diabetic peripheral neuropathy show that taking vitamin B12 (methylcobalamin) 1-1.5 mg for 4-12 months modestly improves pain when compared with baseline or placebo (82841,104923). Some research also shows that vitamin B12 may be beneficial in combination with other ingredients. Studies have evaluated products containing vitamin B12 (methylcobalamin or cyanocobalamin), benfotiamine, and vitamin B6 daily for 9-12 weeks (82931,82939); and vitamin B12 (methylcobalamin) 2 mg, folic acid (L-methylfolate) 3 mg, and vitamin B6 (pyridoxal-5'-phosphate) 35 mg (Metanx; Pamlab) daily for 24 weeks (90375).
• Diarrhea. It is unclear if oral vitamin B12 is beneficial for reducing diarrhea in children. Details: Preliminary clinical research in children aged 6-30 months from low- and middle-income countries shows that taking vitamin B12 at twice the recommended dietary allowance, with or without folic acid, does not reduce the risk for diarrhea when compared with placebo (90391).
• Fatigue. It is unclear if intramuscular vitamin B12 is beneficial for improving well-being in those with fatigue or tiredness. Details: A small crossover trial in patients complaining of tiredness or fatigue shows that receiving intramuscular injections of vitamin B12 (hydroxocobalamin) 5 mg twice weekly for 2 weeks seems to improve general well-being and happiness, and has a trend toward improving fatigue, when compared with placebo (10127). The validity of this study is limited by a large drop-out rate and unstandardized outcome measures.
• Hearing loss. Oral vitamin B12 has only been evaluated in combination with adenosine triphosphate; its effect when used alone is unclear. Details: A small observational study in adults with idiopathic sudden sensorineural hearing loss has found that taking vitamin B12 1.5 mg with adenosine triphosphate 300 mg daily for 8-16 weeks is associated with modestly reduced hearing loss at 4-6 months after starting treatment when compared with taking the combination for less than 8 weeks (104924). This finding is limited due to its observational nature and lack of a control group.
• Hepatitis C. It is unclear if intramuscular vitamin B12 is beneficial for sustaining viral response in patients with chronic hepatitis C infection. Details: A small clinical study in patients with chronic hepatitis C infection shows that intramuscular vitamin B12 (cyanocobalamin) 5000 mcg every 4 weeks along with standard care improves sustained viral response when compared with standard of care alone (90386).
• Hypertriglyceridemia. It is unclear if oral vitamin B12 is beneficial for reducing triglyceride levels. Details: Some evidence shows that taking vitamin B12 7.5 mcg with fish oil 5 grams might be superior to fish oil alone when used daily to reduce total serum cholesterol and triglycerides. This suggests vitamin B12 might have an independent effect in lowering serum cholesterol and triglycerides, but further investigation is needed to confirm this effect (8694).
• Infant development. It is unclear if taking oral vitamin B12 during pregnancy is beneficial for improving infant development. Giving oral vitamin B12 to infants does not seem to be beneficial. Details: Clinical research shows that supplementation with vitamin B12 50 mcg daily from less than 14 weeks gestation until 6 weeks postpartum does not improve cognitive development in infants by 9 months of age when compared with placebo (96174). When these children were evaluated at 30 months of age, a very small benefit of vitamin B12 on expressive language was identified; however, there was no effect on cognition, receptive language, fine motor skills, or gross motor skills (100169). It is unknown whether a longer duration of postpartum supplementation or supplementation in specific populations might be beneficial. Vitamin B12 supplementation in infants has also been evaluated. A large clinical trial in marginally stunted Nepalese infants aged 6-11 months shows that giving vitamin B12 (cyanocobalamin) 2 mcg daily for 12 months reduces homocysteine levels, but does not improve motor or cognitive development, when compared with placebo (104926).
• Inflammatory bowel disease (IBD). Although there is interest in using oral vitamin B12 for IBD, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Lung cancer. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: The association between vitamin B12 and lung cancer is unclear. Some population research found no relationship between blood levels of vitamin B12 and lung cancer (9454). However, other observational research involving over 5,000 case-control pairs found that higher vitamin B12 levels are linked with an increased risk for lung cancer (102383). It is unclear if increased intake of vitamin B12, either through the diet or supplementation, directly affects the risk of lung cancer.
• Male infertility. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A retrospective study in adult males with idiopathic and varicocele-related infertility suggests that taking a combination product containing vitamin B12 1.5 mcg, L-carnitine, acetyl L-carnitine, citric acid, selenium, coenzyme Q10, vitamin C, zinc, and folic acid (Proxeed Plus) twice daily for 6 months is associated with improvements in ejaculate volume, sperm count, sperm concentration, total motility, and progressive motility in patients with idiopathic infertility when compared to baseline. However, improvement in sperm morphology was lacking. Furthermore, patients with more severe varicocele seem to benefit most, especially with regard to progressive motility (111296). The validity of these findings is limited by a lack of comparator group. Further, it is unclear if these effects are due to vitamin B12, other ingredients, or the combination.
• Multiple sclerosis (MS). Although there is interest in using oral vitamin B12 for MS, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin B12 is beneficial for NAFLD. Details: A small clinical study in adults with NAFLD shows that taking vitamin B12 1000 mcg daily for 12 weeks reduces serum levels of homocysteine but has no effect on serum aminotransferases, measures of steatosis, fibrosis scores, fasting blood glucose, serum insulin, measures of insulin resistance, triglycerides, low-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (HDL) cholesterol when compared with placebo (111555).
• Pancreatic cancer. It is unclear if oral vitamin B12 is beneficial for reducing the risk of pancreatic cancer. Details: Most population research has found that increased intake of vitamin B12, as a supplement or in the diet, is not associated with a reduced risk of pancreatic cancer (9327,104927). However, a small, retrospective population study in which smoking and non-smoking adults recalled past eating habits found that increased dietary intake of vitamin B12 is associated with a 33% reduction in pancreatic cancer risk (97976). These conflicting findings may be related to study methodology, as well as the age, gender, or smoking status of the included patients.
• Periodontitis. Although there is interest in using oral vitamin B12 for periodontitis, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Peripheral neuropathy. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific product containing vitamin B12 3 mcg, folic acid 400 mcg, and uridine monophosphate 50 mg (Keltican) daily for 60 days reduces pain by 44% and decreases analgesic use by over 75% when compared to baseline in patients with peripheral neuropathy, including those with lumbar/lumbosacral radiculopathy, sciatic pain, and cervical radiculopathy (90384). The validity of this finding is limited by the lack of a control group. Furthermore, it is unclear if the benefits are due to vitamin B12, other ingredients, or the combination.
• Psoriasis. Topical vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that a specific cream containing vitamin B12 and avocado oil (Regividerm, Regeneratio Pharma AG) reduces symptoms of psoriasis as effectively as calcipotriol ointment (Psorcutan) after 12 weeks of therapy. The vitamin B12 combination cream also causes less irritation than calcipotriol (14909). It is unclear if the benefits are due to vitamin B12, other ingredients, or the combination.
• Respiratory tract infections. A small study suggests that oral vitamin B12 does not reduce the rate of respiratory tract infections in children. Details: Preliminary clinical research in children aged 6-30 months from low-and middle-income countries suggests that taking vitamin B12 at twice the recommended dietary allowance with or without folic acid does not reduce the risk for lower respiratory tract infections when compared with placebo (90391).
• Schizophrenia. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination of vitamin B12 400 mcg and folic acid 2 mg daily for 16 weeks improves negative symptoms when compared with placebo in patients with schizophrenia who have persistent symptoms and a specific genetic variant of the folate transporter gene FOLHI. This variant normally results in reduced folate absorption. However, in patients without this genetic variant, folate is not beneficial with respect to negative symptom improvement (90387).
• Sickle cell disease. Oral vitamin B12 has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B12 4.2-6 mcg, folic acid 700 mcg, and vitamin B6 4.2-6 mg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
• Stroke. It is unclear if oral vitamin B12, either alone or with other B vitamins, is beneficial for stroke prevention. Details: Epidemiological research has found that people with a higher intake of vitamin B12 from dietary sources do not have a reduced risk of ischemic or hemorrhagic stroke (14316). A number of clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with cardiovascular disease (CVD) or impaired kidney function (11387,13482,50420,50423,83050,90379,90380,96150). However, a more recent meta-analysis of 10 clinical trials including over 44,000 patients shows that B vitamin supplementation modestly reduces the relative risk of stroke by 10% when compared with placebo in patients at risk or with a history of CVD (97619). This meta-analysis differed from some of the earlier analyses due to the inclusion of several additional clinical trials. Also, a meta-analysis in adults with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and vascular death by 11% when compared with placebo (107136). In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Unfortunately, even after the publication of higher quality research, it is still unclear which specific combination of B vitamins is optimal and which patients are most likely to benefit. One network meta-analysis suggests that a combination of folic acid and vitamin B6 lowers the risk of stroke more effectively than B vitamin mixtures that include vitamin B12 (96165). However, this analysis is limited because it didn't account for dosing. Another meta-analysis suggests that exposure to low, but not high, amounts of vitamin B12 (cyanocobalamin) seems to reduce stroke risk (96150).
• Tinnitus. It is unclear if intramuscular vitamin B12 is beneficial in patients with tinnitus. Details: A small clinical study shows that intramuscular vitamin B12 2500 mcg weekly for 6 weeks reduces tinnitus severity by 22% when compared to baseline in patients with chronic tinnitus and vitamin B12 deficiency, but not in patients with normal levels of vitamin B12. Vitamin B12 does not improve pitch or volume in either group of patients (96170). The validity of this finding is limited by the lack of a control group.
• Venous thromboembolism (VTE). It is unclear if oral vitamin B12 is beneficial for preventing VTE. Details: Epidemiological research has found that low levels of vitamin B12 are associated with an increased risk for VTE. However, clinical trials evaluating the use of B vitamins for prevention of VTE have shown conflicting results (90398). More evidence is needed to rate vitamin B12 for these uses.

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LIKELY SAFE ...when used orally and appropriately in amounts commonly found in foods. Bilberry has Generally Recognized As Safe status (GRAS) for use in foods in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes. Bilberry fruit extracts have been used with apparent safety in clinical trials at a dose of up to 160 mg daily for up to 6 months (39,40,8139,9739,14280,35472,35510,35512,103190,104192,104195). A higher bilberry extract dose of 1.4 grams daily has been used with apparent safety for up to 4 weeks (104194). Whole bilberries or bilberry juice have also been consumed with apparent safety in quantities of 100-160 grams daily for up to 35 days (35463,91506).

POSSIBLY UNSAFE ...when the leaves are used orally in high doses or for a prolonged period. Death can occur with chronic use of 1.5 gram/kg daily (2).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in the amounts commonly found in foods. However, there is insufficient reliable information available about the safety of bilberry when used in medicinal amounts during pregnancy and lactation; avoid using.

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POSSIBLY SAFE ...when used orally and appropriately, short-term. Most studies have been small and lasted from a few weeks to 6 months, with usual doses of 50 mg daily (793,1635,2133,3231,4249,4251,4252,4253,4254,4255,9691)(9692,10986,12215,12564,14277,21416,88726,90304,99925). Some studies have also used oral DHEA with apparent safety for 12-24 months (2113,6446,10406,11464,12561,15027,88492). ...when used intravaginally and appropriately. Intravaginal ovules of DHEA 3.25 mg to 13 mg have been safely used for up to 12 weeks (21320,21429,21430). ...when used topically and appropriately. A DHEA cream 1% to 10% has been safely used for up to 12 months (4242,21428).

POSSIBLY UNSAFE ...when used orally in high doses or long-term. There is concern that long-term use or use of amounts that cause higher than normal physiological DHEA levels might increase the risk of prostate cancer (2111,12565), breast cancer (10370,10401,10403), or other hormone-sensitive cancers (6445). In some cases, 50-100 mg daily can produce slightly higher than normal physiological DHEA levels (4249,4251). There is insufficient reliable information available about the safety of using DHEA intravenously or intramuscularly.

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally. DHEA can cause higher than normal androgen levels (2133,4249,4251,4253), which might adversely affect pregnancy or a nursing infant.

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

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

(Read more about RHODIOLA)

LIKELY SAFE ...when used orally, topically, intravenously, intramuscularly, or intranasally and appropriately. Vitamin B12 is generally considered safe, even in large doses (15,1344,1345,1346,1347,1348,2909,6243,7289,7881)(9414,9416,10126,14392,15765,82832,82949,82860,82864,90386)(111551,111554).

PREGNANCY: LIKELY SAFE
when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA for vitamin B12 during pregnancy is 2.6 mcg daily (6243). There is insufficient reliable information available about the safety of larger amounts of vitamin B12 during pregnancy.

LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA of vitamin B12 during lactation is 2.8 mcg daily (6243). There is insufficient reliable information available about the safety of larger amounts of vitamin B12 while breastfeeding.

(Read more about VITAMIN B12)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry fruit extract might increase the risk of bleeding when taken with anticoagulant or antiplatelet drugs.  Details In vitro, animal, and clinical research suggest that anthocyanidin extracts from bilberry can inhibit platelet aggregation (16631,35455,35503,35504,35505).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry leaf or fruit extract may increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Animal research suggests that bilberry leaf extract might have blood glucose-lowering activity (1264). Also, one small clinical trial in patients with type 2 diabetes shows that taking bilberry fruit extract 470 mg as a single dose prior to an oral glucose tolerance test lowers plasma glucose levels when compared with placebo (91507).

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry fruit extract might decrease levels of drugs metabolized by CYP2E1.  Details Animal research shows that exposure to small concentrations of bilberry extract in drinking water for around one month increased CYP2E1 activity by 31%. However, exposure over a 2-month period did not increase CYP2E1 activity (103191). This effect has not been reported in humans.

ERLOTINIB (Tarceva) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry fruit extract might reduce the efficacy of erlotinib.  Details In vitro research suggests that bilberry fruit extract and its constituents, delphinidin and delphinidin-3-O-glucoside, inhibit the activity of erlotinib (97031). This interaction has not been reported in humans.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, DHEA might increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Human and laboratory research show that DHEA and DHEA-S can inhibit platelet aggregation (19109,19127).

ANTIDEPRESSANT DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, DHEA might increase the risk of psychiatric adverse events when used with antidepressants.  Details In a human case report, the use of a selective serotonin reuptake inhibitor (SSRI) with DHEA caused a manic episode (7023). Concern for this interaction may be greater in younger individuals with higher baseline DHEA levels.

AROMATASE INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, DHEA might interfere with the clinical effects of aromatase inhibitors.  Details DHEA is a potent estrogen agonist, which may antagonize the anti-estrogen activity of aromatase inhibitors (10401).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, DHEA might increase the levels of drugs metabolized by CYP3A4.  Details Some preliminary evidence shows that DHEA may inhibit CYP3A4 (1389); however, the clinical significance of this potential interaction is not known.

ESTROGENS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, DHEA might increase the effects and adverse effects of estrogen therapy.  Details DHEA is a precursor to estrogen and androgen and is metabolized into those substances. In clinical research, DHEA supplements increase the levels of these hormones (6012,7614,8593,10986,12651,12564,15027,21321,21323,21324)(21325,21326,21327,21328,21330,21331,21356,21364,21389,21393)(21397,21398,21417,21419,21427,47273,47348,88375,90304). Also, in clinical research, estrogen-progestin oral contraceptives and conjugated estrogens reduce blood levels of DHEA and DHEA-S (21372,21373,21374,21437,21438). The clinical significance of these findings is unclear.

FULVESTRANT (Faslodex) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, DHEA might interfere with the anti-estrogen effects of fulvestrant.  Details DHEA is a potent estrogen agonist (10401). Some research shows that it can overcome the estrogen receptor antagonist action of fulvestrant in estrogen-receptor positive cancer cells (10370).

TAMOXIFEN (Nolvadex) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, DHEA might interfere with the anti-estrogen effects of tamoxifen.  Details DHEA is a potent estrogen agonist. Some research shows that it can overcome the estrogen receptor antagonist activity of tamoxifen in estrogen-receptor positive cancer cells (10370,10403).

TESTOSTERONE Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, DHEA might increase the effects and side effects of testosterone therapy.  Details DHEA is a precursor to estrogen and androgen and is metabolized into those substances. In clinical research, DHEA supplements increase the levels of these hormones (6012,7614,8593,10986,12651,12564,15027,21321,21323,21324)(21325,21326,21327,21328,21330,21331,21356,21364,21389,21393)(21397,21398,21417,21419,21427,47273,47348,88375,90304,99924,99925,104162). The clinical significance of these findings is unclear.

TRIAZOLAM (Halcion) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D DHEA can increase blood levels of triazolam.  Details Administration of DHEA 200 mg daily for two weeks was shown to inhibit the cytochrome P450 3A4 (CYP3A4) metabolism of triazolam. This inhibition appears to be due to DHEA-S, rather than DHEA (1389).

TUBERCULOSIS VACCINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D DHEA might reduce the effectiveness of the tuberculosis vaccine.  Details Animal research shows that high doses of DHEA can reduce the efficacy of the Bacillus Calmette-Guérin (BCG) tuberculosis vaccine (21316).

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

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

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

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

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

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

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

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

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(Read more about VITAMIN B12)

General ...Orally, bilberry fruit, juice, and extracts seem to be well tolerated.
Most Common Adverse Effects:
Orally: Dark-colored stools, flatulence, and gastrointestinal discomfort.

Gastrointestinal ...In one small clinical trial, mild-to-moderate flatulence was reported in 33% of patients taking sieved bilberries and concentrated bilberry juice (91506). However, the patients in this study had ulcerative colitis, and the study lacked a control group, limiting the validity of this finding. In another small clinical study of males with age-related cognitive impairment, temporary adverse gastrointestinal (GI) effects were reported in 13% of patients drinking a combination of bilberry and grape juice. However, the adverse GI effect rate was identical in patients drinking a placebo juice (110641). A post-marketing surveillance report of 2295 patients using bilberry extract (Tegens) found that 1% of patients complained of GI discomfort and less than 1% experienced nausea or heartburn (35500).
Theoretically, fresh bilberry fruit may have laxative effects. One clinical trial noted an increased frequency of bowel movements following the administration of a combination formulation containing aerial agrimony parts, cinnamon quills, powdered bilberry fruit, and slippery elm bark (35462). It is unclear if these effects were due to bilberry, other ingredients, or the combination.

Other ...Orally, bilberry may cause discoloration of feces and the tongue. In one study, a dark-bluish to black discoloration of both the feces and the tongue was observed following consumption of sieved bilberries and concentrated bilberry juice. In one patient, a slight discoloration of the teeth has also been observed (91506). In another study, 50% of patients reported dark green stools after taking bilberry extract 700 mg twice daily for 4 weeks (104194).

(Read more about BILBERRY)

General ...Orally and topically, DHEA seems to be well tolerated when used in typical doses, short-term. However, there is some concern that long-term oral use of DHEA may be linked to a greater risk for cancer.
Most Common Adverse Effects:
Orally: Acne, headache, insomnia, mood changes, and nausea. In females, masculinization symptoms including deepening of the voice, increased size of genitals, irregular menses, oily skin, reduced breast size, and unnatural hair growth. In males, aggression, breast tenderness or enlargement (gynecomastia), urinary urgency, and testicular wasting.
Serious Adverse Effects (Rare):
Orally: Possible increased risk for cardiovascular events and various types of cancer.

Cardiovascular ...Incidences of arrhythmia (21334,47540), chest pain (21332,21333), palpitations (21332,21333,88492), hypertension, and transient ischemic attacks (21353,21354,47300) have been reported. DHEA has also been found to decrease high-density lipoprotein (HDL) levels (21344,21345,21346,21347,21348,21349) and increase triglycerides (21334).

Dermatologic ...Acne has been the most commonly reported adverse effect in human research, particularly in females (2113,2114,4242,7614,7559,12561,12574,21346,21351,21354)(21355,21356,21357,21358,21360,21361,21362,21363,21364,47300)(47355,47409,90304,103185). However, it is generally mild and may be treated by reducing the dose (7559). Incidences of contact dermatitis (47402), acneiform dermatitis (2113), greasy hair and skin (17218,21351,21355,21363,21387,21389,47355), keratosis (47402), skin rash (12574,21361,21363), erythema (21334), scalp itching (17218,21357), and skin spots (21387) have also been reported. Increased hair growth and hirsutism have been noted in several clinical trials, including the development of mild mustache in females (2114,4242,12561,12574,17218,21346,21351,21354,21355,21358) (21361,21362,21363,21370,21387,21389,21415,47300). Increased perspiration and odor have also been reported in human research (17218,21354,21356,21357).

Endocrine ...In postmenopausal patients, high doses of DHEA (1600 mg daily) induced insulin resistance, reportedly due to increased androgen levels that occurred during supplementation (21324).

Gastrointestinal ...Gastrointestinal disturbances such as nausea, diarrhea, and abdominal discomfort have been noted in human research (2111,6098,7559,12574,21348,21358,21386).

Genitourinary ...In older adults, elevated and severe urinary symptoms (as evidenced by scores of more than 20, using the American Urological Association Symptom Index for Benign Prostatic Hyperplasia [International Prostate Symptom Score]) and urinary tract infection were reported (21353). Rare incidences of abnormal menses (2114) and increased discharge (21415) have been reported. DHEA has been associated with hematuria (47300).

Hepatic ...Elevated liver enzymes have been reported following DHEA supplementation (21364,47300). However, an analysis of multiple studies in varied patient populations taking DHEA supplements found no elevations in liver enzymes (107791).

Musculoskeletal ...Incidences of asthenia, arthralgia, and myalgia, including calf cramps, have been reported (12574,21354,21358,21365,47355).

Neurologic/CNS ...In humans, dizziness, fatigue, malaise, sleep disturbances, increased dreaming, night sweats, restlessness, "painful spots," and a crawling scalp sensation have been reported (3865,21354,21363,21389). There is a case of seizure associated with DHEA use in a 30 year-old female with fragile X syndrome and no history of convulsive disorder who used DHEA to try to improve ovarian production (47344).

Ocular/Otic ...In patients with Sjögren syndrome, maculae lesions, ocular pain and dryness, and painful eye exams have been reported (21358,21363,21365).

Oncologic ...Preclinical research suggests that DHEA may increase the risk of cancer, particularly prostate, liver, breast, and pancreatic cancers (2111,10370,10401,10403,12565,21332,21333,21334,47251,47256)(47366,47388,47539). High concentrations of DHEA in postmenopausal patients have been associated with an increased risk of breast cancer (2115,6445).

Psychiatric ...DHEA-induced mania has been reported (5870,6102,7023,21383). Clinical studies have also reported anxiety, nervousness, irritability, emotional change, and depression in patients receiving DHEA (2114,21358,21360,21370).

Pulmonary/Respiratory ...Increased cough and nasal congestion have been noted in human research (3865,11334). A report of acute respiratory failure was made in clinical study evaluating the use of DHEA in patients with myotonic dystrophy (type 1) (21334).

Other ...Perceived increases in weight gain have been reported with use of DHEA (2114,21361).

(Read more about DHEA)

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

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

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

(Read more about RHODIOLA)

General ...Orally, intramuscularly, and topically, vitamin B12 is generally well-tolerated.
Most Common Adverse Effects:
Intramuscular: Injection site reactions.
Serious Adverse Effects (Rare):
Intramuscularly: Severe hypokalemia has been rarely linked with correction of megaloblastic anemia with vitamin B12.

Cardiovascular ...In human clinical research, an intravenous loading dose of folic acid, vitamin B6, and vitamin B12, followed by daily oral administration after coronary stenting, increased restenosis rates (12150). Hypertension following intravenous administration of hydroxocobalamin has been reported in human research (82870,82864).

Dermatologic ...Orally or intramuscularly, vitamin B12 can cause allergic reaction such as rash, pruritus, erythema, and urticaria. Theoretically, allergic reactions might be caused by the cobalt within the vitamin B12 molecule (82864,90373,90381,103974). In one case report, oral methylcobalamin resulted in contact dermatitis in a 59-year-old Japanese woman with a cobalt allergy (103974). Vitamin B12 (intramuscular or oral) has also been associated with at least 19 cases of acneiform eruptions which resolved upon discontinuation of vitamin B12 (90365,90369,90388). High-dose vitamin B12 (20 mcg daily) and vitamin B6 (80 mg daily) have been associated with cases of rosacea fulminans characterized by intense erythema with nodules, papules, and pustules. Symptoms may last up to four months after the supplement is stopped and can be treated with systemic corticosteroids and topical therapy (10998,82870,82871).

Gastrointestinal ...Intravenously, vitamin B12 (hydroxocobalamin) 2. 5-10 grams can cause nausea and dysphagia (82864).

Genitourinary ...Intravenously, vitamin B12 (hydroxocobalamin) 5-15 grams has been associated with chromaturia in clinical research (82870,82871).

Hematologic ...According to case report data, the correction of megaloblastic anemia with vitamin B12 may result in fatal hypokalemia (82914).

Musculoskeletal ...According to case report data, correction of megaloblastic anemia with vitamin B12 has precipitated gout in susceptible individuals (82879).

Neurologic/CNS ...Treatment with vitamin B12 has been rarely associated with involuntary movements in infants with vitamin B12 deficiency (90370,90385,90397). In some cases these adverse reactions were misdiagnosed as seizures or infantile tremor syndrome (90370,90385). These adverse reactions presented 2-5 days after treatment with vitamin B12 and resolved once vitamin B12 was discontinued (90370,90385,90397).

Oncologic ...Although some epidemiological research disagrees (9454), most research has found that elevated plasma levels of vitamin B12 are associated with an increased risk of various types of cancer, including lung and prostate cancers and solid tumors (50411,102383,107743). One study found, when compared with blood levels of vitamin B12 less than 1000 ng/mL, plasma vitamin B12 levels of at least 1000 ng/mL was strongly associated with the occurrence of solid cancer (107743). It is unclear if increased intake of vitamin B12, either through the diet or supplementation, directly affects the risk of cancer. It is possible that having cancer increases the risk of vitamin B12 elevation. However, one observational study has found that the highest quintile of dietary intake of vitamin B12 is associated with a 75% increased incidence of developing esophageal cancer when compared with the lowest quintile in never drinkers, but not drinkers (107147).

Renal ...There is a case report of oxalate nephropathy in a 54-year-old male which was determined to be related to the use of intravenous hydroxocobalamin as treatment for cyanide poisoning. Intermittent hemodialysis was started 5 days after admission, along with a low-oxalate diet, oral calcium acetate, and pyridoxine 5 mg/kg daily (107148). A review of the use of intravenous hydroxocobalamin for suspected cyanide poisoning in 21 intensive care units in France between 2011 and 2017 resulted in a 60% increased odds of acute kidney injury and a 77% increased odds of severe acute kidney injury in the first week. However, biopsies were not conducted and a direct link with use of hydroxocobalamin could not be made (107139).

Other ...Several studies have found that higher vitamin B12 levels may be associated with increased mortality or decreased survival rates in hospitalized elderly patients (82889,82812,82857,82895). Human research has also found a positive correlation between vitamin B12 status and all-cause mortality in Pima Indians with diabetes (82863).

(Read more about VITAMIN B12)