Neurologix by Integrative Therapeutics

POSSIBLY EFFECTIVE

• Age-related cognitive decline. Clinical research in elderly patients shows that taking oral or intravenous citicoline daily improves some memory scores, short-term. Details: Several small clinical studies in people 50-85 years of age with age-related cognitive decline shows that taking citicoline 500-2000 mg daily, either orally or by intravenous infusion, for up to 12 weeks moderately improves memory scores when compared with placebo (12130,12131,43284,109016). Citicoline consistently improves short-term recall and verbal memory, but the effects on other domains are less clear (12130,12131,43284). In one clinical study, a specific citicoline product (Cognizin, Kyowa Hakko) 500 mg daily for 12 weeks was used (109016).
• Glaucoma. Clinical research shows that oral, intramuscular, or ophthalmic citicoline may improve vision or slow the rate of vision loss in patients with glaucoma. However, these different routes of administration have not been directly compared. Details: Preliminary clinical research in adults with open-angle glaucoma shows that taking citicoline 1600 mg orally daily for 60 days improves visual evoked potentials, but not intraocular pressure (IOP), when compared with baseline (43256). Other preliminary clinical research in patients with rapidly progressing glaucoma shows that taking a specific citicoline product (Neukron Ofta, Omikron), 500 mg orally daily for 4 four-month cycles over the course of 2 years, reduces the rate of visual field loss when compared with baseline (98448). The validity of both of these studies is limited by the lack of a comparator group. Small clinical studies in adults with open-angle glaucoma also show that treatment with intramuscular citicoline 1000 mg daily for 60 days improves visual evoked potentials, but not IOP, when compared with placebo or baseline (12173,43219,43256). Also, one clinical study shows that using a specific citicoline 2% eye drop (OMK1, Omicron) three times a day for 3 years reduces the loss of retinal nerve fibers and decreases visual field progression rates in patients with open-angle glaucoma and controlled IOP when compared with placebo (104827). Citicoline has also been used as part of a combination product. Preliminary clinical research in adults with primary open-angle glaucoma and controlled IOP shows that taking citicoline 500 mg, homotaurine 50 mg, and vitamin E 12 mg orally once daily for 4 months improves visual contrast sensitivity scores by less than 10% and self-reported quality of life scores by about 10% when compared with no additional interventions (104786). It is unclear if these effects are clinically relevant or if they are due to citicoline, other ingredients, or the combination.

POSSIBLY INEFFECTIVE

• Stroke. Oral or intravenous citicoline, started within 12-24 hours of onset of ischemic stroke symptoms, does not seem to improve outcomes in most patients. However, it may be modestly beneficial in those who are not candidates for recombinant tissue plasminogen activator (rtPA). Details: A meta-analysis of 10 trials shows that treatment with oral or intravenous citicoline 500-2000 mg daily for up to 6 weeks after ischemic stroke does not improve mortality, ability to complete activities of daily living, or neurologic function when compared with placebo or no intervention (104828). A different meta-analysis of 10 trials shows that treatment with oral or intravenous citicoline 250-2000 mg daily for up to 6 weeks after ischemic stroke increases the odds of recovery to independence by 56% and decreases the mortality rate and long-term disability by 10-12% when compared with placebo. However, this second meta-analysis included older, lower-quality trials in which the standard of care with conventional medicines was lower and ischemic stroke diagnoses were not confirmed via imaging (98228). Higher-quality trials have not confirmed these benefits, especially when patients receive early treatment with rtPA (98228,104828). A third meta-analysis of 7 trials with more limited inclusion criteria also did not demonstrate benefit on mortality or functional independence when compared with control (98447). Also, a large clinical trial of patients with moderate to severe acute ischemic stroke who received standard of care stroke management, including rtPA when indicated, shows that citicoline 1000 mg, administered intravenously over 30-60 minutes every 12 hours for 3 days and started within 24 hours of symptom onset, does not increase the rate of recovery at 90 days when compared with placebo (98444).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. It is unclear if oral citicoline is beneficial in patients with Alzheimer disease. Details: Preliminary clinical research in adults with Alzheimer disease shows that taking citicoline 1000 mg orally daily for 12 weeks modestly improves cognitive function scores when compared with placebo (43222). Observational research in adults with Alzheimer disease has also found that taking citicoline 1000 mg orally in conjunction with memantine and rivastigmine for up to 12 months is associated with clinically non-significant improvements in cognitive function scores when compared with memantine and rivastigmine alone. In addition, taking citicoline was not associated with improvement in depression scores or activities of daily living (105730).
• Amblyopia. It is unclear if oral or intramuscular citicoline is beneficial in patients with amblyopia. Details: Preliminary clinical research in children with amblyopia shows that taking citicoline orally once daily, in combination with covering the affected eye with a patch, for 12 months moderately improves visual acuity when compared with the patch alone. Children aged less than 5 years took 250 mg daily and children aged 5-13 years took 500 mg daily (98442). Retrospective research in children aged 5-6 years with amblyopia has also found that citicoline treatment for up to 8 months is associated with modest improvements in visual acuity when compared with baseline. However, preliminary subgroup analyses suggest that benefits may not last longer than 3-4 months (109017). Preliminary clinical research in older patients with amblyopia, aged 9-37 years, shows that treatment with intramuscular citicoline 1000 mg daily for 15 days improves visual acuity in both eyes for 92% of patients when compared with baseline (43281). The validity of this study is limited by the lack of a comparator group.
• Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral citicoline for ADHD, there is insufficient reliable information about the clinical effects of citicoline for this purpose.
• Bipolar disorder. It is unclear if oral citicoline is beneficial in patients with bipolar disorder. Details: Preliminary clinical research in adults with bipolar disorder and cocaine dependence shows that taking citicoline orally for 12 weeks improves verbal learning scores, but not symptoms of depression or mania, when compared with placebo. Citicoline was titrated from 500 mg daily to 2000 mg daily over the first 6 weeks and then continued at 2000 mg daily for 6 weeks (43248).
• Cardiac arrest. It is unclear if intravenous citicoline can improve outcomes in children with cardiac arrest. Details: A small clinical study in children 1-12 years of age with successful resuscitation from cardiac arrest shows that using citicoline 10 mg/kg intravenously every 12 hours for 6 weeks improves disability and coma scores at 12 weeks when compared with no intervention. This study also suggests that using citicoline reduces mortality by 80% and duration of hospitalization by 12% when compared with no intervention (105729). However, the small size of this study limits the reliability of these findings.
• Cerebrovascular disease. It is unclear if oral, intramuscular, or intravenous citicoline is beneficial in patients with cerebrovascular disease. Details: Several small clinical trials in adults with chronic cerebrovascular disease shows that treatment with citicoline 600-1000 mg orally daily for up to 12 months or 600-1000 mg intramuscularly or intravenously daily for up to 12 weeks moderately improves memory and behavior scores when compared with placebo or no intervention (12131,43240,43288,98443). One of these clinical trials failed to show improvement in activities of daily living, although the study may have been inadequately powered to detect a difference between groups (98443).
• Cocaine dependence. It is unclear if oral citicoline is beneficial in patients with cocaine dependence. Details: Preliminary clinical research in adults with cocaine dependence and bipolar disorder shows that taking citicoline orally for 12 weeks reduces the likelihood of positive urine cocaine test results when compared with placebo. Citicoline was titrated from 500 mg daily to 2000 mg daily over the first 6 weeks and then continued at 2000 mg daily for 6 weeks (43248). However, a post-hoc analysis suggests that the effects of citicoline on abstaining from cocaine use decline over time and were no different than placebo in the last weeks of the study (98230). In addition, other clinical research in adults with cocaine dependence that also received weekly counseling shows that taking citicoline 500 mg orally twice daily for 8 weeks does not reduce cocaine craving or consumption levels when compared with placebo (98445).
• Delirium. Although there has been interest in using oral citicoline for delirium, there is insufficient reliable information about the clinical effects of citicoline for this purpose.
• Depression. It is unclear if oral citicoline is beneficial in patients with depression. Details: Preliminary clinical research in patients with major depressive disorder shows that adding citicoline 100 mg orally twice daily for 6 weeks to citalopram therapy improves symptoms of depression, as measured by the Hamilton Depression Rating Scale, and increases the relative rate of remission by 64% when compared with placebo. These results suggest that for every 4 patients treated with citicoline, remission is expected in one additional patient (98446).
• Diabetic retinopathy. Citicoline eye drops have only been evaluated in combination with other ingredients; the effect of citicoline when used alone is unclear. Details: Preliminary clinical research in patients with mild diabetic retinopathy shows that using a specific ophthalmic solution containing citicoline 2% and cyanocobalamin 0.05% (OMK2, Omikron Italia) three times a day for 3 years decreases visual field progression rates and stabilizes retinal nerve fiber thickness when compared with placebo (104825).
• Intracranial hemorrhage. It is unclear if intravenous citicoline is beneficial in patients with intracranial hemorrhage. Details: Preliminary clinical research in patients with non-traumatic intracerebral hemorrhage shows that using citicoline 250 mg intravenously twice daily for 14 days improves muscular strength by 25% when compared with placebo (43252).
• Ischemic optic neuropathy. It is unclear if oral citicoline is beneficial in patients with ischemic optic neuropathy. Details: Preliminary clinical research in patients with non-arteritic ischemic optic neuropathy shows that taking a specific type of citicoline (Cebrolux-Tubilux) 1600 mg orally daily for 60 days improves visual acuity and visual evoked potentials when compared with no intervention (43250).
• Methamphetamine use disorder. It is unclear if oral citicoline is beneficial in patients with methamphetamine use disorder. Details: Preliminary clinical research in adults with methamphetamine dependence shows that taking citicoline 1000 mg orally twice daily for 8 weeks reduces the severity of cravings when compared with baseline, but not when compared with placebo. Taking citicoline also did not reduce the number of methamphetamine positive urine samples when compared with placebo (109015). This study may have been inadequately powered to detect a difference between groups.
• Parkinson disease. It is unclear if oral or intramuscular citicoline is beneficial in patients with Parkinson disease. Details: Preliminary clinical research shows that taking citicoline 1200 mg orally daily for one month improves Parkinson disease symptom scores when compared with no intervention (43259). Other preliminary clinical research in adults with Parkinson disease shows that treatment with citicoline 500 mg orally daily or citicoline 500-1000 mg intramuscularly daily for 30 days improves rigidity and bradykinesia scores, but not tremor scores, when compared with baseline (43253,43262). The validity of these studies is limited by the lack of a comparator group.
• Schizophrenia. It is unclear if oral citicoline is beneficial in patients with schizophrenia. Details: Preliminary clinical research in patients with chronic, stable schizophrenia shows that taking citicoline 1250 mg twice daily for 8 weeks as an add-on to risperidone therapy modestly reduces negative symptoms, but not positive symptoms, of schizophrenia when compared with placebo plus risperidone (100988). Other preliminary clinical research in patients with chronic, stable schizophrenia shows that taking citicoline 500 mg, 1000 mg, or 2000 mg as a single dose does not improve sensory gating when compared with placebo (100987). However, both studies may have been inadequately powered to detect a difference between groups.
• Traumatic brain injury (TBI). It is unclear if oral citicoline is beneficial in patients with TBI; the available research is conflicting. Details: A meta-analysis of 5 low-quality studies in patients with TBI shows that treatment with oral or intravenous citicoline up to 2000 mg daily for up to 9 days does not improve Glasgow outcome scores or cognitive performance. Additionally, one study included in this analysis showed no improvement in survival with citicoline when compared with placebo (98227). However, a very small clinical study not included in this analysis shows that taking citicoline 1000 mg orally daily improves memory, learning, and verbal ability in patients with TBI (43287). Some observational research has found that continuous intravenous infusion of citicoline 3000 mg over 24 hours for up to 21 days is associated with 6.7-fold greater odds of survival while in the intensive care unit (ICU) when compared with matched controls not receiving citicoline. Citicoline therapy was also linked to 2.6-fold greater odds of having a favorable outcome after 6 months, defined as a score of 5-8 on the extended version of the Glasgow Outcome Scale (100989). The discrepant results may be explained by differences in the severity of TBI at baseline and the doses of citicoline used in these studies.
• Vascular dementia. It is unclear if oral citicoline is beneficial in patients with vascular dementia. Details: Preliminary clinical research in adults with vascular dementia shows that taking citicoline 500 mg orally twice daily for 12 months does not improve neuropsychological symptom scores when compared with placebo (12135). More evidence is needed to rate citicoline for these uses.

(Read more about CITICOLINE)

POSSIBLY EFFECTIVE

• Alzheimer disease. Oral saffron might modestly improve cognition in patients with Alzheimer disease. Details: Two small clinical trials in patients with probable Alzheimer disease living in Iran shows that taking saffron extract (Green Plants of Life, Co., previously Impiran) 15 mg orally twice daily for 16-22 weeks improves cognitive ability and disease progression when compared with placebo, and is no different for improving cognition when compared with taking donepezil (Aricept) 10 mg daily (17401,93395). Another small clinical study in adults also living in Iran with moderate to severe Alzheimer disease shows that taking saffron extract 30 mg daily for 48 weeks seems to be no different for improving cognition when compared with taking memantine (Namenda) 20 mg (105617). It is unclear if these findings are generalizable to patients in other geographic locations.
• Chemotherapy-induced peripheral neuropathy. Oral saffron seems to improve symptoms of chemotherapy-induced peripheral neuropathy, although it is unclear how it compares with standard care. Details: A clinical crossover study in adults with mild to severe chemotherapy-induced peripheral neuropathy shows that taking the saffron constituent crocin 15 mg twice daily for 8 weeks progressively improves pain scores when compared with placebo, with significant improvements appearing after 5 weeks of treatment. During a 2-week washout period, pain scores in the treatment group returned to baseline, suggesting a loss of benefit after discontinuation. This study included patients who were actively receiving chemotherapy and those who had completed or discontinued treatment; however, a separate analysis for each subgroup was not conducted (108904).
• Depression. Oral saffron extract seems to improve symptoms of depression when used alone or as an adjunct to conventional antidepressants. Details: Meta-analyses and clinical trials in adults with mild to moderate major depressive disorder show that taking saffron extract 30 mg daily or dried saffron stigma 100 mg daily for 6-12 weeks improves symptoms of depression when compared with control (11024,13103,72434,93399,93404,100140,103928,103931). Saffron extract also seems to be comparable to imipramine 100 mg daily, fluoxetine 10 mg twice daily, citalopram 40 mg daily, or sertraline 100 mg daily (11024,17222,19032,93399,100140,100658,103927). Furthermore, some clinical research shows that taking a specific saffron extract (affron, Pharmactive Biotech Products) 14 mg twice daily for 8 weeks or the saffron constituent, crocin, 15 mg twice daily for 4 weeks, as an adjunct to a selective serotonin reuptake inhibitor (SSRI) also modestly reduces depressive symptoms when compared with placebo (93410,103934). However, other research has produced mixed results, which may be due to the use of different depression scales. An umbrella meta-analysis consisting of 7 separate meta-analyses shows that taking saffron, either alone or with other treatments, improves symptoms of depression when compared with control in studies using the Beck depression inventory criteria, but not in those using the Hamilton depression rating scale, the depression anxiety stress scale, or mixed scales (108911). In general, the validity of the available research is limited by the variety of saffron doses and treatment durations, as well as the fact that most research has been conducted in Iran. It is unclear if saffron is beneficial for comorbid depression and anxiety. A small clinical trial in adults with this condition shows that taking saffron extract 15 mg twice daily for 8 weeks does not improve symptoms of depression, but does improve symptoms of anxiety, when compared with placebo (100137). This study may not have been adequately powered to detect smaller differences between groups. Saffron has also been studied in combination with other ingredients. One clinical trial in adults with major depressive disorder shows that taking saffron 15 mg twice daily in combination with curcumin 250 mg twice daily for 12 weeks does not reduce depressive symptoms when compared with placebo (97359). The validity of this finding may be limited by the large placebo response.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). Small studies suggest that oral saffron might slightly improve visual acuity in AMD. Details: Preliminary clinical research in adults 50 years and older with AMD shows that taking saffron extract 20 mg daily for 3 months has a modest effect on visual acuity and some other measurements of retinal health when compared with placebo. This improvement occurred in patients also taking Age-Related Eye Diseases Study (AREDS) supplements or equivalent. However, these small improvements are unlikely to be considered clinically significant (93398,100135).
• Antidepressant-induced sexual dysfunction. Small studies suggest that oral saffron may reduce some symptoms of fluoxetine-induced sexual dysfunction. Details: One small clinical study in females with major depression stabilized on fluoxetine 40 mg daily shows that taking saffron extract 30 mg daily for 4 weeks improves arousal, lubrication, and pain during sexual intercourse when compared with placebo (93401). A small clinical study in males with major depression stabilized on fluoxetine 40 mg daily shows that taking saffron extract 30 mg daily improves erectile dysfunction and intercourse satisfaction when compared with placebo (93407). However, taking saffron does not appear to significantly improve desire, overall satisfaction, or orgasm in patients taking fluoxetine (93401,93407).
• Antipsychotic-induced metabolic side effects. It is unclear if oral saffron reduces metabolic side effects from antipsychotic treatment. Details: A small clinical study in adults with schizophrenia who are taking olanzapine shows that taking saffron aqueous extract 30 mg daily for 12 weeks, or crocin, a constituent of saffron, 30 mg daily for 6 weeks, reduces fasting blood glucose and the risk of developing metabolic syndrome. At 6 weeks, metabolic syndrome occurred in 0% of patients taking saffron, about 9% of patients taking crocin, and about 27% of patients taking placebo. Levels of cholesterol, HBA1c, and insulin were unchanged (93397).
• Anxiety. Small clinical studies suggest that oral saffron might improve anxiety. Details: One preliminary clinical study in adults with type 2 diabetes and comorbid depression-anxiety (CDA) shows that taking saffron extract 15 mg twice daily for 8 weeks improves symptoms of anxiety by 34% when compared with placebo (100137). Other preliminary clinical research in adults with mild to moderate anxiety shows that taking saffron extract 50 mg twice daily for 12 weeks improves symptoms of anxiety by 81%, compared with an improvement of 53% with placebo (93404).
• Asthma. There is limited evidence on the oral use of saffron in patients with allergic asthma. Details: A small clinical study in patients with mild to moderate allergic asthma shows that taking saffron extract 100 mg daily for 8 weeks improves symptoms of asthma, but not asthma severity, when compared with placebo. The use of salbutamol was reduced by approximately 50% in patients taking saffron. Saffron also produced modest improvements in waking during the night due to asthma symptoms, shortness of breath during the night, and activity limitation (100141). However, due to the low rate of symptoms at baseline, it is difficult to determine if these improvements are clinically significant.
• Athletic performance. It is unclear if oral saffron is beneficial for athletic performance. Details: A small clinical study in healthy, untrained, young adult males shows that taking dried saffron stigma powder 300 mg every evening for 10 days improves muscular force by up to 10% and might improve reaction time when compared with placebo (93406). A very small clinical study in healthy adults suggests that taking crocetin, a constituent of saffron, 15 mg daily for 8 days might improve performance on a 3.5-hour physically exhausting task in males, but not in females, when compared with placebo (19058).
• Burning mouth syndrome. It is unclear if oral saffron reduces burning mouth syndrome. Details: A very small clinical study in patients with burning mouth syndrome shows that taking the saffron constituent crocin 15 mg daily for 11 weeks seems to reduce pain to a similar degree as citalopram 20 mg daily (103937).
• Cancer. Although there is interest in using oral saffron for cancer, there is insufficient reliable information about the clinical effects of saffron for this condition.
• Cough. Although there is interest in using oral saffron for cough, there is insufficient reliable information about the clinical effects of saffron for this purpose.
• Diabetes. Research evaluating oral saffron for glycemic control is conflicting. Details: Some clinical research in patients with type 2 diabetes shows that taking saffron extract 30 mg daily, saffron powder 100 mg daily, or drinking black tea stewed with saffron powder 1 gram three times daily, for 2-3 months, does not improve glycated hemoglobin (HbA1c), but might modestly reduce fasting blood glucose, when compared with placebo (99436,100138,103936,108905). The validity of these findings is limited due to differences in glycemic control at baseline and differences in the dose and form of saffron used. A meta-analysis of clinical trials shows that taking saffron, saffron extract, or the constituent crocin for up to 3 months does not improve levels of fasting blood glucose, blood lipids, or HbA1c when compared with placebo or control. However, this research included healthy individuals, as well as patients with type 2 diabetes, metabolic syndrome, coronary artery disease (CAD), schizophrenia, or depression (100139). Patients with type 2 diabetes were not analyzed separately, limiting the applicability of this finding.
• Dysmenorrhea. Oral saffron has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in students with dysmenorrhea shows that taking a specific combination product containing saffron, celery seed, and anise extracts (SCA, Gol Daro Herbal Medicine Laboratory) 500 mg three times daily for 3 days reduces the severity and duration of menstrual pain when compared with placebo (17214).
• Erectile dysfunction (ED). It is unclear if oral or topical saffron improves ED; the available research is conflicting. Details: Preliminary clinical research in adults with diabetes and ED shows that applying a gel containing saffron 1% to the penis 30 minutes prior to intercourse for one month improves general symptoms when compared with placebo. ED, sexual desire, and orgasmic function improved by 37%, 14%, and 21%, respectively, for those using saffron gel compared to 2%, 2%, and 0%, respectively, for those in the placebo group (93408). A small, open-label study has also shown benefit with dried oral saffron 200 mg daily for 10 days (19057). However, in adults with ED who are naïve to treatment, one small clinical study shows that taking saffron extract 30 mg twice daily by mouth for 12 weeks does not improve symptoms when compared to baseline (93409). These conflicting results may be related to the cause of ED, as well as the route, dose, and form of saffron used.
• Exercise-induced muscle soreness. It is unclear if oral saffron reduces muscle soreness from exercise. Details: Preliminary clinical research in healthy but exercise-naïve young adult males shows that taking dried saffron powder 300 mg every evening for 10 days, starting one week before a leg press exercise, reduces delayed muscle soreness about 11-fold when compared with placebo. Saffron appears to be more effective than indomethacin for reducing pain and maintaining muscle force during the 72-hour period post-exercise (93405).
• Glaucoma. It is unclear if oral saffron reduces intraocular pressure in patients with glaucoma. Details: A small clinical study in patients with primary open-angle glaucoma shows that taking saffron extract 30 mg daily for 4 weeks, in conjunction with timolol and dorzolamide, reduces intraocular pressure by an additional 16.5% when compared with placebo. After a 4-week washout, intraocular pressure returned to baseline in the saffron group (93400).
• Hyperlipidemia. Small studies suggest that oral saffron does not affect lipid levels in most patients; the effect of saffron in adults with diagnosed hyperlipidemia is unclear. Details: A meta-analysis of clinical trials shows that taking saffron, saffron extract, or the constituent crocin for up to 3 months does not reduce levels of total cholesterol, low density lipoprotein (LDL) cholesterol, or triglycerides, or increase levels of high-density lipoprotein (HDL) cholesterol when compared with placebo or control. However, patients evaluated in the available clinical research include those with type 2 diabetes, metabolic syndrome, coronary artery disease (CAD), schizophrenia, and depression, as well as healthy or mildly overweight individuals (100139).
• Hypertension. It is unclear if oral saffron reduces blood pressure; the available research is conflicting. Details: Preliminary clinical research shows that drinking black tea containing saffron 1 gram three times daily for 8 weeks does not reduce blood pressure in patients with diabetes and elevated systolic blood pressure (96669). However, another small clinical study in males with hypertension shows that taking saffron stigma 200 mg daily for 12 weeks seems to reduce blood pressure when compared with no intervention (105618).
• Impaired glucose tolerance (prediabetes). It is unclear if oral saffron improves glycemic control in adults with prediabetes. Details: A small clinical study in patients with prediabetes and obesity shows that taking saffron extract 15 mg daily for 2 months modestly reduces fasting blood glucose and glycated hemoglobin (HbA1c) when compared with placebo (103933). It is unclear if this small improvement in glycemic control is maintained after 2 months.
• Insomnia. It is unclear if oral saffron is beneficial for reducing sleep problems and improving sleep quality in healthy adults or those with underlying medical conditions. Details: A small clinical study in patients with self-reported sleep problems shows that taking a specific saffron extract (affron, Pharmactive Biotech Products) 14 mg twice daily for 4 weeks reduces insomnia, improves sleep quality, and increases restorative sleep when compared with placebo (103935). Another small clinical study in a similar population shows that taking this same product as 14 mg or 28 mg one hour before bedtime for 4 weeks reduces insomnia and improves sleep quality when compared with placebo, with no observed differences between dosage groups (108908). However, a small clinical study in adults with mild to moderate insomnia and anxiety shows that taking a different saffron extract (Saffr'activ SAF 3C PIM, Comercial Quimica Massó) 15.5 mg daily for 6 weeks improves most sleep quality parameters when compared with baseline, but not when compared with placebo (105624). All studies were funded by the supplement manufacturer, which may limit the validity of these findings. A meta-analysis of clinical research evaluating saffron for sleep in a variety of populations, including healthy patients, those with insomnia or type 2 diabetes, or individuals receiving methadone maintenance treatment, suggests that taking saffron or the constituent crocin improves sleep quality when compared with placebo (108912). Furthermore, a small clinical study in patients with type 2 diabetes with overweight or obesity shows that taking saffron 100 mg daily for 8 weeks improves global Pittsburgh Sleep Quality Index (PSQI) scores when compared with placebo (108905).
• Labor pain. Although there is interest in using oral saffron to reduce labor pain, there is insufficient reliable information about the clinical effects of saffron for this purpose.
• Male infertility. It is unclear if oral saffron is beneficial for improving sperm parameters in males with infertility. Details: Clinical research in males under 45 years of age with oligoasthenoteratozoospermia shows that taking a saffron extract 30 mg orally twice daily for 26 weeks does not increase sperm motility, density, or morphology when compared with placebo (18102). Other preliminary clinical research in males with idiopathic infertility shows that taking saffron 50 mg three times each week for 3 months improves sperm motility and morphology, but not sperm count, when compared to baseline (19033). These conflicting outcomes may be related to the cause of infertility, as well as the dose and form of saffron used.
• Menopausal symptoms. It is unclear if oral saffron reduces menopausal symptoms. Details: A small clinical study in patients with menopausal symptoms shows that taking a specific saffron stigma extract (affron, Pharmactive Biotech Products) 14 mg twice daily for 12 weeks improves symptoms of depression and anxiety, but not vasomotor symptoms such as hot flashes, when compared with placebo (105622). Saffron has also been evaluated in combination with other ingredients. A small clinical study in patients with menopausal symptoms shows that taking a combination of saffron 60 mg, fennel 120 mg, and chamomile 1000 mg daily for 12 weeks modestly reduces physical, psychological, and urogenital symptom scores on the Menopause Rating Scale when compared with either placebo or lower doses of this combination (103628). The validity of this study is limited by unclear reporting of results. Also, it is unclear if reported benefits are due to saffron, other ingredients, or the combination.
• Multiple sclerosis-related fatigue. It is unclear if oral saffron reduces symptoms of fatigue in patients with multiple sclerosis. Details: A small clinical study in patients with MS shows that taking one tablespoon of simple syrup containing saffron extract 0.5% every 8 hours for two months reduces fatigue when compared with baseline (103930). The validity of this finding is limited by the lack of a comparator group.
• Obsessive-compulsive disorder (OCD). It is unclear if oral saffron reduces symptoms of opioid withdrawal. Details: A small clinical study in adults with OCD shows that taking crocin, a constituent of saffron, 15 mg daily for 8 weeks reduces symptoms when compared with baseline, but is no better than fluoxetine 20 mg daily (105620). This finding is limited due to small study size and the subjectivity of outcome measures.
• Opioid withdrawal. It is unclear if oral saffron is beneficial for opioid withdrawal; the available research is conflicting. Details: A small clinical study in adults receiving treatment with methadone for opioid abuse shows that taking crocin, a constituent of saffron, 30 mg daily for 12 weeks modestly reduces cravings and withdrawal symptoms when compared with placebo (105616). Conversely, a small clinical study in patients with opioid dependence shows that taking a specific product (Krocina) containing crocin, a constituent of saffron, 15 mg twice daily for 6 weeks in addition to motivational counseling does not improve withdrawal symptoms, cravings, depression, anxiety, or stress during the detoxification or abstinence phase (108913). The reason for these conflicting findings is unclear but may be related to the differences in adjunctive treatments between studies.
• Postpartum depression. It is unclear if oral saffron is beneficial for speeding recovery from postpartum depression. Details: Preliminary clinical research in patients experiencing symptoms of depression less than 12 weeks after giving birth shows that taking saffron 30 mg daily for 6 weeks (SaffroMood, Green Plants of Life Co. Ltd) is as effective as fluoxetine for treating depression. Both treatment groups experienced similar remission and partial response rates (93402). Another preliminary study in breastfeeding Iranian patients with mild to moderate depression shows that taking saffron 15 mg twice daily for 8 weeks improves depressive symptoms by about 50% when compared to baseline (97361). However, it is not clear if the improvement in these studies was related to saffron or the natural resolution of postpartum depression.
• Premenstrual dysphoric disorder (PMDD). It is unclear if oral saffron improves PMDD symptoms. Details: A clinical study in patients with PMDD shows that taking saffron 15 mg twice daily for 14 days prior to menstruation improves patient-rated PMDD symptom severity when compared with placebo, but not when compared with taking fluoxetine 20 mg twice daily (105625).
• Premenstrual syndrome (PMS). It is unclear if oral saffron improves PMS symptoms. Details: A small clinical study in patients aged 20-45 years with PMS shows that taking a specific saffron extract 15 mg twice daily throughout two menstrual cycles improves symptom severity when compared with placebo (16555).
• Psoriasis. Although there is interest in using oral saffron for psoriasis, there is insufficient reliable information about the clinical effects of saffron for this condition.
• Rheumatoid arthritis (RA). It is unclear if oral saffron reduces RA symptoms. Details: A small clinical study in females with RA shows that taking saffron 100 mg daily for 3 months modestly reduces the number of tender and swollen joints and reduces pain when compared with placebo (103932). The validity of this study is limited by its small size and the fact that all clinical parameters were secondary, exploratory outcomes. In contrast, a small clinical study in patients with newly diagnosed RA shows that adding saffron 100 mg daily for 3 months to standard treatment with prednisolone 5 mg daily and methotrexate 7.5 mg once weekly does not improve disease activity or quality of life when compared with placebo and standard treatment (108907). The validity of this finding is limited due to low adherence to treatment protocols.
• Ulcerative colitis. It is unclear if oral saffron reduces ulcerative colitis symptoms. Details: A small clinical study in patients with ulcerative colitis shows that taking saffron extract 100 mg daily for 8 weeks reduces disease activity when compared with placebo (105626). More evidence is needed to rate saffron for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral spearmint extract is beneficial for age-related cognitive decline. Details: A small clinical study in older adults with age-related cognitive decline shows that taking a specific spearmint extract 900 mg daily for 90 days modestly improves quality of working memory, as well as time to sleep, overall mood, and feelings of vigor, when compared with placebo. However, no improvements were seen in attention, overall quality of memory, speed of memory, quality of sleep, or feelings of anxiety, depression, or confusion. Additionally, taking 600 mg daily does not seem to provide benefit (98523).
• Cognitive function. Small clinical studies suggest that oral spearmint extract or spearmint-flavored gum may not improve most measures of cognitive function. Details: One small clinical study in healthy young adults shows that taking a proprietary spearmint extract (Neumentix Phenolic Complex K110-42, Kemin Foods, LC.) 900 mg daily for 90 days modestly improves attention, but not working memory, executive function, speed, reasoning, or other measures of cognitive function, when compared with placebo (101713). Other small clinical studies in healthy adults shows that chewing spearmint-flavored gum during memory testing does not improve memory or attention when compared with chewing unflavored gum (75725,75754).
• Flatulence. Although there has been interest in using oral spearmint for flatulence, there is insufficient reliable information about the clinical effects of spearmint for this purpose.
• Hirsutism. Small clinical studies suggest that drinking spearmint tea may modestly reduce testosterone levels in patients with hirsutism; any effects on hair growth are unclear. Details: A small clinical study in patients with hirsutism associated with polycystic ovary syndrome (PCOS) shows that drinking spearmint tea twice daily for one month can reduce the subjective severity of hirsutism when compared to pretreatment; however, it does not seem to reduce the amount or location of hair based on objective assessment when compared with placebo tea (68500). Any effect of spearmint tea in patients with hirsutism is believed to be related to its antiandrogenic properties. Two small clinical studies in patients with idiopathic hirsutism or hirsutism associated with PCOS show that drinking spearmint tea twice daily for 5-30 days can decrease free testosterone levels and increase levels of luteinizing hormone, estradiol, and follicle-stimulating hormone when compared to baseline (68451,68500).
• Irritable bowel syndrome (IBS). Oral spearmint has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with IBS shows that using 30 drops of a combination product containing lemon balm, spearmint, and coriander (Carmint) three times daily after meals for 8 weeks along with conventional therapy with loperamide or psyllium reduces abdominal pain and discomfort by approximately 81% when compared with conventional therapy alone (19535). It is unclear if these findings are due to spearmint, other ingredients, or the combination.
• Osteoarthritis. It is unclear if drinking spearmint tea is beneficial in patients with knee osteoarthritis. Details: A small clinical study in patients with knee osteoarthritis shows that drinking 2 cups of spearmint tea daily for 16 weeks reduces pain and stiffness when compared to baseline (94923). The validity of these findings is limited by a lack of control group.
• Postoperative nausea and vomiting (PONV). Aromatherapy with spearmint oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study in patients reporting nausea after surgery shows that inhaling vapors from a mixture of spearmint, peppermint, ginger, and cardamom essential oils reduces symptoms of postoperative nausea in approximately 15% more patients when compared with inhaling ginger essential oils alone, and in about 43% more patients when compared with inhaling saline (89888). It is unclear if these findings are due to spearmint oil, other ingredients, or the combination. More evidence is needed to rate spearmint for these uses.

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EFFECTIVE

• Pyridoxine-dependent epilepsy. Intravenous vitamin B6 is effective for controlling pyridoxine-dependent seizures. Details: Pyridoxine-dependent seizures are a rare type of refractory seizures in neonates that do not respond to anticonvulsant drugs. These seizures are typically controlled within minutes of intravenous administration of pyridoxine, a form of vitamin B6. Pyridoxine-dependent seizures can be due to genetic (autosomal recessive) pyridoxine dependency, or more commonly, a result of the use of high-dose pyridoxine during pregnancy (8197,8198).
• Sideroblastic anemia. Oral vitamin B6 is effective for treating hereditary sideroblastic anemia. Details: Taking vitamin B6 (pyridoxine) orally is effective for treating hereditary sideroblastic anemia (15,9518). Taking the active form of vitamin B6 (pyridoxal-5'-phosphate) also seems to be effective in cases in which the patient does not respond to pyridoxine (93049).
• Vitamin B6 deficiency. Oral vitamin B6 is effective for preventing and treating vitamin B6 deficiency. Details: Taking oral vitamin B6 can prevent and treat vitamin B6 deficiency (15).

LIKELY EFFECTIVE

• Hyperhomocysteinemia. Taking vitamin B6 orally, alone or in combination with folic acid, is effective for reducing hyperhomocysteinemia. Details: Vitamin B6 (pyridoxine) seems to lower homocysteine concentrations when folic acid and vitamin B12 are at physiologic levels or when given with folic acid and vitamin B12 supplements (9451,83042,107136). A combination of vitamin B6 100 mg and folic acid 0.5 mg daily seems to lower homocysteine levels by about 35% and is recommended for people with postprandial hyperhomocysteinemia (1489,9406). Other research shows that taking pyridoxine 50-200 mg daily reduces postprandial homocysteine levels by 32% to 35% (9406,10350). Pyridoxine also seems to reduce homocysteine levels in patients with kidney failure, kidney transplant patients (1489,6884,9414,9415), or patients who receive general anesthesia with nitrous oxide (9481). However, some research in healthy adults suggests that adding pyridoxine to folic acid might not provide any additional benefit over folic acid alone (9400,9405,9409,50145). Hyperhomocysteinemia is considered by some to be an independent risk factor for atherosclerosis, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, and ischemic stroke (1899,3323,9402,9405,9408,9409). However, 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 (1489,6883,6884,9308,9400,9405,9409). 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 to help with secondary prevention of death or myocardial infarction, and some research even suggests an increase in cardiovascular disease (CVD) risk (11387,13482,50423,83050,97619). There is also 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 renal function (11387,13482,50423,83050,96150). However, a more recent meta-analysis shows that B vitamin supplementation modestly reduces the relative risk of stroke by 10% when compared with placebo in patients at risk for or with a history of CVD (97619). Also, a meta-analysis in patients with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136).

POSSIBLY EFFECTIVE

• Antipsychotic-induced hyperprolactinemia. It is unclear if oral vitamin B6 is beneficial for patients with antipsychotic-induced hyperprolactinemia. Details: Clinical research in male patients with hyperprolactinemia who are on a consistent antipsychotic dose shows that taking vitamin B6 300 mg twice daily for 16 weeks reduces serum prolactin levels by 68%, compared with 37% in patients taking aripiprazole 5 mg twice daily. Also, 67% of patients taking vitamin B6 had prolactin levels less than 40 mcg/mL versus 2% of those taking aripiprazole (107128).
• Kidney stones (nephrolithiasis). Oral vitamin B6 seems to decrease urinary oxalate levels and decrease the risk of kidney stone formation in some patients. Details: There is some evidence that taking vitamin B6 (pyridoxine) orally, alone or in combination with magnesium, can decrease urinary oxalate levels in people with type I primary hyperoxaluria, a hereditary disorder (1201,6437,6438,6439,6440,8548,8549,8550). Additionally, a small clinical study in this population suggests that intravenous pyridoxine hydrochloride can reduce urinary oxalate by 25.5% when compared to baseline (90796). In patients with idiopathic hyperoxaluria, taking a combination of pyridoxine 25mg and magnesium oxide 400 mg for 3 months decreases urinary oxalate by approximately 16%, with 68% of patients experiencing a reduction. However, supplementation is less effective than following a low-oxalate diet, which reduces urinary oxalate in 91% of patients by an average of 31% (107127). There is also preliminary evidence that higher pyridoxine intake in females with no history of kidney stones is associated with decreased risk of kidney stone formation (6441), but this association has not been found in males (6442).
• Pregnancy-induced nausea and vomiting. Oral vitamin B6 may reduce nausea and vomiting in some pregnant patients and is sometimes used in combination with doxylamine. Details: While some conflicting evidence exists, most small clinical studies suggest that oral vitamin B6 is effective for improving nausea and vomiting associated with pregnancy when compared with baseline or placebo. However, vitamin B6 may not be as effective as ginger (110459). Two small clinical studies show that taking vitamin B6 (pyridoxine) 25 mg every 8 hours for 3-4 days decreases pregnancy-induced nausea severity and vomiting incidence when compared with placebo (6168,16306). A larger clinical trial shows that taking lower doses of vitamin B6, 10 mg every 8 hours over 5 days, improves pregnancy-induced nausea, but not vomiting, when compared with placebo (6167). A small clinical study in patients with mild to moderate nausea and vomiting shows that taking a higher dose of 40 mg twice daily for 4 days is more effective than placebo, but no better than ginger 500 mg twice daily (99404). The American College of Obstetrics and Gynecology (ACOG) considers vitamin B6 at a dose of 10-25 mg 3 to 4 times daily a first-line treatment for pregnancy-induced nausea and vomiting due to its benign safety profile (111601). However, it is not effective for all patients, such as those with hyperemesis gravidarum, a severe form of pregnancy-induced nausea and vomiting. Adding vitamin B6 20 mg three times daily for 2 weeks to intravenous rehydration, metoclopramide, and thiamine seems to be no more effective than placebo for reducing vomiting in hyperemesis gravidarum (99405). Vitamin B6 is also sometimes used in combination with doxylamine. In fact, a combination of vitamin B6 plus doxylamine (Diclegis or Bonjesta, Duchesnay Inc., and various generics) has been approved by the US Food and Drug Administration (FDA) as a prescription product111601). ACOG recommends vitamin B6 in combination with doxylamine as another first-line treatment option (111601). However, the clinical trial used to obtain FDA approval has some methodological problems, and the significance of the results has been questioned. The improvement in symptom scores seen with Diclegis was less than one point on a 13-point scale, which is unlikely to be clinically significant (97998). Also, some clinical research shows that taking pyridoxine 25 mg and doxylamine 12.5 mg is less effective than ondansetron 4 mg when taken every 8 hours for 5 days. Only 41% of the patients using pyridoxine and doxylamine had a clinically significant reduction in nausea, compared to 92% of patients using ondansetron (90797). The combination of vitamin B6 and doxylamine is also studied with acupuncture. A large clinical study in patients with moderate to severe pregnancy-induced nausea and vomiting conducted in China shows that taking vitamin B6-doxylamine (Diclegis, Duchesnay, Inc) 20 to 40 mg each at bedtime for 14 days in combination with daily acupuncture modestly improves patient-reported nausea and vomiting scores when compared with either intervention alone (111820). However, it is unclear whether this improvement is clinically significant.
• Premenstrual syndrome (PMS). Oral vitamin B6 seems to reduce PMS symptoms. Details: There is some evidence that taking vitamin B6 (pyridoxine) orally can improve symptoms of PMS such as breast pain or tenderness (mastalgia) and depression in some patients. Pyridoxine in doses of at least 50 mg daily, plus magnesium oxide 200 mg daily, seems to relieve PMS-related anxiety and other symptoms (8555,39007,82962). Although some clinicians advocate doses of pyridoxine 200-500 mg daily for PMS, doses of 50-100 mg daily seem to work just as well. There is no apparent dose-response curve for PMS, so the lowest effective dose should be used. Higher doses might increase the risk of side effects (3093).

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Oral vitamin B6 does not seem to slow age-related cognitive decline. Details: 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). Furthermore, other clinical research shows that taking vitamin B6 (pyridoxine) 3-75 mg daily in combination with folic acid and vitamin B12 does not improve cognitive function in elderly adults (14392,50225,50510).
• Alzheimer disease. Oral vitamin B6 does not seem to improve cognitive function in patients with Alzheimer disease when used in combination with other B vitamins. Also, oral vitamin B6 does not seem to reduce the risk of developing this condition. Details: Clinical research in patients with probable Alzheimer disease taking routine medications shows that taking vitamin B6 25 mg with folic acid 5 mg and vitamin B12 1 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, population research in elderly adults has found that a high intake of vitamin B6 from dietary or supplemental sources is not associated with a decreased risk of Alzheimer disease when compared to lower vitamin B6 intake (13165,15270).
• Carpal tunnel syndrome. Oral vitamin B6 does not seem to reduce symptoms of carpal tunnel syndrome. Details: Most research shows that people with carpal tunnel syndrome are not generally deficient in vitamin B6 and do not benefit from taking vitamin B6 supplements (8203,8937,9448,9450,9478,9482). Although early studies by a single group of researchers, as well as anecdotal reports, suggest that taking vitamin B6 may relieve carpal tunnel symptoms, more reliable research has not supported these findings (8202,9445,9447,9449,9483,15955,83086). Vitamin B6 has also been evaluated in combination with other ingredients. A moderate-sized clinical study in adults with mild to moderate carpal tunnel syndrome shows that taking a combination product containing vitamin B6, alpha-lipoic acid, acetyl-L-carnitine, phosphatidylserine, turmeric, and vitamins C, E, B1, B2, and B12 twice daily for 60 days reduces symptom severity and pain but does not improve measures of hand and wrist function when compared with a control (111702). The dose of vitamin B6 was not provided. The validity of this study is limited by the lack of blinding and placebo. Additionally, it is unclear if the effects are due to vitamin B6, other ingredients, or the combination.
• Cataracts. Oral vitamin B6 does not seem to slow cataract development. Details: Clinical research in females with existing cardiovascular disease (CVD) or at increased risk of CVD shows that taking a combination of folic acid 2.5 mg, vitamin B6 (form not specified) 50 mg, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of cataracts when compared with placebo. Furthermore, the risk of cataract extraction was increased by 28% (96149).
• Chemotherapy-induced acral erythema. While some conflicting evidence exists, most research suggests that oral or topical vitamin B6 does not seem to prevent or reduce the severity of acral erythema induced by chemotherapy. Details: A meta-analysis of 10 clinical trials and 4 observational studies shows that taking vitamin B6 60-500 mg daily for up to 8 chemotherapy cycles does not prevent chemotherapy-induced acral erythema or reduce the incidence of severe cases when compared with control. Most studies used capecitabine chemotherapy alone or in combination, and one study used pegylated liposomal doxorubicin; however, no subgroup analysis was conducted to differentiate chemotherapy regimens. Results did not seem to vary based on study location, study design, or vitamin B6 dose (104930). However, a more recent preliminary clinical study in patients receiving doxorubicin for multiple myeloma shows that taking vitamin B6 100 mg on the first day of chemotherapy then twice daily for 7 days with each cycle reduces the risk of developing acral erythema by 72%, but does not improve the severity of acral erythema, when compared with no vitamin B6 supplementation (110458). Also, one small, low-quality clinical study suggests that taking vitamin B6 400 mg daily reduces the risk of moderate or severe chemotherapy-induced acral erythema when compared with vitamin B6 200 mg daily; however, the higher dose also seems to be associated with worsened tumor response and increased treatment failure (97620). Topical vitamin B6 has also failed to show benefit. A small clinical study in patients with acral erythema from capecitabine or pegylated liposomal doxorubicin shows that applying vitamin B6 1% cream to affected areas three times daily for 6 weeks does not improve symptoms when compared with placebo (104929).
• Colorectal adenoma. Oral vitamin B6 does not seem to reduce the risk of developing colorectal adenomas. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 2.5 mg, vitamin B6 (pyridoxine) 50 mg, and vitamin B12 1 mg, daily for up to 9.2 years does not reduce the risk of colorectal adenoma in females at high risk of cardiovascular disease when compared with placebo (90389).
• Eclampsia. Oral or intramuscular vitamin B6 does not seem to reduce the risk of eclampsia. Details: Meta-analyses of limited clinical research in pregnant patients show that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of eclampsia when compared with control (83046,96166).
• Osteoporosis. Oral vitamin B6 does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in patients with cerebrovascular disease shows that taking a combination of B vitamins, including folic acid 2 mg, vitamin B6 (form not specified) 25 mg, and vitamin B12 500 mcg daily for up to 10.5 years does not prevent osteoporotic fractures when compared with placebo (90377). Furthermore, a secondary analysis of two large studies in patients with cardiovascular disease has found that taking vitamin B6 (pyridoxine) 40 mg daily in addition to folic acid and vitamin B12 for 1-3 years is associated with a 42% increased risk of hip fracture over an 11-year period when compared with only folic acid and vitamin B12 (96163). This finding is limited because these studies were not designed to assess the effects of vitamin B6 on fracture risk and the analyses were not adjusted for baseline bone health or fall risk.
• Pre-eclampsia. Oral or intramuscular vitamin B6 does not seem to reduce the risk of pre-eclampsia. Details: Meta-analyses of limited clinical research in pregnant patients show that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of pre-eclampsia when compared with placebo (83046,96166).
• Preterm labor. Oral or intramuscular vitamin B6 does not seem to reduce the risk of preterm labor. Details: Meta-analyses of limited clinical research in pregnant patients shows that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of preterm labor when compared with placebo (83046,96166).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults and children with inflammatory acne shows that taking 1-4 tablets of a specific product (NicAzel, Elorac Inc.) containing vitamin B6 (pyridoxine), nicotinamide, azelaic acid, zinc, copper, and folic acid for 8 weeks reduces inflammatory lesions and improves appearance in 88% and 81% of patients, respectively, when compared to baseline (90800). The validity of these findings is limited by the lack of a comparator group.
• Age-related macular degeneration (AMD). Oral vitamin B6 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 B6 (pyridoxine) 50 mg, vitamin B12 1000 mcg, and folic acid 2.5 mg daily reduces the risk for AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or with 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 B6, other ingredients, or the combination.
• Angioplasty. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that vitamin B6 (pyridoxine) 10 mg, folic acid 1 mg, and vitamin B12 400 mcg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412). 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, vitamin B6 (pyridoxine), and vitamin B12 followed by oral administration of folic acid 1.2 mcg, vitamin B6 (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). 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 B6, other ingredients, or the combination.
• Antipsychotic-induced metabolic side effects. It is unclear if oral vitamin B6, as an adjunct to progesterone, is beneficial in patients with antipsychotic-induced amenorrhea. Details: A small clinical study in females with antipsychotic-induced amenorrhea shows that taking vitamin B6 80 mg three times daily for 1 month plus intramuscular progesterone daily for 5 days increases levels of estradiol and follicle stimulating hormone, reduces prolactin levels, and increases the rate of clinical efficacy, defined as the normalization of menstruation and improvement in endocrine indicators, by 14% when compared with progesterone alone (110457).
• Anxiety. It is unclear if oral vitamin B6 is beneficial in patients with anxiety. Details: Clinical research in college students shows that taking vitamin B6 100 mg daily for one month does not reduce anxiety scores when compared with placebo (110453). However, because a diagnosis of anxiety was not a requirement for study participation, it is unclear if these findings can be generalized to patients diagnosed with anxiety.
• Asthma. It is unclear if oral vitamin B6 is beneficial in patients with asthma. Details: Preliminary clinical studies show that taking vitamin B6 (pyridoxine) 200-300 mg daily may improve symptoms of asthma in some patients, but not others, when compared with placebo (7064,7065). Studies have yielded conflicting results, with some research suggesting that it may only be beneficial in children with severe asthma (7065). Additionally, some research suggests that theophylline may lower vitamin B6 levels, although it is unclear if vitamin B6 supplementation is beneficial (4522,7066,9503).
• Atherosclerosis. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with intermediate risk for coronary heart disease shows that taking a specific supplement (Kyolic, Total Heart Health, Formula 108, Wakunga) containing vitamin B6 12.5 mg, aged garlic extract 250 mg, vitamin B12 100 mcg, folic acid 300 mcg, 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 B6, other ingredients, or the combination.
• Atopic dermatitis (eczema). It is unclear if oral vitamin B6 is beneficial in patients with eczema. Details: A small clinical study in children with eczema shows that taking vitamin B6 (pyridoxine hydrochloride) 50 mg daily for 4 weeks does not reduce symptoms such as redness and itchiness when compared with placebo (83090).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral vitamin B6 is beneficial for ADHD. Details: A small crossover study in children with ADHD shows that taking vitamin B6 600 mg, niacinamide and ascorbic acid 3 grams, and calcium pantothenate 1.2 grams daily for 6 weeks does not improve behavior scores when compared with placebo (9957).
• Autism spectrum disorder. Although there is interest in using oral vitamin B6 for autism, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Bipolar disorder. It is unclear if oral vitamin B6 is beneficial in patients with bipolar disorder. Details: A small clinical trial in patients with type 1 bipolar disorder who are taking lithium and experiencing an acute episode of mania shows that taking vitamin B6 80 mg daily for 8 weeks does not improve cognitive function or the severity of mania when compared with placebo. Cognitive function was reduced in patients taking vitamin B6; any effect on sleep was unclear (107132).
• Cancer. It is unclear if oral vitamin B6 reduces overall cancer risk. Details: Population research has found that higher dietary intake of vitamin B6 is associated with a 22% reduced risk of cancer, including esophageal, pancreatic, gastric, colorectal, and breast cancer. However, when dietary and supplemental vitamin B6 intake is considered, the inverse association between vitamin B6 and cancer risk is weaker and limited to fewer tumor sites. Furthermore, a meta-analysis of 9 clinical studies shows that taking vitamin B6 3-100 mg orally daily for 2-7.3 years, in combination with vitamin B12 and folate, does not reduce the risk of cancer in patients with cardiovascular disease or kidney failure (96164).
• Cardiovascular disease (CVD). Oral vitamin B6, 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 lower the risk of stroke. Details: Overall evidence from clinical research and meta-analyses shows that taking vitamin B6 in combination with folic acid and/or vitamin B12 does not seem to help with secondary prevention of 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, some research shows that taking vitamin B6 in combination with other B vitamins modestly reduces the risk of stroke, although results are conflicting (11387,13482,50423,83050,96150,96165,97619,107136). Additionally, it is unclear which specific combination of B vitamins is 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).
• Cognitive function. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy adults aged 40-65 years shows that taking a supplement containing vitamin B6, ginkgo leaf, bacopa, and other B vitamins twice daily for 12 weeks does not improve memory or attention when compared with placebo (111334).
• Colorectal cancer. It is unclear if oral vitamin B6 reduces the risk of colorectal cancer. Details: A meta-analysis of observational studies suggests that the highest dietary intake of vitamin B6 is associated with a 20% reduced risk of colorectal cancer when compared with the lowest dietary intake. However, this association was not shown in subgroup analyses of studies conducted in Australia, Europe, or North America (111600). The validity of this analysis is limited by the heterogeneity of the included studies.
• Dental caries. There is limited evidence on the oral use of vitamin B6 for dental decay during pregnancy. Details: Meta-analyses of limited clinical research show that taking vitamin B6 (pyridoxine), 25 mg daily or a single dose of 100 mg orally or intramuscularly, may reduce the risk of dental decay during pregnancy when compared with placebo (83046,96166).
• Depression. It is unclear if oral vitamin B6 reduces the risk of developing depression or improves symptoms of depression. Details: Clinical research in healthy college students shows that taking vitamin B6 100 mg daily for one month does not reduce depression scores when compared with placebo (1104453). However, because a diagnosis of depression was not a requirement for study participation, it is unclear if these findings can be generalized to patients diagnosed with depression. Whether vitamin B6 reduces the risk of developing depression is also unclear. A meta-analysis of population research has found that the highest dietary intake of vitamin B6 is associated with a 19% lower risk of depression when compared with the lowest intake. However, sub-analyses suggest that this association is only relevant in females and not males (107133). In one individual population study in community dwelling older adults included in the analysis, the consumption of at least 1.71 mg of vitamin B6 daily from food was associated with a 43% reduction in the likelihood of becoming depressed when compared with the consumption of 1.33 mg or less daily in females. However, there was no association between vitamin B6 levels and risk of depression in males, and the finding in females was no longer significant when adjusted for total energy intake, since foods rich in vitamin B6 are energy-dense (96168). Another observational longitudinal study in healthy adults starting oral contraceptives containing ethinyl estradiol and levonorgestrel has found that taking vitamin B6 25 mg daily for 6-12 months is associated with a 40% lower risk of depression when compared with no supplementation (90789). Most available studies are cross-sectional in nature, making any conclusions related to causation difficult.
• Diabetes. It is unclear if oral vitamin B6 is beneficial in patients with type 2 diabetes or gestational diabetes. Details: Observational research in Chinese adults with type 2 diabetes has found that dietary intake of vitamin B6 in the highest quartile is associated with 53% lower odds of developing cardiovascular disease, defined as a non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina, when compared with vitamin B6 intake in the lowest quartile (110452). Small clinical studies in patients with gestational diabetes and vitamin B6 deficiency shows that taking vitamin B6 (pyridoxine) 100 mg daily for 2 weeks improves glucose tolerance and blood glucose levels when compared with baseline (82967,83088). However, there is concern that these findings were confounded by dietary alterations. This benefit was not observed in a subsequent small case series in patients with gestational diabetes (22380).
• Diabetic neuropathy. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research suggests that taking a combination of B vitamins, including folic acid (L-methylfolate), vitamin B12 (methylcobalamin), and vitamin B6 (pyridoxal-5'-phosphate) for 24 weeks does not improve neural dysfunction based on vibration perception when compared with placebo in patients with diabetic neuropathy. However, taking this combination appears to modestly improve neuropathy symptoms and quality of life related to mental functioning when compared with placebo (90375).
• Dysmenorrhea. It is unclear if oral vitamin B6 is beneficial in patients with dysmenorrhea. Details: Preliminary clinical research shows that taking vitamin B6 (form not specified) 200 mg daily reduces pain associated with dysmenorrhea when compared with placebo. However, taking vitamin B6 in combination with magnesium does not reduce pain when compared with placebo (77388).
• Fibromyalgia. It is unclear if oral vitamin B6 is beneficial in patients with fibromyalgia. Details: A small clinical study in patients with fibromyalgia shows that taking vitamin B6 80 mg daily for 8 weeks does not improve pain, disease severity, anxiety, depression, or quality of life when compared with placebo (110454).
• Gastroenteritis-associated nausea and vomiting. It is unclear if oral vitamin B6 is beneficial in children with gastroenteritis. Details: A small clinical study in children aged 6 months to 12 years with acute viral gastroenteritis shows that taking vitamin B6 (form not specified) does not improve symptoms of dehydration or the frequency of vomiting when compared with placebo (90793).
• Helicobacter pylori. It is unclear if oral vitamin B6 is beneficial for Helicobacter pylori. Details: A large clinical study in adults with Helicobacter pylori infection shows that taking vitamin B6 20 mg twice daily for 2 weeks alongside conventional quadruple therapy does not improve eradication rates when compared with a control group not receiving vitamin B6 (113551). Conventional therapy consisted of a proton pump inhibitor, bismuth, minocycline, and metronidazole. The validity of this study is limited by the lack of placebo and inadequate blinding.
• Hypertension. It is unclear if oral vitamin B6 reduces blood pressure. Details: One small clinical study in patients with essential hypertension shows that taking vitamin B6 (pyridoxine hydrochloride) 5 mg/kg daily for 4 weeks can reduce systolic and diastolic blood pressure when compared with baseline (83091). The validity of this finding is limited by the lack of a control group.
• Hypertriglyceridemia. It is unclear if oral vitamin B6 reduces triglyceride levels. Details: Preliminary clinical research shows that vitamin B6 (form not specified) 50 mg daily for 12 weeks does not reduce triglyceride levels in people with hypertriglyceridemia when compared with placebo. However, vitamin B6 appears to decrease total cholesterol and high-density lipoprotein (HDL) cholesterol by approximately 9% in these patients (59028).
• Infertility. Although there is interest in using oral vitamin B6 for infertility, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Insomnia. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in healthy adults with self-reported sleep difficulty shows that taking a specific product (LZ Complex3, Sanofi Consumer Healthcare Pty Ltd.) containing vitamin B6, zizyphus extract, hops extract, hydrolyzed milk protein (Lactium), and magnesium oxide nightly, 30 minutes before bed, for 2 weeks does not improve sleep quality, daytime functioning, or physical fatigue when compared with placebo. However, due to the large improvement seen in both the treatment and placebo groups, the effectiveness of this product is unclear (95971).
• Isoniazid-induced neuropathy. It is unclear if oral vitamin B6 prevents the development of neuropathy in patients taking isoniazid. Details: Preliminary clinical research in patients taking isoniazid for tuberculosis shows that taking vitamin B6 (pyridoxine) 6 mg daily reduces the development of neuropathy when compared with control (83068).
• Lactation. It is unclear if oral vitamin B6 helps to suppress postpartum lactation. Details: A meta-analysis of two small clinical trials shows that taking vitamin B6 (pyridoxine) 400-600 mg daily for 6-7 days postpartum does not suppress lactation when compared with no treatment (83047).
• Levetiracetam-induced side effects. While some conflicting evidence exists, several small, low-quality studies suggest that oral vitamin B6 (pyridoxine) may reduce some neuropsychiatric adverse effects related to the use of levetiracetam. Details: In an analysis of case reports, retrospective studies, and a single low-quality prospective study, improvement in levetiracetam-associated neuropsychiatric symptoms occurred in approximately 73% of patients taking pyridoxine (107137). A more recent preliminary clinical trial in children ages 1-17 years shows that taking pyridoxine 10 or 15 mg/kg daily as needed based on symptoms improves behavioral side effects associated with levetiracetam by a small amount when compared with low-dose pyridoxine 0.5 mg/kg daily used as placebo (107124). Also, observational research in children ages 9 months to 14 years has found that taking vitamin B6 is associated with improved behavior and a 44% lower risk of levetiracetam discontinuation when compared with no vitamin B6 supplementation (110455). Some observational research in adults with levetiracetam-associated irritability has found that taking vitamin B6 is associated with an improvement in irritability in 45% of patients when compared to baseline (107129). However, a small clinical trial in adults with epilepsy shows that taking pyridoxine 40 mg daily for 3 weeks does not improve levetiracetam-related psychiatric adverse effects when compared with placebo (110456). This study may have been underpowered to detect differences between groups. Pyridoxine doses used in the studies above have ranged from 50-400 mg daily in children and 40-600 mg daily in adults (107124,107129,107137,110456).
• Lung cancer. It is unclear if dietary or oral vitamin B6 reduces lung cancer risk. Details: Epidemiological research has found that higher serum levels of vitamin B6 in male smokers is associated with a lower risk of lung cancer (9454). Also, people with blood levels of vitamin B6 in the top quartile have a modestly lower risk of lung cancer when compared with those whose levels are in the lowest quartile. The association is stronger for males and for people who have smoked (97999). However, other epidemiological research found that increased dietary intake of vitamin B6 is not associated with a reduced risk of lung cancer (96164).
• Menopausal symptoms. Although there is interest in using oral vitamin B6 for menopausal symptoms, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Motion sickness. Although there is interest in using oral vitamin B6 for motion sickness, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Nausea and vomiting. It is unclear if oral vitamin B6 is beneficial for nausea and vomiting in patients taking oral contraceptives or antibiotics for Helicobacter pylori. Details: A large clinical study in adults with Helicobacter pylori infection shows that taking vitamin B6 20 mg twice daily for 2 weeks alongside conventional quadruple therapy reduces the incidence and severity of gastrointestinal adverse effects when compared with a control group not receiving vitamin B6 (113551). Conventional therapy consisted of a proton pump inhibitor, bismuth, minocycline, and metronidazole. The validity of this study is limited by the lack of placebo and inadequate blinding. An observational longitudinal study in healthy females taking oral contraceptives containing ethinyl estradiol and levonorgestrel has found that taking vitamin B6 25 mg daily for 6-12 months is associated with a 43% reduced risk of nausea when compared with no supplementation (90789).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin B6 for patients with NAFLD. Details: A small clinical trial in patients with NAFLD shows that taking vitamin B6 (pyridoxine) 30 mg three times daily for 12 weeks does not reduce levels of liver transaminases or plasma lipids when compared with baseline. However, hepatic fat accumulation was modestly reduced (107130). The validity of this study is limited by the lack of a comparator group.
• Obesity. It is unclear if oral vitamin B6 in beneficial in overweight or obese individuals. Details: A small clinical trial in females with a body mass index (BMI) of at least 25 kg/m² shows that taking vitamin B6 as pyridoxine 80 mg daily for 8 weeks reduces fat mass and improves insulin resistance and triglyceride levels by a small amount when compared with placebo. Although some other anthropometric and metabolic indices were improved when compared with baseline, there was no effect of pyridoxine on body weight, visceral adiposity, or other endpoints when compared with placebo (107131).
• Overall mortality. It is unclear if oral vitamin B6 reduces the risk of overall mortality. Details: Observational research in US adults has found that dietary intake of vitamin B6 in the highest quintile is associated with a 12% to 21% lower risk of all-cause mortality and a 31% to 44% lower risk of cardiovascular mortality when compared with the lowest quintile of dietary vitamin B6 intake (110451).
• Pancreatic cancer. It is unclear if oral vitamin B6 reduces the risk of pancreatic cancer. Details: Observational research has found that higher dietary intake of vitamin B6 is associated with a 37% lower risk of developing pancreatic cancer when compared with lower intake (104927).
• Postpartum depression. It is unclear if oral vitamin B6 is beneficial in patients with postpartum depression. Details: Preliminary clinical research in individuals considered at increased risk for postpartum depression, but without clinical depression, shows that taking vitamin B6 80 mg daily from the 28th week of pregnancy until birth, and then 40 mg daily for one month, reduces symptoms of depression 1.5 months after birth when compared with baseline (measured during the third trimester) and when compared with placebo. However, it is unclear if any of the patients included in the study developed postpartum depression, as there were no changes in overall symptoms in patients taking placebo (107126).
• Proton pump inhibitor-induced gastrointestinal (GI) symptoms. It is unclear if oral vitamin B6 is beneficial for proton pump inhibitor-induced GI symptoms. Details: A large clinical study in adults with Helicobacter pylori infection shows that taking vitamin B6 20 mg twice daily for 2 weeks alongside conventional quadruple therapy reduces the incidence and severity of gastrointestinal adverse effects when compared with a control group not receiving vitamin B6 (113551). Conventional therapy consisted of a proton pump inhibitor, bismuth, minocycline, and metronidazole. The validity of this study is limited by the lack of placebo and inadequate blinding.
• Restless legs syndrome (RLS). It is unclear if oral vitamin B6 is beneficial in patients with RLS. Details: A small clinical study in adults with RLS who are beginning treatment with pramipexole shows that also taking vitamin B6 40 mg daily for 2 months moderately improves RLS scores and sleep quality scores when compared with pramipexole and placebo (110052).
• Schizophrenia. It is unclear if oral vitamin B6 is beneficial for patients with treatment-resistant schizophrenia. Details: Clinical research in male patients with treatment-resistant schizophrenia who are on a consistent antipsychotic dose shows that adding vitamin B6 300 mg twice daily for 16 weeks modestly improves psychotic symptoms and some measures of cognitive performance when compared with adding aripiprazole 5 mg twice daily (107128). More research is needed to determine if these benefits are clinically relevant.
• Seizures. It is unclear if oral vitamin B6 is beneficial for preventing seizures in patients with glycosylphosphatidylinositol (GPI) deficiency. Details: Observational case series in a small number of children and young adults with GPI deficiency has found that taking vitamin B6 20-30 mg/kg daily for 3-12 months is associated with some reduction in seizure frequency in 9 of 13 patients. However, no patient reached seizure freedom (107125,107135). In one case series, treatment for 12 months was associated with modest developmental improvements in almost all patients (107135). The study patient populations were slightly different in terms of age and underlying genetic causes for GPI deficiency.
• Sickle cell disease. Oral vitamin B6 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 B6 4.2-6 mg, vitamin B12 4.2-6 mcg, and folic acid 700 mcg 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 B6, either alone or with other B vitamins, is beneficial for stroke prevention. Details: There is some debate about whether supplementation with homocysteine-lowering B vitamins, including vitamin B6, can reduce the risk of stroke. 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 (11387,13482,50423,83050,96150). However, a more recent meta-analysis of 10 clinical trials, including over 44,000 patients at risk for or with a history of CVD, shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo (97619). This meta-analysis differed from some of the earlier analyses due to the inclusion of several additional clinical trials. Also, another meta-analysis of three clinical trials including 9900 patients with a history of stroke shows that B vitamin supplementation reduces the relative risk of stroke recurrence by 13% when compared with placebo, although this finding was determined to have a low level of certainty. Based on two clinical trials, there was also a 17% reduced risk of vascular death and an 11% reduction in the combined risk of stroke, myocardial infarction, and vascular death (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 shows 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. Exposure to low, but not high amounts, of vitamin B12 (cyanocobalamin) seems to reduce stroke risk (96150).
• Tardive dyskinesia. It is unclear if oral vitamin B6 prevents tardive dyskinesia in patients taking neuroleptic drugs. Details: A small clinical study in patients taking neuroleptic drugs for schizophrenia shows that taking vitamin B6 (form not specified) 400 mg daily seems to improve Parkinsonian, dystonic, and dyskinetic symptoms when compared with placebo (8558).
• Tourette syndrome. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, nonblinded clinical study in children aged 4-17 years with untreated Tourette syndrome or with chronic tic disorder and associated symptoms of anxiety shows that taking a liquid nutritional supplement providing vitamin B6 2.8 mg and L-theanine 200 mg daily for 2 months improves scores on the Yale Global Tic Severity Scale, but does not reduce anxiety, when compared with patients receiving psychoeducation (108555). This study may have been inadequately powered to detect a difference between groups.
• Vincristine-induced neuropathy. Oral vitamin B6 has only been evaluated in combination with pyridostigmine; its effect when used alone is unclear. Details: A small clinical study in children ages 11 months to 13 years with neuropathy due to vincristine treatment for acute lymphoblastic leukemia, shows that taking vitamin B6 150 mg/m2 and pyridostigmine 3 mg/kg twice daily for 3 months is associated with reduced severity of sensory and motor neuropathy when compared with baseline (104928). The validity of this finding is limited by the lack of a control group. More evidence is needed to rate vitamin B6 for these uses.

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POSSIBLY SAFE ...when used orally and appropriately, short-term (12131). Citicoline 1000-2000 mg daily has been used with apparent safety for up to 12 weeks (12130,43248,98230,104828,109015,109016). Citicoline 2500 mg daily has also been used with apparent safety for up to 7 weeks (100988). ...when citicoline is used intravenously or intramuscularly under medical supervision (12131). Citicoline has been administered intravenously with apparent safety at a dose of 500 mg daily for 7 days, or 2000 mg daily for 3 days (43229,98444,104828). ...when used topically on the eye. Citicoline 2% eye drops have been used with apparent safety for up to 3 years alone or in combination with cyanocobalamin 0.05% (98229,104824,104825,104826,104827).

CHILDREN: POSSIBLY SAFE
when citicoline is used orally and appropriately. Citicoline has been used with apparent safety for up to 1 year at a dose of 250 mg daily in children under 5 years of age and 500 mg daily in children 5-13 years of age (98442). There is insufficient reliable information available about the safety of citicoline when used intravenously in children.

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

(Read more about CITICOLINE)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Saffron has Generally Recognized as Safe (GRAS) status in the US for use as a spice or food coloring agent (4912).

POSSIBLY SAFE ...when used orally and appropriately in larger amounts, short-term. Saffron extracts have been used with apparent safety in clinical trials at doses of up to 100 mg daily for up to 26 weeks (11024,13103,16555,17214,17401,18102,93395,93397,93400,93403)(93407,97359,99436,100135,100138,100140,100658,100659). The saffron constituent crocin has been used with apparent safety at a dose of up to 30 mg daily for up to 3 months (93410,100139,105616).

POSSIBLY UNSAFE ...when used orally in high doses or for longer than 26 weeks. Taking 5 grams or more of saffron can cause severe side effects. Doses of 12-20 grams can be lethal (12,18). There is insufficient reliable information available about the safety of saffron when used topically.

PREGNANCY: LIKELY UNSAFE
when used orally in amounts exceeding those commonly found in foods. Larger amounts of saffron have uterine stimulant and abortifacient effects (18); avoid using.

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about SAFFRON)

LIKELY SAFE ...when used in amounts commonly found in foods. Spearmint and spearmint oil have Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used orally or topically for medicinal reasons (11,12). Spearmint extract up to 900 mg daily has been used safely for up to 90 days (94925,101713,101714). Spearmint tea has been consumed safely twice daily for up to 16 weeks (68500,94923).

PREGNANCY: LIKELY SAFE
when used in the amounts commonly found in foods (4912).

PREGNANCY: POSSIBLY UNSAFE
when used orally during pregnancy in excessive amounts. Animal research suggests that spearmint tea may cause uterine damage (68448). Avoid using in amounts greater than those typically found in foods during pregnancy.

LACTATION: LIKELY SAFE
when used in the amounts commonly found in foods (4912). There is insufficient reliable information available about the safety of spearmint during lactation. Avoid using in amounts greater than those typically found in foods.

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LIKELY SAFE ...when used orally and appropriately in doses that do not exceed the tolerable upper intake level (UL) of 100 mg daily in the form of pyridoxine for adults (15,6243). ...when used parenterally and appropriately. Injectable vitamin B6 (pyridoxine) is an FDA-approved prescription product (15).

POSSIBLY SAFE ...when used orally and appropriately in doses of 101-200 mg daily (6243,8558).

POSSIBLY UNSAFE ...when used orally in doses at or above 500 mg daily. High doses, especially those exceeding 1000 mg daily or total doses of 1000 grams or more, pose the most risk. However, neuropathy can occur with lower daily or total doses (6243,8195). ...when used intramuscularly in high doses and frequency due to potential for rhabdomyolysis (90795).

CHILDREN: LIKELY SAFE
when used orally and appropriately in doses that do not exceed the tolerable upper intake level (UL) of vitamin B6 in the form of pyridoxine 30 mg daily for children aged 1-3 years, 40 mg daily for 4-8 years, 60 mg daily for 9-13 years, and 80 mg daily for 14-18 years (6243).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately in amounts exceeding the recommended dietary allowance (5049,8579,107124,107125,107135).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses, long-term (6243).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. A special sustained-release product providing vitamin B6 (pyridoxine) 75 mg daily is FDA-approved for use in pregnancy. Vitamin B6 (pyridoxine) is also considered a first-line treatment for nausea and vomiting in pregnancy by the American College of Obstetrics and Gynecology (111601). However, it should not be used long-term or without medical supervision and close monitoring. The tolerable upper intake level (UL) refers to vitamin B6 in the form of pyridoxine and is 80 mg daily for those aged 14-18 years and 100 mg daily for 19 years and older (6243).

PREGNANCY: POSSIBLY UNSAFE
when used orally in excessive doses. There is some concern that high-dose maternal vitamin B6 (pyridoxine) can cause neonatal seizures (4609,6397,8197).

LACTATION: LIKELY SAFE
when used orally in doses not exceeding the tolerable upper intake level (UL) of vitamin B6 in the form of pyridoxine 80 mg daily for those aged 14-18 years and 100 mg daily for those 19 years and older. The recommended dietary allowance (RDA) in lactating women is 2 mg daily (6243). There is insufficient reliable information available about the safety of vitamin B6 when used in higher doses in breast-feeding women.

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(Read more about CITICOLINE)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of saffron with antidiabetes drugs might increase the risk of hypoglycemia.  Details Some clinical research shows that taking saffron extract reduces fasting levels of glucose when used in addition to hypoglycemic agents (100138). However, saffron powder itself has not been shown to reduce fasting glucose levels (99436).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of saffron with antihypertensive drugs might have additive effects.  Details Animal and human research suggests that saffron extract can decrease blood pressure (72518,72365,72473,93409).

CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, saffron might inhibit the metabolism of caffeine.  Details A small clinical study suggests that taking saffron powder 300 mg in 150 mL water daily for 5 days and then taking caffeine 200 mg seems to reduce caffeine metabolite levels in the saliva and urine in males, but not females. Theoretically, this may be due to the inhibition of cytochrome P450 1A2 by saffron (100130).

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of saffron and CNS depressants might have additive sedative effects.  Details Clinical research shows that taking saffron extract 60 mg orally daily for 26 weeks can cause drowsiness and sedation (18102). Animal research suggests that adding saffron to hexobarbital further increases sleeping and slows motor activity (72544).

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CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, spearmint might alter the sedative effects of CNS depressants.  Details Animal research suggests that (-)-carvone, a major constituent of spearmint, has sedative effects (39800,75758). However, in humans, chewing spearmint-flavored gum induced arousal effects (75699).

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, high doses of spearmint might increase the risk of liver damage when taken with hepatotoxic drugs.  Details Animal research suggests that drinking spearmint tea for 30 days can increase markers of liver damage, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and cause liver degeneration and necrosis, in a dose-dependent manner (12731). This effect has not been reported in humans.

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AMIODARONE (Cordarone) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, vitamin B6 might increase the photosensitivity caused by amiodarone.  Details Despite initial case reports suggesting that pyridoxine may have a protective effect against amiodarone-induced photosensitivity, preliminary clinical research suggests that pyridoxine may actually exacerbate this adverse effect (8892,8893).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, vitamin B6 may have additive effects when used with antihypertensive drugs.  Details Research in hypertensive rats shows that vitamin B6 can decrease systolic blood pressure (30859,82959,83093). Similarly, clinical research in patients with hypertension shows that taking high doses of vitamin B6 may reduce systolic and diastolic blood pressure, possibly by reducing plasma levels of epinephrine and norepinephrine (83091).

LEVODOPA Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Vitamin B6 may increase the metabolism of levodopa when taken alone, but not when taken in conjunction with carbidopa.  Details Vitamin B6 (pyridoxine) enhances the metabolism of levodopa, reducing its clinical effects. However, this interaction does not occur when carbidopa is used concurrently with levodopa (Sinemet). Therefore, it is not likely to be a problem in most people (3046).

PHENOBARBITAL (Luminal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D High doses of vitamin B6 may reduce the levels and clinical effects of phenobarbital.  Details Preliminary clinical evidence suggests that vitamin B6 200 mg daily can reduce plasma levels of phenobarbital, possibly by increasing metabolism. It is not known whether lower doses have any effect. Advise people taking phenobarbital to avoid high doses of vitamin B6 (3046,10801).

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D High doses of vitamin B6 may reduce the levels and clinical effects of phenytoin.  Details Preliminary clinical evidence suggests that vitamin B6 200 mg daily can reduce plasma levels of phenytoin, possibly by increasing metabolism. It is not known whether lower doses have any effect. Advise people taking phenytoin to avoid high doses of vitamin B6 (3046,10801).

(Read more about VITAMIN B6)

General ...Orally, intramuscularly, and intravenously, citicoline seems to be well-tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, back pain, blurred vision, constipation, diarrhea, edema, headache, insomnia, nausea, rash.

Cardiovascular ...Orally, citicoline may cause chest pain, palpitations, hypotension, bradycardia, tachycardia, and peripheral edema in some patients, although the incidence is likely similar to placebo (12130,12131,12132,43225).

Dermatologic ...Orally, citicoline may cause skin rash in some patients (12130,12132,43248).

Gastrointestinal ...Orally, citicoline may cause abdominal pain, constipation, diarrhea, and nausea in some patients (12130,12132,98846,100988,105730,109015).

Musculoskeletal ...Orally, citicoline may cause back pain in some patients (43225).

Neurologic/CNS ...Orally, citicoline may cause headache and insomnia in some patients (12130,43230,43273,98846,100988,109015,109016).

Ocular/Otic ...Orally, citicoline may cause blurred vision in some patients (12130,12132).

Other ...Orally, citicoline may cause edema of the extremities in some patients (43225).

(Read more about CITICOLINE)

General ...Orally, saffron extract seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Gastrointestinal complaints, nausea, sedation, vomiting.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis.

Dermatologic ...Orally, sweating and flushing have been reported in clinical research for patients taking saffron 30-60 mg daily (93402,93409). Saffron poisoning can occur with oral intake of doses of 5 grams or more and symptoms include yellow appearance of the skin (2,11).

Gastrointestinal ...Orally, saffron has been associated with changes in appetite, nausea, and vomiting when given at doses of 30 mg twice daily for 26 weeks, or when the saffron constituent crocin was given as 15 mg twice daily for 12 weeks (18102,105616). At lower doses of 30 mg daily, the occurrence rate of these and other adverse events such as dry mouth, dyspepsia, diarrhea, and constipation was rare or similar to placebo (13103,93395,93402,93409). Saffron poisoning can occur with oral intake of doses of 5 grams or more and symptoms include yellow appearance of the mucous membranes (mimicking icterus), vomiting, and bloody diarrhea (2,11).

Genitourinary ...One report of excessive uterine bleeding occurred in a clinical trial. The patient was taking the saffron constituent crocin 15 mg twice daily. It is unclear whether this event was related to treatment with the saffron constituent (93410).
Saffron poisoning can occur with oral intake of doses of 5 grams or more; symptoms include bleeding from the uterus (2,11).

Hematologic ...Orally, saffron extract has been reported to cause decreases in platelet, white blood cell, and red blood cell counts after 7 days to 12 weeks of use with doses of 60-200 mg daily. Many of these decreases were only significant when compared to baseline but did not maintain significance when compared to placebo. These reductions were not considered clinically significant (18102,72473,93403,93409).
Saffron poisoning can occur with oral intake of doses of 5 grams or more; symptoms include bloody diarrhea, hematuria, bleeding from the nose, lips, eyelids or uterus, and thrombocytopenic purpura (2,11).

Immunologic ...Allergy to oral saffron has been reported in clinical trials (93404). Anaphylactic reactions can occur within minutes of eating food prepared with saffron (4107,72555). Occupational exposure to saffron has been associated with the development of rhinoconjunctivitis and allergy-induced asthma (4106).

Neurologic/CNS ...Orally, saffron has been reported to cause drowsiness, headache, agitation, and sedation when given at doses of 30 mg twice daily for up to 26 weeks or when crocin is given as 15 mg twice daily for 12 weeks (18102,105616). At doses of 30 mg daily for 6 weeks, the side effect occurrence rate was similar to placebo (13103). Saffron poisoning can occur with oral intake of doses of 5 grams or more; symptoms include vertigo and numbness (2,11).

Ocular/Otic ...Orally, saffron poisoning with oral intake of doses of 5 grams or more can cause ocular symptoms such as yellow appearance of the sclera (2,11).

Psychiatric ...Orally, saffron has been reported to cause anxiety and hypomania when given at doses of 30 mg twice daily for 26 weeks (18102). At doses of 30 mg daily for 6 weeks, the occurrence rate was similar to placebo (13103,93395). One report of agitation occurred in a clinical trial. The patient was taking the saffron constituent crocin 15 mg twice daily. It is unclear whether this event was related to treatment with the saffron constituent (93410).

Renal ...Orally, the saffron constituent crocin given as 15 mg twice daily for 12 week was associated with one case of urinary incontinence (105616). Saffron poisoning can occur with oral intake of doses of 5 grams or more; symptoms include hematuria and uremic collapse (2,11).

(Read more about SAFFRON)

General ...Orally, spearmint is well tolerated.
Most Common Adverse Effects:
Topically: Allergic contact dermatitis or cheilitis in sensitive individuals.

Cardiovascular ...Orally, taking spearmint extract 600 mg daily has been associated with one report of tachycardia in one clinical trial. However, it is not certain that this adverse event was caused by spearmint extract (94925).

Dermatologic ...Orally, drinking 2 cups of spearmint tea with normal amounts of rosmarinic acid has been associated with one report of itchy skin in clinical research (94923).

Gastrointestinal ...Orally, taking spearmint extract 600 mg daily has been associated with dyspepsia in one clinical trial (94925). Taking a higher dose of 900 mg daily has been associated with diarrhea and belching (94925). Drinking 2 cups of spearmint tea with normal amounts of rosmarinic acid has been associated with one report of dry mouth in clinical research. Drinking 2 cups of spearmint tea containing high amounts of rosmarinic acid has been associated with three reports of constipation and one report of loose bowel movements (94923). Taking 1 mL of spearmint oil equivalent to 500 mg of spearmint has been associated with reports of regurgitation in clinical research (75700).

Immunologic ...Topically, spearmint oil and leaves have caused allergic dermatitis (75711,75731,75737). Allergic contact cheilitis has also occurred from spearmint oil in toothpaste or chewing gum (31403,31528,75706,75739,75777,75790). Spearmint oil inhalation has also caused allergic dermatitis (56955). Orally, spearmint leaves have caused allergy-associated swelling of the soft palate. A specific 50 KDa protein in the spearmint was found to be the responsible allergen (94922). In some cases, spearmint allergy was associated with oral lichen planus of the tongue, lips, palate, buccal mucosa, and gingivae. Observational studies suggest that exposure to spearmint is associated with exacerbation of oral lichen planus as confirmed by patch testing (94924,112844).

Neurologic/CNS ...Orally, drinking 2 cups of spearmint tea containing high amounts of rosmarinic acid has been associated with two reports of headache in clinical research (94923).

Psychiatric ...Orally, taking spearmint extract 600 mg daily has been associated with one report of anxiety in one clinical trial. However, it is not certain that this adverse event was caused by spearmint extract (94925).

Other ...Orally, taking spearmint extract 600 mg daily has been associated with one report of increased appetite and weight gain in one clinical trial. However, it is not certain that these adverse events were caused by spearmint extract (94925).

(Read more about SPEARMINT)

General ...Orally or by injection, vitamin B6 is well tolerated in doses less than 100 mg daily.
Most Common Adverse Effects:
Orally or by injection: Abdominal pain, allergic reactions, headache, heartburn, loss of appetite, nausea, somnolence, vomiting.
Serious Adverse Effects (Rare):
Orally or by injection: Sensory neuropathy (high doses).

Dermatologic ...Orally, vitamin B6 (pyridoxine) has been linked to reports of skin and other allergic reactions and photosensitivity (8195,9479,90375). High-dose vitamin B6 (80 mg daily as pyridoxine) and vitamin B12 (20 mcg daily) have been associated with cases of rosacea fulminans characterized by intense erythema with nodules, papules, and pustules. Symptoms may persist for up to 4 months after the supplement is stopped, and may require treatment with systemic corticosteroids and topical therapy (10998).

Gastrointestinal ...Orally or by injection, vitamin B6 (pyridoxine) can cause nausea, vomiting, heartburn, abdominal pain, mild diarrhea, and loss of appetite (8195,9479,16306,83064,83103,107124,107127,107135). In a clinical trial, one patient experienced infectious gastroenteritis that was deemed possibly related to taking vitamin B6 (pyridoxine) orally up to 20 mg/kg daily (90796). One small case-control study has raised concern that long-term dietary vitamin B6 intake in amounts ranging from 3.56-6.59 mg daily can increase the risk of ulcerative colitis (3350).

Hematologic ...Orally or by injection, vitamin B6 (pyridoxine) can cause decreased serum folic acid concentrations (8195,9479). One case of persistent bleeding of unknown origin has been reported in a clinical trial for a patient who used vitamin B6 (pyridoxine) 100 mg twice daily on days 16 to 35 of the menstrual cycle (83103). It is unclear if this effect was due to vitamin B6 intake.

Musculoskeletal ...Orally or by injection, vitamin B6 (pyridoxine) can cause breast soreness or enlargement (8195).

Neurologic/CNS ...Orally or by injection, vitamin B6 (pyridoxine) can cause headache, paresthesia, and somnolence (8195,9479,16306). Vitamin B6 (pyridoxine) can also cause sensory neuropathy, which is related to daily dose and duration of intake. Doses exceeding 1000 mg daily or total doses of 1000 grams or more pose the most risk, although neuropathy can occur with lower daily or total doses as well (8195). The mechanism of the neurotoxicity is unknown, but is thought to occur when the liver's capacity to phosphorylate pyridoxine via the active coenzyme pyridoxal phosphate is exceeded (8204). Some researchers recommend taking vitamin B6 as pyridoxal phosphate to avoid pyridoxine neuropathy, but its safety is unknown (8204). Vitamin B6 (pyridoxine) neuropathy is characterized by numbness and impairment of the sense of position and vibration of the distal limbs, and a gradual progressive sensory ataxia (8196,10439). The syndrome is usually reversible with discontinuation of pyridoxine at the first appearance of neurologic symptoms. Residual symptoms have been reported in patients taking more than 2 grams daily for extended periods (8195,8196). Daily doses of 100 mg or less are unlikely to cause these problems (3094).

Oncologic ...In females, population research has found that a median intake of vitamin B6 1. 63 mg daily is associated with a 3.6-fold increased risk of rectal cancer when compared with a median intake of 1.05 mg daily (83024). A post-hoc subgroup analysis of results from clinical research in adults with a history of recent stroke or ischemic attack suggests that taking folic acid, vitamin B12, and vitamin B6 does not increase cancer risk overall, although it was associated with an increased risk of cancer in patients who also had diabetes (90378). Also, in patients with nasopharyngeal carcinoma, population research has found that consuming at least 8.6 mg daily of supplemental vitamin B6 during treatment was associated with a lower overall survival rate over 5 years, as well as a reduced progression-free survival, when compared with non-users and those with intakes of up to 8.6 mg daily (107134).

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