Memory Support Basic Formula [Discontinued] by Vitaganic Inc

POSSIBLY EFFECTIVE

• Age-related cognitive decline. Oral acetyl-L-carnitine may improve age-related cognitive decline. Details: Clinical research shows that taking acetyl-L-carnitine 1500-2000 mg daily for 3 months seems to improve some measures of cognitive function and memory in elderly people with age-related cognitive decline (42,3600,3601).
• Age-related fatigue. Oral acetyl-L-carnitine may improve age-related physical and mental fatigue. Details: One clinical trial shows that taking acetyl-L-carnitine 2 grams twice daily for 180 days reduces physical fatigue by 52% and mental fatigue by 43%, compared with only 4% and 8%, respectively, for elderly patients taking placebo. Fatigue after exercise is also reduced by 51% in those taking acetyl-L-carnitine, compared with only 4% in those taking placebo (58375).
• Alcohol use disorder. Intravenous acetyl-L-carnitine may reduce cravings and other symptoms of withdrawal during alcohol detoxification. It is unclear if oral acetyl-L-carnitine is beneficial for managing withdrawal or complications of alcohol use disorder. Details: Clinical research in adults with alcohol use disorder who are in withdrawal shows that acetyl-L-carnitine 1-3 grams daily, administered as a slow intravenous infusion over 3-4 hours for 10 days, followed by 3 grams daily orally for an additional 80 days, improves cravings, the inability to feel pleasure (anhedonia), and melancholic symptoms and increases the time to the first drink when compared with placebo. However, most symptom improvement appears to occur during the first week, so it is unclear if taking acetyl-L-carnitine 3 grams daily orally for an additional 80 days is beneficial (90766,90767). One small clinical trial in adults with chronic alcohol use disorder and cognitive impairment shows that taking acetyl-L-carnitine 2 grams daily for 90 days seems to improve memory and visuospatial capacity when compared with placebo (1589).
• Alzheimer disease. Oral acetyl-L-carnitine may slow the progression of Alzheimer disease and improve some measures of cognitive function. Details: Clinical research shows that taking acetyl-L-carnitine 1.5-3 grams daily for 3-12 months might slow the rate of Alzheimer disease progression and improve memory, some measures of cognitive function, and behavioral performance. It is more likely to show some effect in those with early-onset Alzheimer disease who are less than 66 years of age and have a faster rate of disease progression and mental decline (1594,1595,1596,1597,1598,1599,9105,10391). It is unclear how acetyl-L-carnitine compares with prescription medications.
• Depression. Oral acetyl-L-carnitine may reduce symptoms of depression, with comparable effects to conventional antidepressants, in patients with dysthymia and depression. It may be most effective in elderly patients and at higher doses. Details: Several clinical trials addressing the use of acetyl-L-carnitine in elderly patients with dysthymia and depression have been conducted (3602,3603,3604). A meta-analysis of these and other studies, all conducted in Europe, shows that taking acetyl-L-carnitine 1-4 grams daily for 3-24 weeks moderately reduces depressive symptoms when compared with placebo, and appears to have similar effects as conventional antidepressants. Acetyl-L-carnitine seems to be most effective when used at higher dosages. Duration of follow-up and baseline symptoms do not appear to influence results (95065).
• Diabetic neuropathy. Oral acetyl-L-carnitine may reduce pain in patients with diabetic neuropathy when taken at doses of at least 2-3 grams daily. It is unclear if oral acetyl-L-carnitine can improve nerve conduction velocity in these patients. Details: Although most clinical research evaluating acetyl-L-carnitine for use in diabetic neuropathy has shown benefit, this evidence is of overall low quality. A meta-analysis shows that taking acetyl-L-carnitine 2-3 grams daily for up to 12 months modestly reduces pain scores by about 15 points on a 100-point visual analog scale, while lower doses of 1.5 grams daily improve pain scores to a similar extent as placebo. Some research included in this analysis shows that acetyl-L-carnitine seems to increase nerve fibers, regenerate nerve fiber clusters, and improve vibratory sensations. In two studies, vibration sensation improved after 12 months when compared with placebo, but numerical data are lacking (102126). Other clinical research shows that taking acetyl-L-carnitine 1000 mg 2-3 times daily decreases pain within 6 months. Acetyl-L-carnitine seems to be most effective for reducing pain in patients with a shorter duration of diabetes and in patients with poorly controlled type 2 diabetes. Some research shows that taking acetyl-L-carnitine 500 mg (Liaoning Haisike Pharmaceutical Co. Ltd.) three times daily for 24 weeks is as effective as methylcobalamin 0.5 mg three times daily for improving electrophysiological parameters and symptoms as measured by the Neuropathy Disability Score (95067,102126). However, research on the use of acetyl-L-carnitine to improve nerve conduction velocity in patients with diabetic neuropathy is conflicting (1593,12743,12753,13007,95067).
• Male infertility. Oral acetyl-L-carnitine, taken in combination with L-carnitine, may increase sperm motility in males with infertility. It is unclear if oral acetyl-L-carnitine alone can improve sperm function or pregnancy outcomes. Details: Although some research disagrees (111861), taking acetyl-L-carnitine in combination with L-carnitine, usually in doses of 1 gram and 2 grams, respectively, daily for 3-6 months seems to increase sperm motility in males with infertility of various etiologies. The evidence related to the effect of this combination on sperm count and morphology is mixed (12352,58182,58194,58469,101560,107394,111459,111890). However, it is unclear if taking L-carnitine increases the odds of pregnancy. One meta-analysis of randomized controlled trials shows that taking these carnitines in combination increases the odds of pregnancy by 3.7-fold over placebo. However most clinical research investigating the effect of L-carnitine alone or with acetyl L-carnitine on pregnancy rates disagrees (12352,58182,101560,111861,111459). Taking acetyl-L-carnitine 500 mg and L-carnitine 1 gram twice daily after taking nonsteroidal anti-inflammatory drugs for 2 months seems to increase sperm count and motility in those with abacterial prostatovesiculoepididymitis, an inflammation of the prostate gland, seminal vesicles, and epididymis (9791). Acetyl-L-carnitine has also been evaluated in combination with other ingredients. One study shows that taking acetyl-L-carnitine 50 mg in combination with L-carnitine 150 mg, L-arginine 1660 mg, and Panax ginseng 200 mg daily for 3 months increases sperm motility and sexual satisfaction in those with asthenospermia when compared with no treatment (32189). Another small clinical trial shows that taking this combination along with prulifloxacin 600 mg daily for 6 months improves sperm concentration and motility when compared with treatment with prulifloxacin alone in patients with chronic prostatitis due to Chlamydia trachomatis infection (59006). Other small and preliminary Iclinical studies have investigated the effects of a specific combination product providing acetyl-L-carnitine 500 mg twice daily for 6 months, along with L-carnitine, coenzyme Q10, selenium, zinc, vitamin C, folic acid, vitamin B12, and citric acid (Proxeed Plus). Taking this combination product has been shown to improve measures of sperm quality such as sperm count, sperm concentration, total motility, and progressive motility when compared to baseline. The effect on sperm volume and morphology is unclear. Most research has been conducted in patients with oligoasthenozoospermia, although some benefit has also been shown in patients with varicocele-related infertility, especially those with more severe varicocele (102017,107395,111296). The validity of these findings is limited by the lack of comparator group. Also, it is unclear if these effects are due to L-carnitine, other ingredients, or the combination.

POSSIBLY INEFFECTIVE

• Chemotherapy-induced peripheral neuropathy. The evidence related to the effect of oral acetyl-L-carnitine on symptoms of chemotherapy-induced peripheral neuropathy is mixed. Some research shows that it may actually worsen symptoms. Details: High quality clinical research in females treated with taxane-based therapy for early-stage breast cancer shows that taking acetyl-L-carnitine 1000 mg three times daily for 24 weeks does not improve symptoms of neuropathy when compared with placebo. In fact, acetyl-L-carnitine treatment may actually make symptoms worse in some patients, with worsened symptoms persisting for up to at least 2 years (90758,96938,111882). Also, a small clinical trial in patients with multiple myeloma receiving bortezomib, doxorubicin, and dexamethasone shows that taking acetyl-L-carnitine 1.5 grams daily does not reduce symptoms of peripheral neuropathy when compared with not taking acetyl-L-carnitine (90756). A small clinical trial in patients with ovarian cancer or castration-resistant prostate cancer receiving sagopilone shows that taking acetyl-L-carnitine 1000 mg every three days appears to reduce the more severe symptoms of peripheral neuropathy; however, the overall incidence or duration of peripheral neuropathy is not reduced when compared with placebo (90757). Some research disagrees. One clinical trial in patients with taxoid-related neuropathy shows that taking acetyl-L-carnitine3 grams daily for 8 weeks modestly improves the severity of neuropathy by at last one grade in 51% of patients compared with 24% of those taking placebo. Functional improvement was also modestly improved (111862). Based on the available research, the American Society of Clinical Oncology strongly discourages the use of acetyl-L-carnitine for the prevention of chemotherapy-induced peripheral neuropathy, noting that the harms outweigh the potential benefits (104168).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related testosterone deficiency. Oral acetyl-L-carnitine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study in older males shows that taking acetyl-L-carnitine 2 grams, in combination with propionyl-L-carnitine 2 grams, daily for 6 months seems to attenuate symptoms of androgen decline. The combination appears to be similar to testosterone for improving sexual dysfunction, depression, and fatigue (12353). It is unclear if these findings are due to acetyl-L-carnitine, propionyl-L-carnitine, or the combination.
• Aging skin. Although there has been interest in using oral acetyl-L-carnitine for aging skin, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Amenorrhea. Although there has been interest in using oral acetyl-L-carnitine for amenorrhea, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if oral acetyl-L-carnitine is beneficial in patients with ALS. Details: One small clinical trial in patients with ALS shows that taking acetyl-L-carnitine 1000 mg three times daily for 48 weeks, along with riluzole 50 mg twice daily, reduces the number of patients who lose self-sufficiency by about 17%, increases patient survival by a median of 23 months, and improves some measures of physical function when compared with riluzole alone (90755).
• Antiretroviral toxic neuropathy. Small clinical studies suggest that oral acetyl-L-carnitine may modestly improve symptoms in patients with antiretroviral toxic neuropathy. It is unclear if intramuscular or intravenous acetyl-L-carnitine is beneficial in patients with this condition. Details: Small clinical trials show that taking acetyl-L-carnitine 1000-1500 mg twice daily for up to 33 months might relieve symptoms of distal symmetrical polyneuropathy caused by antiretroviral treatment in HIV-positive patients (12745,58342). Also, a small, uncontrolled clinical study shows that intramuscular or intravenous administration of acetyl-L-carnitine 500-1000 mg daily for 3 weeks reduces pain intensity when compared to baseline in some HIV-positive patients receiving antiretroviral therapy (12747). However, another clinical study shows that intramuscular acetyl-L-carnitine 500 mg twice daily for 14 days does not reduce pain when compared with placebo (58342).
• Athletic performance. Although there has been interest in using oral acetyl-L-carnitine for athletic performance, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). Small clinical trials suggest that oral acetyl-L-carnitine is not beneficial in children with ADHD. Details: One small clinical trial in children and adolescents with ADHD shows that taking acetyl-L-carnitine 1-3 grams daily, based on body weight, in two divided doses along with methylphenidate 20-30 mg daily for 3 weeks does not reduce symptoms of ADHD when compared with methylphenidate alone (90754). Based on this and another small trial, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that acetyl-L-carnitine in doses of 1-3 grams daily is not recommended for adjunctive or monotherapy use for ADHD in children (110318).
• Bell palsy. Although there has been interest in using oral acetyl-L-carnitine for Bell palsy, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Bipolar disorder. Oral acetyl-L-carnitine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial in patients with type I or type II bipolar disorder shows that taking acetyl-L-carnitine 1000 mg plus alpha-lipoic acid 600 mg up to three times daily for 12 weeks does not improve depression when compared with placebo (90441).
• Cancer-related fatigue. Although there has been interest in using oral acetyl-L-carnitine for cancer-related fatigue, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Carpal tunnel syndrome. It is unclear if oral acetyl-L-carnitine is beneficial in patients undergoing surgery for carpal tunnel syndrome. Details: A small clinical study in adults undergoing carpal tunnel release surgery shows that taking acetyl-L-carnitine 3000 mg daily for 2 months postoperatively does not improve nerve regeneration or functional recovery when compared with placebo (100349). However, this study may have been inadequately powered to detect a difference between groups. Acetyl-L-carnitine has also been investigated in combination with other ingredients. In patients with mild to moderate symptoms awaiting carpal tunnel release, preliminary clinical research shows that taking acetyl-L-carnitine as part of a multi-ingredient formulation for 60 days reduces pain by 31%, but does not improve function, when compared with no treatment. The formulation provided a total of 600 mg twice daily of acetyl-L-carnitine with alpha-lipoic acid, phosphatidylserine, curcumin, thiamine, riboflavin, and vitamins C, E, B6, and B12 (111702).
• Cataracts. Although there has been interest in using oral acetyl-L-carnitine for cataracts, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Chronic fatigue syndrome (CFS). It is unclear if oral acetyl-L-carnitine is beneficial in patients with CFS. Details: Preliminary clinical research in patients with CFS shows that taking acetyl-L-carnitine 2 grams daily for 6 months improves general fatigue in up to 59% of patients when compared with baseline. The combination of acetyl-L-carnitine and propionyl-L-carnitine appears to be less effective than either supplement alone, with only 37% of patients taking this combination achieving improvement when compared with baseline (11788).
• Diabetes. It is unclear if oral acetyl-L-carnitine improves glycemic control in people with type 2 diabetes. Details: Clinical research in patients with type 2 diabetes, hypertension, and dyslipidemia shows that taking acetyl-L-carnitine 1 gram twice daily for 6 months does not improve blood glucose levels, glycated hemoglobin, fasting insulin levels, insulin resistance, or glucose disposal rate when compared with placebo. Most patients were already taking one or more antidiabetes drug, as well as medication for hypertension and dyslipidemia (96937). It is unclear if acetyl-L-carnitine improves glycemic profile in patients with uncontrolled diabetes.
• Down syndrome. Although there has been interest in using oral acetyl-L-carnitine for Down syndrome, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Dyslipidemia. It is unclear if oral acetyl-L-carnitine reduces lipid levels in adults with dyslipidemia. Details: Clinical research in patients with dyslipidemia, type 2 diabetes, and hypertension shows that taking acetyl-L-carnitine 1 gram twice daily for 6 months does not improve cholesterol, triglycerides, or lipoprotein(a) levels when compared with placebo. All patients were taking statins prior to treatment with acetyl-L-carnitine, and most were receiving medication for hypertension and diabetes (96937). It is unclear if acetyl-L-carnitine is beneficial in patients not taking statins.
• Fibromyalgia. It is unclear if oral and/or intramuscular acetyl-L-carnitine can improve symptoms of fibromyalgia. Details: One clinical study in patients with fibromyalgia shows that taking acetyl-L-carnitine 1000 mg daily orally plus acetyl-L-carnitine 500 mg daily intramuscularly for 2 weeks, followed by acetyl-L-carnitine 1500 mg daily orally for 8 weeks, reduces muscle pain and improves mood, general health, and quality of life when compared with placebo (90768). A smaller clinical study in patients with fibromyalgia shows that taking acetyl-L-carnitine 500 mg three times daily for 12 weeks improves quality of life (physical) scores and symptoms of depression, but not pain, anxiety, or quality of life (mental) scores when compared with baseline (90761). The validity of these findings is limited by the lack of a comparator group. Acetyl-L-carnitine has also been investigated in combination with other ingredients. Clinical research shows that taking acetyl-L-carnitine 500 mg and palmitoylethanolamide (PEA) 600 mg twice daily for 12 weeks increases the proportion of patients with at least a 30% reduction in pain by 86% when compared with not taking this combination. There was also a modest improvement in the overall assessment of status. All patients were on stable treatment with duloxetine and pregabalin for 3 months prior to the initiation of acetyl-L-carnitine and PEA, and this treatment continued throughout the study (111901).
• Fragile X syndrome. Small clinical studies suggest that oral acetyl-L-carnitine is not beneficial in children with fragile X syndrome. Details: Two small clinical studies in children with fragile X syndrome shows that acetyl-L-carnitine 20-50 mg/kg daily for one year does not improve intellectual function when compared with placebo. Also, while it may reduce hyperactive behavior in these patients based on parent assessment, it does not appear to reduce hyperactive behavior based on teacher assessment (9956,93063).
• Frailty. It is unclear if oral acetyl-L-carnitine prevents frailty. Details: Clinical research in pre-frail older adults shows that taking acetyl-L-carnitine 1.5 grams twice daily for 3 months modestly improves cognition and the distance walked in 6 minutes when compared with taking placebo (111889). It is unclear whether taking acetyl-L-carnitine is beneficial for frailty treatment or prevention.
• Hepatic encephalopathy. Small clinical studies suggest that oral acetyl-L-carnitine may not improve quality of life or fatigue in patients with hepatic encephalopathy due to cirrhosis. Details: The benefits of acetyl-L-carnitine in the management of hepatic encephalopathy due to cirrhosis are unclear (58922,58949,59002,90759). A meta-analysis of the available clinical research shows that taking acetyl-L-carnitine 2 grams twice daily for 90 days does not improve quality of life or fatigue in this population when compared with placebo. However, major clinical outcomes, such as all-cause mortality, days of hospitalization, and serious adverse events, have not been evaluated. Additionally, the validity of these findings is limited by the small size, high risk for bias, and heterogeneity of the included studies (100350).
• Hypertension. It is unclear if oral acetyl-L-carnitine lowers blood pressure in adults with hypertension. Details: Clinical research in patients with hypertension, type 2 diabetes, and dyslipidemia shows that taking acetyl-L-carnitine 1 gram twice daily for 6 months does not improve systolic or diastolic blood pressure when compared with placebo. Most patients were already being treated with antihypertensive drugs prior to treatment with acetyl-L-carnitine, in addition to medications for dyslipidemia and diabetes (96937). It is unclear if acetyl-L-carnitine reduces blood pressure in patients with uncontrolled hypertension.
• Infertility. Although there has been interest in using oral acetyl-L-carnitine for infertility in females, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Lyme disease. Although there has been interest in using oral acetyl-L-carnitine for Lyme disease, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Multiple sclerosis-related fatigue. It is unclear if oral acetyl-L-carnitine is beneficial in patients with multiple sclerosis-related fatigue. Details: One small clinical study in patients with multiple sclerosis shows that taking acetyl-L-carnitine 1 gram twice daily for one month reduces fatigue by approximately 25% when compared with placebo (90760).
• Obesity. Although there has been interest in using oral acetyl-L-carnitine for obesity, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Peripheral neuropathy. Although there has been interest in using oral acetyl-L-carnitine for peripheral neuropathy, there is insufficient reliable information about the clinical effects of acetyl-L-carnitine for this purpose.
• Peyronie disease. A small clinical study suggests that oral acetyl-L-carnitine may modestly improve symptoms of Peyronie disease. Details: One small clinical trial in patients with acute and early chronic Peyronie disease shows that taking acetyl-L-carnitine 1 gram twice daily for 3 months reduces pain and slows disease progression when compared with tamoxifen 20 mg twice daily (10076).
• Polycystic ovary syndrome (PCOS). It is unclear if acetyl-L-carnitine is beneficial in patients with PCOS. Details: A clinical study in patients with PCOS shows that taking acetyl-L-carnitine 1.5 grams, in combination with metformin and pioglitazone, twice daily for 12 weeks improves menstrual irregularity and insulin resistance when compared with baseline. The lack of statistical comparison to placebo, as well as the combined use with metformin and pioglitazone, limits the validity of these findings (107396).
• Schizophrenia. It is unclear if oral acetyl-L-carnitine is beneficial in patients with schizophrenia. Details: A very small, open-label clinical study in patients with schizophrenia who partially responded to clozapine therapy shows that taking acetyl-L-carnitine 1 gram daily, in combination with clozapine 300-600 mg daily, for 12 weeks reduces positive symptoms of schizophrenia, but not cognitive function or other clinical symptoms, when compared with baseline (95063). The validity of these findings is limited by the lack of a comparator group.
• Sciatica. It is unclear if oral acetyl-L-carnitine is beneficial in patients with sciatica. Details: One small clinical trial in patients with sciatica secondary to a herniated disc shows that taking acetyl-L-carnitine (Nicetile, SigmaTau Ind. Farm. Riunite SpA,) 1180 mg daily for 60 days decreases the use of analgesics when compared with baseline. However, acetyl-L-carnitine appears to be less effective than alpha-lipoic acid (Byodiniral 300 QR, MDM SpA,) 600 mg daily for reducing lower limb pain and the use of analgesics (21671).
• Stroke. It is unclear if oral acetyl-L-carnitine is beneficial following a stroke. Details: Clinical research in patients with an acute ischemic stroke given routine care shows that oral or nasogastric acetyl-L-carnitine 1 gram three times daily for 3 days modestly improves stroke impairment and overall function 3 months after the stroke when compared with taking placebo. The proportion of patients taking acetyl-L-carnitine with no symptoms or obvious disability at 3 months was 53%, compared with 29% of patients taking placebo. The patients in this study were not candidates of reperfusion therapy and initiated acetyl-L-carnitine within 24 hours of the stroke (111894).
• Toxin-induced liver damage. Oral acetyl-L-carnitine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients being treated with anti-tuberculosis drugs shows that taking acetyl-L-carnitine 250 mg, along with coenzyme Q10 and alpha-lipoic acid, twice daily for 2 weeks reduces the risk of drug-induced liver injury by 73% when compared with placebo (107445). It is unclear if these findings are due to acetyl-L-carnitine, other ingredients, or the combination. More evidence is needed to rate acetyl-L-carnitine for these uses.

(Read more about ACETYL-L-CARNITINE)

POSSIBLY INEFFECTIVE

• Athletic performance. Taking oral choline before exercise does not improve athletic performance. Details: Clinical research in trained athletes shows that taking oral choline 2.43 grams as a single dose does not delay fatigue during endurance sports when compared with placebo (5164). Other clinical research in untrained adults shows that taking oral choline 8.425 grams or 50 mg/kg once prior to participating in exhaustive, load-carrying exercise does not improve dexterity, upper or lower body strength, grip strength, or run time-to-exhaustion following exercise when compared with placebo (42229,42237).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral choline is beneficial in patients with age-related cognitive decline. Details: Small clinical studies in adults with memory loss shows that taking choline 2 grams four times daily orally for 21 days does not improve memory when compared with placebo (5170). Observational research in adults over 60 years of age has found that intake of choline 187-399.5 mg daily is associated with a 33% to 42% reduced odds of low cognitive function when compared with intake of less than 187 mg daily. Intake of more than 399.5 mg daily was not associated with low cognitive function when compared with less than 187 mg daily (109100).
• Allergic rhinitis (hay fever). It is unclear if oral choline is beneficial in patients with allergic rhinitis. Details: Preliminary clinical research shows that taking oral choline, as tricholine citrate, 500 mg three times daily for 8 weeks is less effective than intranasal budesonide 200 mcg twice daily for reducing symptoms of allergic rhinitis (42252).
• Alzheimer disease. Although there has been interest in using oral choline for Alzheimer disease, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Asthma. Small clinical studies suggest that oral choline may modestly improve symptoms in patients with asthma. Details: Preliminary clinical research shows that taking choline 500-1000 mg orally three times daily for 3-4 months decreases the severity of symptoms, the number of symptomatic days, and the need to use bronchodilators in patients with asthma when compared with placebo (5165,5166). Preliminary data also shows that choline 3 grams daily might be more effective than 1.5 grams daily (5165).
• Autism spectrum disorder. Oral choline has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination of donepezil 2.5-5 mg daily and choline bitartrate 350 mg daily for 12 weeks improves receptive language skills, but no other outcomes, for up to 6 months after treatment when compared with placebo in children aged 5-10 years with autism spectrum disorder. Also, adolescents aged 11-16 years experienced no benefits, and some experienced an increase in behavioral symptoms, such as irritability (103571). It is unclear if this effect is due to choline, donepezil, or the combination.
• Breast Cancer. It is unclear if dietary intake of choline reduces the risk of breast cancer. Details: A meta-analysis of 6 low to moderate-quality observational studies suggests that neither high nor low dietary intake of choline is associated with breast cancer risk. This finding is largely influenced by inclusion of the European Prospective Investigation into Cancer and nutrition (EPIC) cohort study, which analyzed data from over 300,000 subjects. However, subanalysis of 3 case-control studies suggests that high dietary intake of choline may be associated with a decreased risk of breast cancer when compared with low choline intake (111416). The interpretation of these findings is limited by the heterogeneity of the included studies, self-reported data, and a small number of studies.
• Bronchitis. Although there has been interest in using oral and inhaled choline for bronchitis, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Cancer. It is unclear if dietary choline intake reduces the risk for cancer. Details: A meta-analysis of 11 low-quality population studies has found that high dietary intake of choline is associated with an 18% lower risk of cancer when compared with low choline intake. High dietary intake of both choline and betaine was associated with a 40% lower risk of cancer (97390).
• Cardiovascular disease (CVD). It is unclear if dietary choline intake reduces the risk of CVD or improves outcomes in patients with CVD. Details: A meta-analysis of population research has found that high intake of dietary choline is not associated with a lower risk of coronary artery disease, stroke, or mortality when compared with a diet low in choline (97388). A more recent population study has found that energy-adjusted total choline intake is not associated with the incidence of CVD over ten years. However, the highest intake of free choline is associated with a 34% reduced risk of CVD when compared with the lowest intake (109104).
• Cerebellar ataxia. It is unclear if oral choline is beneficial in patients with cerebellar ataxia. Details: Despite some anecdotal reports suggesting that taking choline improves motor function, preliminary clinical research shows that taking choline 4-5 grams orally daily for 4 days to 6 weeks does not reduce cerebellar ataxia (5161,5173,23679).
• Cognitive function. It is unclear if oral choline is beneficial for improving cognitive function in healthy adults. Details: Preliminary clinical research shows that taking a single dose of choline 50 mg/kg orally prior to participating in an exhaustive, load-carrying task does not improve reaction time, reasoning, memory, or serial addition and subtraction ability following the task when compared with placebo (42237). Also, preliminary clinical research in patients requiring long-term total parenteral nutrition (TPN) shows that adding choline chloride 2 grams daily to TPN for 24 weeks might improve delayed visual memory, but does not improve other measures of cognitive performance, when compared with TPN alone (42232).
• Cirrhosis. Although there has been interest in using oral choline for cirrhosis, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Complex partial seizures. Although there has been interest in using oral choline for complex partial seizures, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Dementia. Although there has been interest in using oral choline for dementia, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Depression. It is unclear if oral choline is beneficial for the treatment or prevention of depression. Details: Observational research has found that dietary choline intake of at least 198 mg daily is associated with a 32% to 43% decreased risk of depressive symptoms when compared with intakes of less than 198 mg daily (109106). It is unclear if choline supplementation is beneficial for depression.
• Diabetes. It is unclear if oral choline is beneficial for the treatment or prevention of type 2 diabetes; the available research is conflicting. Details: Preliminary clinical research shows that taking oral choline bitartrate 1000 mg daily for 2 months does not affect coagulation parameters or levels of triglycerides, low-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (HDL) cholesterol in patients with type 2 diabetes (103569). Choline has also been evaluated for the prevention of type 2 diabetes. In Finnish males, observational research has found that dietary intake of total choline at levels of more than 482 mg daily, especially as phosphatidylcholine, is associated with a 25% lower risk of developing type 2 diabetes over the following 19.3 years when compared with intakes of less than 382 mg daily (103567). However, in males and females in the US, additional observational research has found no association between dietary choline and risk of type 2 diabetes over a mean of 9 years (103570). In addition, a sub-analysis found that the highest intakes of choline (a median of 487 mg daily) were associated with a 54% higher risk of type 2 diabetes among females, but not males, when compared with the lowest intakes (a median of 175 mg daily) (103570). Population research in patients with diabetes has found that an intake of dietary choline in amounts of at least 279 mg daily is associated with a 2.1-fold increased odds of diabetic retinopathy in females, but not males, when compared with an intake less than 206 mg daily (109102). It is unclear if choline itself is responsible for the increased odds of diabetic retinopathy in this population.
• Fetal alcohol spectrum disorders (FASD). It is unclear if oral choline improves cognition in children with fetal alcohol spectrum disorders (FASD). Details: Clinical research in children aged 2.5-5 years with FASD shows that taking oral choline bitartrate, providing choline 500 mg, daily for 9 months does not improve global cognitive development or hippocampal-dependent memory when compared with placebo. However, a subgroup analysis of only children aged 2.5-4 years suggests that choline may improve hippocampal-dependent memory (92112). Follow-up of this study at 7 years shows that choline improves motor speed and suggests a trend towards improved color naming, which are components of executive functioning testing, when compared with placebo (111745). The validity of these findings is limited by the high rate of patient discontinuation which limits statistical power. A small clinical trial in children 5-10 years old with FASD shows that taking oral glycerophosphocholine, providing choline 625 mg, daily for 6 weeks does not improve cognitive function, executive function, attention, or hyperactivity when compared with placebo (97389).
• Hepatitis. Although there has been interest in using oral choline for hepatitis, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Huntington disease. Although there has been interest in using oral choline for Huntington disease, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Hypertension. It is unclear if oral choline is beneficial for the prevention or treatment of hypertension. Details: Population research has found that every 100-mg increase in daily dietary choline intake is associated with a 15% decreased risk of developing hypertension over the next 4.6 to 9.1 years (109098). However, it is unclear if any benefits are specifically related to dietary choline or whether choline supplementation is beneficial.
• Infant development. It is unclear if oral choline intake during pregnancy is beneficial for infant development; the available research is conflicting. Details: Two observational studies have found that higher intake of choline during the second and third trimesters of pregnancy is associated with improvement in offspring cognitive development and visual memory at the age of 18 months and 7 years, respectively, when compared with lower choline intake (94654,94657). One of these studies found that each 1 mcmol/L increase in maternal blood levels of choline at 16 weeks' gestation was associated with a 2.23-point increase in cognitive skill score based on the Bayley Scales of Infant Development (BSID-III) at 18 months of age (94657). Also, some observational research has found that higher plasma levels of choline during pregnancy are associated with higher processing speed and decreased social withdrawal at 4 years of age in the offspring (109101). In contrast, 3 observational studies have found that higher intake of choline during pregnancy, as well as higher maternal and cord blood levels of choline, are not associated with improved offspring intelligence at 5 years of age or cognitive performance at 3 or 7 years of age (94654,94655,94656). However, many of these observational studies, including those with positive findings, included populations with a mean intake of choline that was below the recommended adequate intake of 450 mg daily (94654,94656). It's possible that higher intake of choline is needed to observe a benefit; however, research on the effects of choline supplementation is limited. One small clinical trial shows that taking choline 930 mg daily during the third trimester modestly improves sustained attention in the child at 7 years of age when compared with taking 480 mg daily (109105).
• Metabolic syndrome. It is unclear if oral choline is beneficial in patients with metabolic syndrome. Details: Preliminary clinical research in adults with metabolic syndrome shows that taking oral choline 400 mg daily for 4 weeks does not decrease body weight, blood pressure, plasma glucose levels, or low-density lipoprotein (LDL) cholesterol levels, or increase high-density lipoprotein (HDL) cholesterol levels, when compared with baseline (105731).
• Neural tube birth defects. It is unclear if oral choline intake is beneficial for preventing neural tube defects. Details: Population research has found that females who have a high dietary choline intake around the time of conception have a lower risk of having offspring with a neural tube defect when compared to those with lower intake (13134).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral choline is beneficial in patients with nonalcoholic fatty liver disease (NAFLD). Details: A cross-sectional analysis of results from observational and clinical research shows that low dietary intake of choline is associated with increased fibrosis in postmenopausal adults with NAFLD, but not in children, males, or premenopausal adults with NAFLD. Dietary choline intake was not associated with steatosis severity in any patient subgroup (92109).
• Schizophrenia. Although there has been interest in using oral choline for schizophrenia, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Tourette syndrome. Although there has been interest in using oral choline for Tourette syndrome, there is insufficient reliable information about the clinical effects of choline for this purpose.
• TPN-associated hepatic steatosis. It is unclear if intravenous choline is beneficial in patients with TPN-associated hepatic steatosis. Details: In patients receiving long-term total parenteral nutrition (TPN), plasma levels of choline can decrease. Small, low-quality clinical studies show that administering intravenous choline 1-4 grams daily for 24 weeks improves some markers of TPN-associated hepatic steatosis when compared with baseline or placebo (5174,42235). More evidence is needed to rate choline for these uses.

(Read more about CHOLINE)

POSSIBLY EFFECTIVE

• Genital herpes. Oral eleuthero root extract might help to prevent and reduce the severity of genital herpes outbreaks. Details: One clinical study in patients with recurrent genital herpes infections shows that taking a specific eleuthero root extract (Elagen) 400 mg, standardized to contain eleutheroside 0.3%, daily for at least 3 months reduces the frequency, severity, and duration of outbreaks when compared with placebo (730).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. Small clinical studies suggest that oral eleuthero root is not beneficial for improving athletic performance. Details: One study in trained distance runners shows that a specific eleuthero root liquid extract, standardized to eleutherosides B and E content, taken as 3.4 mL daily for 6 weeks, does not affect endurance, performance, or psychological, cardiac, or respiratory parameters when compared with placebo (7522). Small studies in trained athletes or healthy adults show that taking eleuthero 800-1200 mg daily (Endurox) for 1-6 weeks does not seem to have any effect on cycling performance time, respiration, lactate production, or heart rate recovery during cycling, stair-stepping exercise, treadmill, or cycle ergometry when compared with placebo (2335,7600,7601,8994). However, there has been some speculation that a longer duration of supplementation is needed for benefit. One study in recreationally trained athletes shows that taking a specific powdered eleuthero root product 400 mg twice daily for 8 weeks increased cycling endurance time by 23% and maximal oxygen consumption by 12% when compared with placebo. This product was standardized to contain eleutheroside B 0.11% and eleutheroside E 0.12% (17186).
• Bipolar disorder. It is unclear if oral eleuthero root is beneficial for bipolar disorder. Details: A small clinical study in Chinese adolescents aged 12-17 years with bipolar disorder shows that taking eleuthero root 750 mg orally three times daily, in conjunction with lithium for 6 weeks, induces similar response rates and remission rates when compared with lithium plus fluoxetine 20 mg (75028). It is not clear how this response rate compares to the use of lithium alone.
• Cardiovascular disease (CVD). It is unclear if oral eleuthero fruit is beneficial for preventing the development of CVD. Details: One small clinical study in healthy adults with at least two cardiovascular risk factors shows that taking an aqueous extract of eleuthero fruit 500 mg daily for 12 weeks seems to modestly reduce systolic blood pressure and arterial stiffness, as measured by brachial-ankle pulse wave velocity, when compared with placebo. It did not affect diastolic blood pressure, flow-mediated dilation, or carotid intima-media thickness. Also, taking a higher 1000 mg dose of the same eleuthero extract daily did not have significant effects on any measured parameters (105025).
• Chronic fatigue syndrome (CFS). It is unclear if oral eleuthero root is beneficial for CFS. Details: One clinical study in adults with CFS shows that taking eleuthero root extract 2 grams daily for 2 months improves fatigue severity and duration when compared to baseline, but not when compared with placebo (11099).
• Cognitive function. It is unclear if oral eleuthero is beneficial for cognitive function. Details: A very small clinical study in middle-aged people shows that taking eleuthero 325 mg twice daily might improve selective memory when compared with placebo (2574). Another very small study in healthy adults shows that taking a combination product containing extracts of eleuthero leaf 203 mg and Drynaria fortunei 20 mg daily for 12 weeks improves figure recall, but not immediate memory or attention, when compared with placebo (102316). It is unclear if this effect is due to eleuthero, Drynaria fortunei, or the combination.
• Common cold. Oral eleuthero has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some clinical research shows that taking capsules of a specific combination product containing eleuthero plus andrographis (Kan Jang, Swedish Herbal Institute) orally improves symptoms of the common cold when started within 72 hours of symptom onset. Some symptoms can improve after 2 days of treatment; however, it typically takes 4-5 days of treatment for maximal symptom relief (5784,10795,12380). Some research shows the combination of eleuthero and andrographis relieves cold symptoms better than echinacea or placebo in children (12381). It is unclear if this effect is due to eleuthero, andrographis, or the combination.
• Coronavirus disease 2019 (COVID-19). Oral eleuthero extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with a history of COVID-19 infection and current symptoms of long COVID-19 shows that taking a specific combination product containing eleuthero extract 78 mg, rhodiola extract 90 mg, and schisandra extract 300 mg (ADAPT-232/Chisan, Swedish Herbal Institute) twice daily for 2 weeks increases exercise capacity by about 13 minutes but does not reduce the duration of cough, fatigue, headache, pain, or other respiratory problems when compared with placebo (109635). It is unclear if these findings are due to eleuthero, other ingredients, or the combination.
• Diabetes. It is unclear if oral eleuthero is beneficial for improving glycemic control in type 2 diabetes. Details: One small clinical study in adults with type 2 diabetes shows that taking a specific eleuthero extract, standardized to contain eleutherosides E and B 1.12%, as 480 mg daily for 3 months, decreases fasting glucose by a mean of 36 mg/dL, postprandial blood glucose by a mean of 35 mg/dL, glycated hemoglobin (HbA1c) by a mean of 0.8%, triglycerides by a mean of 106 mg/dL, and total cholesterol by a mean of 21 mg/dL when compared with placebo (91509).
• Diabetic neuropathy. It is unclear if oral eleuthero is beneficial for diabetic neuropathy. Details: One small clinical study in adults with type 2 diabetes shows that taking a specific eleuthero extract, standardized to contain eleutherosides E and B 1.12%, as 480 mg daily for 3 months, modestly improves subjective symptoms of diabetic neuropathy when compared with placebo (91509).
• Dry eye. Oral eleuthero root has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults with dry eye disease shows that taking a specific combination product containing eleuthero root 50 mg, zinc 10 mg, L-carnitine 50 mg, elderberry fruit extract 300 mg, and currant 100 mg (Meramirt CM) once daily improves dry eye symptom scores when compared with no intervention. Contrast sensitivity scores also improved when compared to baseline in the treated group, but not in the control group (111295). It is unclear if these effects are due to eleuthero, other ingredients, or the combination.
• Familial Mediterranean fever. Oral eleuthero has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in children ages 3-15 years with familial Mediterranean fever shows that taking a specific combination product (ImmunoGuard, Inspired Nutritionals) containing eleuthero, andrographis, schisandra, and licorice for one month reduces the duration, frequency, and severity of disease recurrence when compared with placebo (12382). It is unclear if this effect is due to eleuthero, other ingredients, or the combination.
• Fibromyalgia. Although there is interest in using oral eleuthero for fibromyalgia, there is insufficient reliable information about the clinical effects of eleuthero for this condition.
• Hangover. It is unclear if oral eleuthero root is beneficial for hangovers. Details: One small clinical study in healthy males shows that consuming one bottle of a powdered polysaccharide-rich extract of eleuthero root before and after consuming alcohol modestly reduces the severity of hangover as measured by the Acute Hangover Scale questionnaire score when compared with placebo (91508). However, the validity of these findings is brought into question due to the incomplete study information provided.
• Influenza. Oral eleuthero has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with influenza shows that taking a specific combination product containing eleuthero 20-30 mg plus andrographis 178-266 mg (Kan Jang, Swedish Herbal Institute) three times daily for 3-5 days relieves symptoms more quickly than amantadine. This combination product also reduced the risk of post-influenza complications, such as sinusitis or bronchitis, when compared with amantadine (10441). It is unclear if these effects are due to eleuthero, andrographis, or the combination.
• Osteoarthritis. Oral eleuthero has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking two capsules each containing 400 mg of a combination of eleuthero, Panax pseudoginseng, and rehmannia daily for 6 weeks improves physical function in individuals with knee osteoarthritis when compared with placebo. However, the combination does not seem to reduce pain or stiffness when compared with placebo (74950). It is unclear if this effect is due to eleuthero, other ingredients, or the combination.
• Osteoporosis. Oral eleuthero has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in postmenopausal patients shows that taking low-dose calcium and vitamin D3 in combination with a 250 mg blend of rehmannia root and eleuthero stem bark extracts twice daily for 12 months attenuates the loss of spine and femur bone mineral density when compared with placebo or high-dose calcium and vitamin D (75036). It is unclear if this effect is due to eleuthero, rehmannia, or the combination.
• Pneumonia. Oral eleuthero has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with acute, nonspecific pneumonia shows that taking a specific combination product (ADAPT-232), containing eleuthero, rhodiola, and schisandra, as 20 mL twice daily for 10-15 days in conjunction with conventional treatment, reduces the duration of antibiotic treatment and improves quality of life when compared with conventional treatment alone (71152).
• Quality of life. It is unclear if oral eleuthero root improves quality of life in older healthy adults. Details: A small clinical study in elderly volunteers shows that taking eleuthero 300 mg daily improves social functioning and mental well-being after 4 weeks of treatment when compared with placebo. However, this improvement was not maintained after 8 weeks of treatment (15586).
• Rheumatoid arthritis (RA). Although there is interest in using oral eleuthero for RA, there is insufficient reliable information about the clinical effects of eleuthero for this condition.
• Stress. It is unclear if oral eleuthero root is beneficial for stress. Details: One clinical study in adults 30-50 years of age with symptoms of stress shows that taking a specific eleuthero root extract (WS 1070) 120 mg daily for 8 weeks does not improve fatigue, exhaustion, cognitive alertness, or measures of stress when taken alone or in conjunction with stress management training (91510). However, another small clinical study in healthy females 20-68 years of age who have experienced stress for a prolonged period of time shows that taking 270 mg of a combination agent (ADAPT-232) containing eleuthero, rhodiola, and schisandra improves attention and cognitive speed and accuracy when compared with placebo (19289). It is unclear if these effects are due to eleuthero, other ingredients, or the combination.
• Upper respiratory tract infection (URTI). Oral eleuthero has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in adults with an uncomplicated URTI shows that taking 30 mL of a combination product (Kan Jang, Swedish Herbal Institute) containing extracts of eleuthero root (eleutherosides B and E 0.03 mg/mL), echinacea root, and malabar nut leaf daily does not reduce the severity or frequency of cough by a clinically meaningful amount after 3-4 days of treatment when compared with bromhexine hydrochloride or placebo (95648). However, a non-blinded clinical study shows that taking 30 mL of this same product three times daily for 6 days improves the severity and frequency of coughing and the degree of nasal congestion when compared with bromhexine. Additionally, patients taking the combination product recovered two days sooner, on average, than those taking bromhexine (48569). The reason for these conflicting findings is unclear but may be due to an inadequate duration of treatment in the first study and/or lack of blinding in the second study. Also, it is unclear if any benefit is due to eleuthero, other ingredients, or the combination. Other research has evaluated a capsule formulation of Kan Jang (Swedish Herbal Institute), with each capsule containing eleuthero root 11.4 mg and andrographis 195 mg. One small clinical study in patients with an uncomplicated URTI shows that taking this product as two capsules three times daily for 5 days reduces the median number of sick leave days to 2 days, compared with 3 days in the placebo group. It also increases the total number of recovered patients on day 3 to 75%, compared with 55% of those taking placebo (107471). More evidence is needed to rate eleuthero for these uses.

(Read more about ELEUTHERO)

POSSIBLY EFFECTIVE

• Anxiety. Oral ginkgo seems to modestly reduce anxiety symptoms. Details: Clinical research shows that taking a specific ginkgo extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) for 4 weeks can modestly reduce symptoms of anxiety in a greater percentage of adults with generalized anxiety disorder or adjustment disorder with anxious mood when compared with placebo. After 4 weeks of treatment, a reduction in anxiety rating score of at least 50% was seen in 44% of patients treated with 480 mg daily, 39% of patients treated with 240 mg daily, and 22% of patients treated with placebo (15578). It is unclear whether these effects would persist when taken for longer than 4 weeks. This study was also included in a meta-analysis that performed indirect comparisons of multiple herbs for the treatment of anxiety. This analysis suggests that taking ginkgo may reduce anxiety scores modestly more than kava (110711). However, the interpretation of these results is limited by the small amount of data available for ginkgo.
• Dementia. Oral ginkgo 240 mg seems to improve symptoms of various types of dementia, but lower doses are not always effective. Oral ginkgo does not seem to prevent or slow down the progression of dementia. Details: Most evidence shows that higher doses of a specific ginkgo extract (EGb761) modestly improve symptoms of Alzheimer, vascular, or mixed dementias. Meta-analyses of clinical research in patients with dementia show that taking ginkgo, usually 240 mg daily for 24 weeks, modestly improves cognition and activities of daily living when compared with placebo. When analyses pooled studies testing low-dose (120 mg) and high-dose (240 mg) ginkgo together, the benefit was not always present (87855,87819,87851,87866,88006,89713,102183,102185,102186,103572)(111333). Although most clinical trials show benefit, there are some clinical trials with conflicting findings, suggesting inconsistent and unpredictable effects (16637,87726). There has been some debate about whether ginkgo is more effective in dementia patients who have neuropsychiatric symptoms. Most clinical research shows that this is not the case. However, high-dose ginkgo 240 mg daily seems to modestly relieve most neuropsychiatric symptoms other than psychosis (17717,87794,87897,102185,102187). Few clinical studies compare ginkgo leaf extract to conventional drugs such as cholinesterase inhibitors. Some preliminary comparative studies show that taking a specific ginkgo leaf extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) 160-240 mg daily for 22-24 weeks seems to be comparable to donepezil (Aricept) 5-10 mg daily for mild to moderate Alzheimer disease (14499,87826). Similarly, a clinical study in patients with Alzheimer disease or mild cognitive impairment shows that taking ginkgo extract 150 mg three times daily for 6 months seems to be comparable to donepezil 5 mg daily for improvement of cognitive scores (106611). However, indirect comparisons suggest that ginkgo leaf extract might be less effective than the conventional drugs donepezil, tacrine (Cognex), rivastigmine (Exelon), and other cholinesterase inhibitors (6224,6490,11981,89710). Also, some studies show that taking ginkgo in combination with conventional medications for 12-24 weeks does not improve cognitive scores by a clinically meaningful extent when compared with conventional medications alone (95902,106611). However, a meta-analysis of 17 mostly small, low quality clinical studies in patients with Alzheimer disease, that includes some of these studies, shows that taking ginkgo in combination with donepezil for 3-9 months modestly improves cognitive scores when compared with donepezil alone. Adding ginkgo may also improve activities of daily living scores (111332). Another meta-analysis of mostly small clinical studies in adults with vascular dementia also shows that taking ginkgo extract orally or intravenously daily for 4-12 weeks, in addition to donepezil, moderately improves cognitive scores and functional scores when compared with donepezil alone (114767). However, the validity of these findings is limited by the heterogeneity of the included studies, which utilized various doses and forms of ginkgo. Ginkgo does not appear to be beneficial for preventing or slowing the progression of dementia. Epidemiologic research shows that taking ginkgo extract is not associated with a decreased risk of developing dementia in elderly patients with memory impairment (14812). Three large-scale clinical trials also show that taking ginkgo extract 120 mg twice daily does not reduce the risk of developing all-cause dementia or Alzheimer disease in elderly patients with normal cognitive function or in those with mild cognitive impairment (16634,87848,87904). In addition, taking ginkgo extract does not seem to prevent disease progression in Alzheimer patients (89713). Most of the clinical studies on the effectiveness of ginkgo leaf for dementia have used the standardized extracts EGb 761 (Dr. Willmar Schwabe Pharmaceuticals and Ipsen) and LI 1370 (Lichtwer Pharma). These two extracts are similar and prepared to contain approximately 24% to 25% flavone glycosides and 6% terpene lactones. Other products with similar ingredients include Ginkai (Lichtwer Pharma), Ginkgo 5 (Pharmline), Ginkgold and Ginkgo (Nature's Way), and Quanterra Mental Sharpness (Warner-Lambert).
• Hearing loss. Intravenous ginkgo appears to improve hearing loss when used in conjunction with corticosteroids. The effectiveness of oral ginkgo is unclear. Details: A meta-analysis of randomized controlled trials (RCTs) in adults with sudden hearing loss shows that using intravenous ginkgo leaf extract 40-175 mg daily, in addition to corticosteroids, for 5-14 days increases clinical cure rates by 1.3 times that of corticosteroids alone. Ginkgo leaf in combination with corticosteroids also improved hearing sensitivity (107360). Another meta-analysis of 27 mostly low-quality RCTs in patients with sudden hearing loss, that includes some of the same studies as the prior analysis, shows that adding ginkgo extract to usual care for 1-14 days leads to improvement or no further deterioration in 91% of patients when compared with 75% of patients receiving usual care (111339). However, the interpretation of these results is limited by unclear ginkgo dosing and inclusion of studies that administered ginkgo orally, as an injection, or unknown route. In addition, usual care treatments were not described. In addition, one clinical study in patients with short-term idiopathic hearing loss shows that oral ginkgo leaf extract 120 mg twice daily for 8 weeks might improve hearing recovery rates when compared with ginkgo leaf extract 12 mg twice daily (8543). However, there was a high spontaneous recovery rate in both groups, so it is unclear how much benefit, if any, can be attributed to ginkgo leaf extract.
• Premenstrual syndrome (PMS). Oral ginkgo seems to reduce symptoms of PMS. Details: Taking ginkgo leaf extract orally 80 mg twice daily or 40 mg three times daily seems to produce significant relief in breast tenderness and other physical and psychological symptoms associated with PMS when started during the 16th day of the menstrual cycle and continued until the 5th day of the following cycle for up to two cycles (6229,87839). Specific ginkgo leaf extracts that have been assessed for this condition include Ginko T.D. (Tolidaru Pharmaceuticals) and EGb 761, which is an ingredient in several commercial products including Tebonin (Dr. Willmar Schwabe Pharmaceuticals), Tanakan (Ipsen), and Quanterra Mental Sharpness (Warner-Lambert).
• Schizophrenia. Oral ginkgo seems to reduce total and negative symptoms of schizophrenia, and may be beneficial for reducing antipsychotic-associated adverse effects. Details: Taking a standardized ginkgo leaf extract EGb 761 (Yi Kang Ning, Yang Zi Jiang Pharmaceuticals Ltd.), 120-360 mg orally daily in addition to standard antipsychotic medications (such as olanzapine, clozapine, or haloperidol) for 8-16 weeks, can reduce total and negative symptoms of schizophrenia when compared to treatment with antipsychotic medications alone (87844,95901). Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that ginkgo extract at doses of 120-360 mg daily is weakly recommended for adjunctive use in schizophrenia, primarily for negative symptoms (110318). Treatment with ginkgo leaf extract might also reduce anticholinergic side effects such as thirst and constipation and adverse behavioral, cardiovascular, and nerve symptoms associated with antipsychotic treatment (87708,95901). Additional clinical research is needed to determine the role of ginkgo on antipsychotic-associated adverse effects.
• Stroke. Oral and intravenous ginkgo seem to improve recovery from stroke; intravenous ginkgo might be more effective. Details: While some individual studies show conflicting results, meta-analyses of small, low-quality clinical trials in patients recovering from ischemic stroke show that oral or intravenous ginkgo extract along with conventional therapy seems to improve neurologic function and activities of daily living scores, but does not improve quality of life or reduce the risk of recurrent stroke or death, when compared with conventional therapy alone (14435,102883,102884,107452). However, the overall methodological quality of the meta-analyses is described as critically low, with a high risk of bias (113783). One meta-analysis shows that intravenous ginkgo extract is associated with greater improvements in these measures than oral ginkgo extract (102884). Ginkgo diterpene lactone meglumine (GDLM) is a derivative of ginkgo composed of active ingredients ginkgolides A, B, and K that has been investigated for the treatment of acute ischemic stroke both as monotherapy and in combination with thrombolysis. Large clinical trials in adults with moderate acute ischemic stroke show that giving an intravenous infusion of GDLM 25 mg daily, initiated within 48 hours of symptom onset and continuing for up to 14 days, increases the proportion of patients achieving a favorable outcome, defined as a score of 0 or 1 on the modified Rankin Scale (mRS) on day 90, by 15% when compared with placebo. About 62% of patients treated with GDLM show clinically significant improvement in Montreal Cognitive Assessment scores, compared with 56% of those on placebo. The most significant improvements occur in measures of language and visuo-spatial and executive function (111693,113784). Additionally, a meta-analysis shows that combination therapy with GDLM and tissue plasminogen activator (rTPA) is associated with greater improvements than conventional treatments alone or other traditional Chinese herbal medicines that contain ginkgo (i.e. ginaton, danhong, xueshuantong, and shuxuening injections). This specific formulation also appears to be more effective than intravenous ginkgolides or ginkgolide B; however, investigators did not provide a statistical comparison of outcomes between groups, limiting the validity of this finding (108610). Another meta-analysis shows that intravenous administration of ginkgo leaf extract plus dipyridamole 10-40 mL daily for 14-30 days along with conventional therapy also improves neurologic function and activities of daily living when compared with conventional therapy alone (102882). In patients not treated with thrombolytics, a small clinical study in adults in China shows that administering ginkgo diterpene lactone meglumine 25 mg intravenously daily for 14 days, starting within 48 hours after an ischemic stroke, in addition to aspirin 100 mg daily for 90 days, led to improvement in scores related to stroke severity or the degree of disability at 90 days in 94% of patients when compared with 83% of patients treated with aspirin alone (111340). However, the patients in this study had minor or moderate strokes; these results may not apply to patients with more severe strokes. In patients with hemorrhagic stroke, preliminary clinical research shows that daily intravenous administration of ginkgo extract (Taiwan Jisheng Chemical Pharmaceutical Co., Ltd.) 17.5 grams for 2 weeks, in conjunction with routine treatment and intravenous oxiracetam 6 grams, reduces cerebral edema and bleeding and modestly improves recovery of neurological and cognitive function and activities of daily living when compared with oxiracetam plus routine care or routine care alone (103573). A meta-analysis of 19 Chinese clinical trials in patients with hemorrhagic stroke shows that treatment with ginkgo leaf extracts for 7-20 days in combination with standard treatment is associated with lower NIH and Chinese stroke scale scores, lower residual hematoma and cerebral edema volumes, lower serum levels of inflammatory factors, and higher cognitive function and activity of daily living scores, when compared with standard treatment alone, although with considerable heterogeneity in the results (113781).
• Tardive dyskinesia. Oral ginkgo seems to reduce the severity of tardive dyskinesia in schizophrenic patients being treated with antipsychotic medications. Details: Clinical research shows that taking a specific ginkgo extract called EGb 761 (Yi Kang Ning, Yang Zi Jiang Pharmaceuticals Ltd.) 80 mg three times daily for 12 weeks can reduce the severity of tardive dyskinesia by at least 30% when compared with placebo in schizophrenic patients being treated with antipsychotic medications (87864).
• Vascular dementia. Oral ginkgo extract seems to modestly improve scores related to cognitive function in patients with this condition. Details: A meta-analysis of small randomized controlled trials in adults with vascular dementia shows that taking ginkgo extract orally or intravenously daily for 4-12 weeks, in addition to donepezil, moderately improves cognitive scores and functional scores when compared with donepezil alone (114767). However, the results of this study are limited by high heterogeneity. In addition, these trials do not report standard doses of ginkgo. A small clinical study in patients with vascular dementia shows that taking a specific extract of ginkgo EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) 240 mg daily for 24 weeks modestly improves scores related to cognitive function, neuropsychiatric symptoms, and activities of daily living when compared with placebo (17191). A preliminary open-label clinical study in patients aged 50 years or older in China shows that taking the same ginkgo extract 240 mg daily for 24 weeks, starting within 7-14 days after an ischemic stroke, modestly improves scores related to cognitive function and mental health, but not neuropsychiatric symptoms, when compared with standard care (111335). However, the patients in this study had minor strokes; these results may not apply to patients with more severe strokes. Ginkgo has also been evaluated in combination with other ingredients to treat vascular dementia. A small clinical study in patients aged 60 years or older with vascular dementia shows that taking a supplement containing extracts of ginkgo, Panax ginseng, and saffron 60 mg three times daily for 16 weeks modestly improves some cognitive function scores, caregiver assessed activities of daily living, and patient-reported quality of life. However, these effects were not maintained after patients stopped taking the supplement (111336).
• Vertigo. Oral ginkgo seems to improve symptoms of vertigo in people with vestibular disorders. It is unclear if it is beneficial for vertigo caused by cerebral arteriosclerosis. Details: Taking ginkgo leaf extract 120-160 mg daily orally seems to improve symptoms of vertigo and equilibrium disorders (5721,6220,6221,107359,108608). There is evidence from two clinical studies that ginkgo leaf extract (EGb 761) for 3 months is significantly more effective than placebo (6220), and possibly as effective as betahistine, for improving vertigo and dizziness caused by vascular vestibular disorders and vestibular disorders of unknown origin (6220,6221). However, adding balance training to treatment with ginkgo leaf extract (EGb 761) orally 80 mg twice daily for 3 months is no better than taking ginkgo leaf extract alone (107359). Ginkgo has also been evaluated in patients with vertigo caused by mild cerebral arteriosclerosis. A clinical study in this population shows that taking oral ginkgo leaf extract (Zhejiang Jiu Xu Pharmaceutical Co, Ltd) 40 mg three times daily for 6 weeks improves scores of traditional Chinese medicine symptom pattern, specifically dizziness, blurry vision, headache, and amnesia, but does not impact Dizziness Handicap Inventory scores, when compared with naoxinqing (NXQ), a standardized herbal product that contains Japanese persimmon leaf extract (108608). The validity of this study is limited due to the lack of comparison to placebo or an accepted conventional treatment.

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Most research shows that oral ginkgo does not improve symptoms of age-related cognitive impairment. Details: While some preliminary clinical research shows a modest benefit of ginkgo leaf extract on memory and cognitive function in patients with age-related memory or thinking impairment (5717,6216,89712), most clinical research shows that taking ginkgo leaf extract orally does not improve memory or attention in elderly individuals with normal mental function (5718,8586,8587,8588,87848). Clinical research also shows that taking a standardized ginkgo leaf extract (Thorne Research Inc.) 240 mg daily for 3.5 years does not reduce the risk of developing age-related cognitive impairment in elderly patients aged 85 years and older who have normal cognitive function (16635).
• Antidepressant-induced sexual dysfunction. Most research shows that oral ginkgo does not improve symptoms of sexual dysfunction in people using antidepressants. Details: Although some preliminary clinical research shows that taking ginkgo leaf extract orally might help sexual dysfunction caused by antidepressant therapy (3965,3967), subsequent research indicates that it not likely to be beneficial (207,3966,3969,10893,14383).
• Cardiovascular disease (CVD). Oral ginkgo does not seem to prevent CVD. Details: A large-scale randomized trial shows that taking a specific ginkgo leaf extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) 240 mg daily orally for an average of 6.1 years does not reduce the risk of myocardial infarction, angina, stroke, CVD-related hospitalization, or mortality in elderly patients when compared with placebo (17402).
• Chemotherapy-related cognitive impairment. Oral ginkgo does not seem to improve symptoms of cognitive impairment in people using chemotherapy. Details: Clinical research shows that taking a specific ginkgo leaf extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) 60 mg twice daily, starting prior to the second cycle of chemotherapy and continuing until one month after chemotherapy completion, does not prevent chemotherapy-related cognitive dysfunction when compared with placebo in chemotherapy-naïve breast cancer patients (89701).
• Hypertension. Oral ginkgo does not seem to reduce blood pressure in older, hypertensive patients. Details: A meta-analysis of low-quality research in subjects with hypertension shows that taking ginkgo orally daily for 4-26 weeks modestly improves systolic and diastolic blood pressure when compared with control (114766). However, the validity of this study is limited by high heterogeneity, differing co-interventions, including known antihypertensives, and differing controls. Other clinical research shows that taking a standardized ginkgo leaf extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) 240 mg daily for up to 6 years does not reduce blood pressure when compared with placebo in hypertensive patients aged 75 years or older (87853).
• Multiple sclerosis (MS). Most research shows that oral ginkgo does not improve symptoms of MS. Details: Most clinical research shows that taking ginkgo leaf extract or ginkgolide B, a constituent of ginkgo leaf extract, does not improve cognition or disability in patients with MS (87739,87787,87903,87947). However, a single preliminary clinical study shows that taking a standardized ginkgo leaf extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) may improve processing speed when compared with placebo in patients with multiple sclerosis (89705).
• Tinnitus. Most research shows that oral ginkgo does not improve symptoms of tinnitus. Details: Taking ginkgo leaf extract orally does not seem to improve symptoms of tinnitus. Although some studies have shown benefit, the majority of the clinical evidence indicates that ginkgo leaf extract is not consistently effective for patients with tinnitus (221,910,5721,6218,6219,9871,87754,87901,110093,111337)(111513).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). It is unclear if oral ginkgo is beneficial in AMD. Details: Preliminary clinical research suggests that taking a specific ginkgo leaf extract (EGb 761) 60-240 mg orally in divided doses for up to 6 months might improve symptoms of AMD (6227,6228,11797). There is limited evidence that ginkgo leaf extract might significantly improve distance vision in patients with AMD (6227).
• Aging. Although there has been interest in using oral ginkgo for aging, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Allergic rhinitis (hay fever). Topical ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with seasonal allergic conjunctivitis shows that applying two drops of specific eye drops (Trium, SOOFT) containing ginkgo extract 0.05% and hyaluronic acid 0.15%, three times daily for one month can decrease redness by 80%, discharge by 40%, and swelling by 10% when compared to using eye drops with hyaluronic acid alone (87829).
• Altitude sickness. Research on the use of oral ginkgo for altitude sickness is conflicting. Details: Some research shows that taking ginkgo extract 80-120 mg twice daily for 4 days before the ascent to an altitude of 4300-5400 meters significantly reduces the occurrence of symptoms of acute altitude sickness, including headache, fatigue, dyspnea, nausea, and vomiting, when compared with placebo (6230,87827). A standardized ginkgo leaf extract called EGb 761, 160 mg in two divided doses daily, was used in one of these studies (6230). However, a large-scale trial using a different ginkgo extract (GK501, Pharmaton Natural Health Products) 120 mg twice daily for 1-2 days before the climb from an altitude of 4280 meters to 4928 meters, shows that ginkgo extract has no effect on preventing altitude sickness (11766). Also, another small study suggests that taking ginkgo extract 120 mg twice daily for 3 days before an ascent does not reduce altitude sickness when compared with placebo (87827). The conflicting results may be due to differences in starting baseline altitudes before ascent, duration of the pre-treatment period, or the source of the ginkgo product.
• Angina. Some low-quality evidence suggests that oral ginkgo may reduce angina symptoms when taken in addition to standard of care. Details: A large meta-analysis of variable-quality studies in patients with unstable angina shows that taking ginkgo orally or intravenously for up to 12 weeks modestly improves angina symptoms when compared with control (114768). However, the results of this study are limited by the heterogeneity of included studies, including different control treatments. A small clinical study in patients with stable angina shows that taking ginkgo extract formulated with a polyethylene glycol matrix to improve bioavailability, 315 mg three times daily with standard therapy for 12 weeks, does not improve the overall Seattle Angina Questionnaire score when compared with placebo, although there is a trend towards a reduction in angina attack frequency (113782).
• Asthma. Oral ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that a taking two capsules of a specific combination product (AKL1, AKL International Ltd.) containing ginkgo extract 130 mg/capsule, ginger 100 mg/capsule, and Picrorhiza 270 mg/capsule twice daily for 12 weeks does not improve lung function, respiratory symptoms, or quality of life when compared with placebo in adult patients with asthma (87786).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral ginkgo is beneficial in ADHD. Details: One clinical study shows that taking a standardized ginkgo extract (Ginko T.D., Tolidaru Pharmaceuticals) 80-120 mg daily for 6 weeks is less effective than methylphenidate 20-30 mg daily in children aged 6-14 years with newly diagnosed ADHD. Only 8% of children taking ginkgo extract had at least a 40% improvement in a teacher/parent ADHD rating scale, compared with 64% in children taking methylphenidate (17112). Another clinical study in children aged 6-12 years with ADHD shows that taking the same standardized ginkgo extract 80-120 mg daily in combination with methylphenidate 20-40 mg daily for 6 weeks does not improve parent- or teacher-rated ADHD scores by a clinically meaningful amount when compared with methylphenidate alone (95669). However, one preliminary clinical study shows that taking a specific combination product (AD-fX, CV Technologies) containing ginkgo leaf extract 100 mg, in combination with American ginseng extract 400 mg, in two divided doses for 4 weeks might significantly improve ADHD symptoms such as anxiety, hyperactivity, and impulsivity in children aged 3-17 years (8235). Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that ginkgo extract at doses of 80-120 mg daily is not currently recommended for monotherapy or adjunctive use in children with ADHD due to mixed evidence (110318).
• Autism spectrum disorder. It is unclear if oral ginkgo is beneficial in children with autism. Details: A small clinical trial shows that taking a specific ginkgo extract (Ginko T.D., Tolidaru Pharmaceuticals) 80-120 mg daily for 10 weeks along with risperidone 1-3 mg daily does not improve symptoms of autism when compared with risperidone alone in children aged 4-12 years (89708).
• Bronchitis. Although there has been interest in using oral ginkgo for bronchitis, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Chronic fatigue syndrome (CFS). Oral ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with CFS shows that taking ginkgo leaf 120-180 mg in combination with Cistanche tubulosa root 300-450 mg orally daily for 60 days improves fatigue scores by 16% to 19% when compared with placebo. Taking this combination also improved quality of life scores when compared with placebo (107361).
• Chronic kidney disease (CKD). There is limited evidence on the intravenous use of ginkgo leaf extract in adults with hypertensive nephropathy. It has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small meta-analysis in patients with hypertensive nephropathy shows that intravenous administration of 20-30 mL of ginkgo leaf extract and dipyridamole injection once daily for 3-4 weeks along with conventional antihypertensive therapy improves levels of 24-hour urinary total protein, serum creatinine, and blood urea nitrogen by 0.6 grams/dL, 33 mg/dL, and 7 mg/dL, respectively (106610). It is unclear if these effects are due to ginkgo, dipyridamole, or the combination.
• Chronic obstructive pulmonary disease (COPD). Oral ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking two capsules of a specific combination product (AKL1, AKL International Ltd.) containing ginkgo extract, ginger, and Picrorhiza twice daily for 8 weeks does not improve respiratory symptoms when compared with placebo in patients with COPD (89702).
• Cocaine dependence. It is unclear if oral ginkgo is beneficial for maintenance of abstinence from cocaine. Details: A small clinical trial shows that taking a standardized ginkgo leaf extract called EGb 761 in a dose of 120 mg twice daily for 10 weeks does not help maintain abstinence from cocaine use when compared with placebo in cocaine-dependent patients (87723).
• Cognitive function. It is unclear if oral ginkgo is beneficial for cognitive function. Details: Clinical research in healthy adults shows that taking ginkgo leaf extract daily for up to 12 weeks might improve some measures of cognitive function, such as working and long term memory, attention based tasks, speed of information processing, executive function, immediate and delayed recall, and recognition (6214,6215,8236,8544,8585,8588,9759,16635,87788,87879,95668). Doses used in these studies include single doses of ginkgo extract 240-600 mg (6215,8236), a standardized ginkgo extract called EGb 761, 120-240 mg taken once daily or in 2-3 divided doses daily for 4-24 weeks (5717,6216,8585,8588,87879,95668), or another specific ginkgo extract called LI 1370 (Lichtwer Pharma), 120-300 mg daily in three divided doses for 2 days (6214). However, other clinical studies and one clinical review show no significant effect of ginkgo on gait ability, attention, memory, or executive function regardless of participant age, dose, or formulation used (87907,5718,8586,8587,8588,87907,95667). Due to the small number of study participants, significant differences in baseline cognitive function between groups, and variability in outcome measures, no definitive conclusions can be drawn. Larger scale studies are needed to determine the effect of ginkgo on cognitive function in healthy individuals. There is also conflicting evidence about the effect of ginkgo on cognitive function when taken in combination with other products. Some research suggests that taking ginkgo in combination with Panax ginseng or codonopsis enhances memory in healthy young or middle-aged adults, and the combinations might be more effective than the individual products (8591,9759,87758). These studies have used a specific combination product (Ginkoba M/E, Pharmaton SA) containing ginkgo extract 100-600 mg and Panax ginseng 60-360 mg, taken as a single dose or once daily for 12 weeks (8591,9759) or two capsules of a product containing ginkgo extract 40 mg/capsule and Codonopsis 75 mg/capsule daily (87758). However, other clinical research shows that taking ginkgo combined with Panax ginseng (Gincosan, Pharmaton Natural Health Products) or bacopa extract (Ginkgo Brahmi, Blackmore's Ltd.) for up to 12 weeks does not improve cognition when compared with placebo in healthy adults (87767,87748). Similarly, a moderate-sized clinical study in healthy adults aged 40-65 years shows that taking a supplement containing ginkgo leaf, bacopa, and B vitamins twice daily for 12 weeks does not improve memory or attention when compared with placebo (111334).
• Cognitive impairment. It is unclear if ginkgo is beneficial for cognitive impairment. Details: A clinical study of 500 patients with mild cognitive impairment that is abnormal for their age shows that taking a specific ginkgo standardized extract (EGb761, Tanakan) 40 mg three times daily for 24 months improves scores for cognitive decline, memory, activities of daily living, and depression when compared with baseline (105530). However, it is not clear if these improvements are clinically significant and the validity of the study is limited by the lack of a control group. Cognitive impairment is common side effect of electroconvulsive therapy (ECT). A small clinical study in patients aged 18-60 years with psychiatric disorders undergoing ECT in Iran shows that taking ginkgo (Vitarmonil Co., France) 200 mg after meals, starting 48 hours before initiation of ECT and continuing until the end of ECT sessions, modestly improves scores related to cognitive impairment and memory when compared with placebo (111338). However, it is unclear if these improvements are clinically significant.
• Colorectal cancer. Intravenous ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that adding intravenous ginkgo extract (EGb 761 ONC), 350 mg over 30 minutes on days 1-6 of every 3-week cycle to treatment with 5-fluorouracil 500 mg/m2 daily on days 2-6 of every 3-week cycle for 4 courses of treatment, might reduce disease progression in some patients with metastatic colorectal cancer (9872). However, since the study did not include a control group, it is unclear if the effects of treatment were greater than the effects of 5-fluorouracil alone.
• Cough. Although there has been interest in using oral ginkgo for cough, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Depression. It is unclear if oral ginkgo is beneficial in depression. Details: Preliminary clinical research in elderly patients shows that taking an unknown dose of a specific ginkgo extract (Harbin HaoBo Pharmaceutical Co., Ltd.) in conjunction with citalopram 20 mg daily for 12 weeks improves depression scores by 75% or more in an additional 3% of patients when compared with taking citalopram alone. Taking ginkgo extract with citalopram also produces a faster onset of action when compared to taking citalopram alone. However, it is not clear if these improvements are clinically significant (98811). A meta-analysis of 21 mainly Chinese studies shows that adding ginkgo preparations in various doses to conventional treatment for depression improves Hamilton Depression Scale scores and increases serotonin levels when compared with conventional treatment alone, but there is high heterogeneity in the results (113779).
• Diabetes. Research on the use of oral ginkgo in type 2 diabetes is conflicting. Details: In patients with uncontrolled type 2 diabetes taking metformin, preliminary clinical research shows that taking ginkgo extract (EGb 761) 120 mg for 90 days reduces glycated hemoglobin (HbA1c) levels from an average of 8.6% at baseline to an average of 7.7%. Fasting serum glucose and insulin were also reduced, when compared with baseline, by approximately 20% and 28%, respectively (103574). However, a meta-analysis of 7 clinical studies shows that taking ginkgo is associated with an increase in HbA1c levels, with no effect on fasting serum glucose levels. The only beneficial effect identified in this analysis was an increase in high density lipoprotein (HDL) cholesterol levels (105529). Another meta-analysis of mainly Chinese studies, shows that adding various ginkgo preparations to metformin for 1-3 years does not improve fasting serum glucose, HbA1c, or cholesterol levels, but does reduce blood viscosity and hematocrit while improving dorsalis pedis artery blood flow and ankle brachial index, suggesting a beneficial effect on peripheral arterial disease associated with diabetes (113780).
• Diabetic retinopathy. It is unclear if oral ginkgo is beneficial for this condition. Details: Preliminary clinical research shows that taking a specific ginkgo leaf extract called EGb 761 120 mg daily orally for 6 months improves measures of color vision when compared with placebo in patients with early diabetic retinopathy (6175).
• Dry eye. Ginkgo eye drops have only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A nonblinded clinical study in adults undergoing cataract surgery and receiving standard treatment shows that applying a specific, preservative-free eye drop (Trium Free; SOOFT) containing ginkgo extract 0.05% and hyaluronic acid 0.15%, three times daily, beginning the first day after surgery and continued for 4 weeks, reduces dry eye severity and symptoms when compared with standard treatment alone. After 4 weeks, 50% of patients in the standard treatment group reported dry eye symptoms, compared with 16% of patients using ginkgo (108609). The effects of ginkgo in patients with chronic dry eye or dry eye caused by other factors is unclear.
• Dyslexia. It is unclear if oral ginkgo is beneficial for dyslexia in children. Details: Preliminary clinical research shows that taking a standardized ginkgo leaf extract (EGb 761) 80 mg daily for an average of 34 days can help reduce dyslexia when compared to baseline in children aged 5-16 years (87790). The validity of this finding is limited by the lack of a comparator group.
• Fibromyalgia. Oral ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking tablets containing ginkgo extract (Bio-Biloba, Pharma Nord) 200 mg daily in conjunction with capsules containing coenzyme Q10 (Bio Quinone Q10, Pharma Nord) 200 mg daily orally for 84 days improves patient-reported quality of life, such as physical fitness levels, emotional feelings, social activities, overall health, and pain, when compared to baseline (17716). The validity of these findings is limited by the lack of a comparator group.
• Gastric cancer. It is unclear if oral ginkgo is beneficial in gastric cancer. Details: Preliminary clinical research shows that taking carbohydrates from the outer layer of ginkgo fruit 250 mg orally twice daily for 30 days may reduce tumor size in patients with gastric cancer when compared with pre-treatment (87742).
• Glaucoma. It is unclear if oral ginkgo is beneficial in glaucoma. Details: A small observational study has found that taking ginkgo leaf extract 80 mg twice daily for up to 12.3 years is associated with reduced progression of visual field damage in patients with normal tension glaucoma (87900). Furthermore, a small clinical study in patients with normal tension glaucoma shows that taking ginkgo leaf extract 40 mg three times daily for up 4 weeks might improve pre-existing damage and reduce the progression of damage to the visual field (10378). However, conflicting evidence exists. Another small study in patients with newly diagnosed normal tension glaucoma shows that taking a specific ginkgo extract (Ginaton, Dr. Willmar Schwabe Pharmaceuticals) 40 mg three times daily for 4 weeks does not improve damage or progression of glaucoma (89707). Reasons for the discrepancies may be due to the formulation of ginkgo leaf extract used or the severity of glaucoma at baseline.
• Hemorrhoids. Oral ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study shows that taking a combination of ginkgo extract, troxerutin, and heptaminol for one week may decrease some symptoms of hemorrhoids, including bleeding, pain, feelings of incomplete defecation, and discharge when compared to baseline (87751). The validity of these findings is limited by the lack of a comparator group. Additionally, it is unclear if these effects are due to ginkgo, other ingredients, or the combination.
• Hypercholesterolemia. Although there has been interest in using oral ginkgo for hypercholesterolemia, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Intestinal parasite infection. Although there has been interest in using oral ginkgo for intestinal parasite infection, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Lyme disease. Although there has been interest in using oral ginkgo for cognitive dysfunction associated with Lyme disease, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Migraine headache. Oral ginkgolide B, a constituent of ginkgo biloba extract, has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that ginkgolide B (BN52021), a constituent of ginkgo extract, along with coenzyme Q10, riboflavin, and magnesium, taken twice daily for 3 months, may help prevent migraines in school-aged children when compared to baseline (44181,87876). Also, a specific product (Migrasoll, Pharmaval Srl) containing ginkgolide B 60 mg, coenzyme Q10 11 mg, and vitamin B2 8.7 mg, taken twice daily for 4 months, may help prevent migraines in females when compared to baseline (44103). The validity of the findings from these studies is limited by the lack of a comparator group.
• Ovarian cancer. It is unclear if oral ginkgo is beneficial in preventing ovarian cancer. Details: Epidemiological evidence found that use of ginkgo extract for 6 months is associated with a decreased risk for developing ovarian cancer (14813).
• Pancreatic cancer. Intravenous ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that adding a specific intravenous ginkgo extract called EGb 761 ONC 350 mg on days 1-6 of every 3-week cycle to treatment with 5-fluorouracil 500 mg/m2 daily on days 2-6 of every 3-week cycle until disease progression might slow the progression of pancreatic cancer in some patients (87699). However, since the study did not include a control group, it is unclear if the effects of treatment were greater than the effects of 5-fluorouracil alone.
• Parkinson disease. It is unclear if oral ginkgo is beneficial for drug-induced Parkinsonism. Details: Preliminary clinical research in patients with psychiatric diagnoses treated with antipsychotic drugs shows that taking dried ginkgo extract, 80 mg three times daily orally for 3 months, reduces resting tremors, rigidity, bradykinesia, and the severity of motor symptoms when compared with placebo (112945).
• Peripheral arterial disease (PAD). It is unclear if oral ginkgo is beneficial in PAD. Details: Some small clinical studies show that taking a specific ginkgo leaf extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals and Ipsen) orally increases pain-free walking distance in patients with Fontaine's IIb peripheral arterial occlusive disease and intermittent claudication and might decrease overall peripheral vascular disease (PVD) event incidence, such as surgery or amputation, in elderly patients (3461,6211,6212,6213,17402). Significant benefit has been found with doses as low as 120-160 mg daily (6211). However, there is some evidence that a higher dose of 240 mg daily might be more beneficial in some patients (3461,6212). Although some research is positive, other research shows that taking a specific ginkgo leaf extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) 300 mg daily for 16 weeks does not significantly improve maximum treadmill walking time when compared with placebo in patients with PAD (16638). A reason for this discrepancy may be due to the duration of treatment. A meta-analysis of clinical research shows that taking ginkgo leaf extract does not improve maximum treadmill walking distance when compared with placebo in patients with Fontaine stage II PVD and intermittent claudication when administered for 6-8 weeks or 12-16 weeks, but does increase maximum treadmill walking distance by about 85 meters when administered for at least 24 weeks (89440).
• Pulmonary hypertension. It is unclear if intravenous ginkgo is beneficial in patients with pulmonary hypertension and cor pulmonale. Details: A meta-analysis of 28 small, low-quality clinical trials, including nearly 2500 Chinese patients with pulmonary hypertension and cor pulmonale, shows that intravenous administration of ginkgo leaf extract plus dipyridamole 15-40 mL daily for 1-4 weeks along with conventional therapy increases the total effective rate by 28% and improves various blood gas measures when compared with conventional therapy alone (102881). It is unclear if these effects are due to ginkgo, dipyridamole, or the combination. Large, high-quality clinical trials are needed to confirm these results.
• Quality of life. Some preliminary clinical studies suggest that oral ginkgo might improve quality of life in elderly individuals. Details: A large survey-based study shows that taking a standardized ginkgo leaf extract called LI 1370 (Lichtwer Pharma) 120 mg daily for 4-10 months may improve quality of life measures such as activities of daily living, mood, sleep, and alertness in elderly individuals when compared with control (87715,87760).
• Radiation exposure. It is unclear if intravenous ginkgo is beneficial in people who have been exposed to radiation. Details: Preliminary clinical research shows that taking a standardized ginkgo leaf extract called EGb 761 (Tanakan, Ipsen) 120 mg daily for 2 months might reduce clastogenic factors in the blood of patients who had previously been irradiated. The reduction in clastogenic factors was observed for at least 7 months after initiation of ginkgo in most patients (17719).
• Radiation dermatitis. Topical ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that applying a specific cream product (Radioskin 2, Herbalab di Perazza Massimiliano Company) containing ginkgo extract, Aloe vera, and metal esculetina, along with another specific cream product (Radioskin 1) containing alga atlantica and ethylbisiminomethylguaicolo manganese cloruro, may improve skin hydration and reduce skin toxicity associated with radiation therapy in patients with breast cancer (89727). The creams were applied topically 2-3 times daily at least 3 hours before and after radiation treatment from 15 days prior to radiation until one month after completion. It is unclear if these effects are due to ginkgo, other ingredients, or the combination.
• Raynaud syndrome. Evidence for the use of oral ginkgo for flare reduction is conflicting. Details: Some research shows that taking a standardized ginkgo extract (Seredrin, Health Perception Ltd.) 120 mg orally three times daily for 10 weeks can decrease the number of painful attacks per week in patients with Raynaud syndrome (11363). However, other research shows that ginkgo extract is no different than placebo in decreasing the number of attacks in these patients (87888). Also, another study shows that taking ginkgo extract 120 mg daily is less effective than nifedipine SR 30 mg daily orally in decreasing Raynaud syndrome flares (87818).
• Scabies. Although there has been interest in using topical ginkgo for scabies, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Seasonal affective disorder (SAD). It is unclear if oral ginkgo is beneficial for SAD. Details: One small clinical study shows that taking ginkgo leaf extract orally does not seem to prevent winter depression symptoms in patients with SAD when compared with placebo (8233).
• Sexual dysfunction. It is unclear if oral ginkgo is beneficial for sexual dysfunction in females. Details: Some clinical research shows that taking a ginkgo leaf extract 300 mg daily for 8 weeks does not significantly improve sexual function in females with sexual arousal disorder when compared with placebo (16640). However, other preliminary clinical research shows that taking a specific combination product (ArginMax for Women, Daily Wellness Company) containing ginkgo leaf extract, Panax ginseng root extract, damiana leaf extract, L-arginine, multivitamins, and minerals for 4 weeks can improve sexual satisfaction when compared with placebo in females who self-report sexual dysfunction (46933). It is unclear if these effects are due to ginkgo, other ingredients, or the combination.
• Venous thromboembolism (VTE). Although there has been interest in using oral ginkgo for thrombosis, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Vitiligo. It is unclear if oral ginkgo is beneficial for reducing vitiligo progression. Details: Preliminary clinical research shows that taking a specific ginkgo extract (Ginkgo Plus, Seroyal) 120 mg in two divided doses daily for up to 6 months reduces the progression of vitiligo vulgaris and lesion size when compared to baseline (17718,87728). The validity of these findings is limited by the lack of a comparator group.
• Wound healing. Although there has been interest in using topical ginkgo for healing of skin sores or chilblains, there is insufficient reliable information about the clinical effects of ginkgo for these conditions. More evidence is needed to rate ginkgo for these uses.

(Read more about GINKGO)

POSSIBLY EFFECTIVE

• Age-related cognitive decline. Oral bovine cortex-derived phosphatidylserine seems to improve attention and memory in patients with age-related cognitive decline. It is unclear if plant-derived phosphatidylserine is beneficial or whether phosphatidylserine is beneficial for preventing cognitive decline. Details: Clinical studies in people with age-related cognitive decline show that phosphatidylserine improves attention, arousal, verbal fluency, and memory (2440,2441,7119,7120,15539). Bovine- and plant-sourced phosphatidylserine 100 mg three times daily for up to 6 months has been used in these studies (2440,2441,15539). Most clinical studies have used phosphatidylserine derived from bovine cortex. However, most supplements now use soy- or cabbage-derived phosphatidylserine. There is some preliminary evidence that plant-derived phosphatidylserine also improves memory in people with age-associated memory impairment (15539). Also, clinical research in elderly females with complaints of memory loss shows that taking 1-3 capsules of a specific product (Vayacog, Enzymotec Ltd.) containing soybean-derived phosphatidylserine 100 mg/capsule, enriched with docosahexaenoic acid (DHA) 19.5 mg/capsule and eicosapentaenoic acid (EPA) 6.5 mg/capsule, daily for 15 weeks modestly improves immediate memory and sustained attention when compared with placebo (66055,90711). A post-hoc analysis of the results from this study suggests that cognitive improvements are greatest in patients with relatively good cognitive performance at baseline (66055). There is also interest in using phosphatidylserine to prevent age-related cognitive decline. In 2003, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that consuming phosphatidylserine may reduce the risk of developing age-related cognitive decline. However, the FDA has determined that there is very little scientific evidence supporting this claim (102363).
• Alzheimer disease. Oral bovine cortex-derived phosphatidylserine seems to improve cognitive function and behavior in patients with Alzheimer disease when used for up to 12 weeks, although benefits may disappear after 16 weeks. It is unclear if plant-derived phosphatidylserine is beneficial. Details: Taking phosphatidylserine orally can improve cognitive function and global improvement rating scales and improve behavioral rating scales over 6-12 weeks of treatment (2255,2437,2438,2439,7114,7118). Bovine-sourced phosphatidylserine 300-400 mg in divided doses daily for up to 16 weeks has been used (2255,2437,2438,2439). Phosphatidylserine seems to be most effective in patients with less severe symptoms (2437,2439). Phosphatidylserine might lose its effectiveness with extended use. After 16 weeks of treatment, progression of Alzheimer disease seems to overcome any benefit of phosphatidylserine (2255). Most clinical studies have used phosphatidylserine derived from bovine cortex. However, most supplements now use soy- or cabbage-derived phosphatidylserine. Clinical studies have not yet evaluated phosphatidylserine from soy or other sources. It is not known if phosphatidylserine from these sources is as effective as bovine-derived products.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. It is unclear if oral phosphatidylserine is beneficial for athletic performance. Details: One small clinical trial in golfers shows that taking nutritional bars containing phosphatidylserine 200 mg daily for 6 weeks improves the number of good ball flights, which may improve golf score; however, perceived stress levels and heart rate are not significantly affected (68855). A clinical study in recreationally active adults shows that taking phosphatidylserine 400 mg and caffeine 100 mg daily, along with niacin 28 mg, vitamin C 60 mg, vitamin B1 1.5 mg, vitamin B5 10 mg, vitamin B6 2 mg, vitamin E 12 IU, calcium 100 mg, magnesium 40 mg, and carbohydrates in the form of evaporated cane juice, brown rice syrup, and rice syrup solids 16 grams (Nutravail Technologies) for 14 days modestly reduces post-exercise mood disturbances and perception of fatigue when compared with vitamins and minerals alone. The combination does not appear to improve cognitive function or reaction time (91463). It is not clear if the effect of the combination supplement is due to phosphatidylserine, caffeine, or the combination.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral phosphatidylserine is beneficial for ADHD. Details: A meta-analysis of three generally low-quality randomized clinical trials shows that taking phosphatidylserine 200-300 mg daily for 8-15 weeks modestly improves symptoms of inattention in children with ADHD when compared with placebo. However, there were no significant effects on hyperactivity-impulsivity or on overall ADHD symptoms. Also, two of the three clinical trials included in the analysis investigated the effects of phosphatidylserine in combination with the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (105247). One preliminary clinical trial included in the analysis shows that taking soy-derived phosphatidylserine 200 mg daily for 2 months improves ADHD symptoms, including inattention, hyperactivity-impulsivity, and short-term memory, when compared to baseline in treatment-naïve children with ADHD aged 4-14 years. However, results from this study are limited due to a lack of statistical comparison to the placebo group (89498).
• Cognitive function. Although there is interest in using oral phosphatidylserine for improving cognitive function in healthy adults, there is insufficient reliable information about the clinical effects of phosphatidylserine for this purpose.
• Dementia. It is unclear if oral phosphatidylserine is beneficial for dementia prevention or treatment. Details: In 2003, the FDA determined that it would allow a qualified health claim stating that consuming phosphatidylserine may reduce the risk of dementia in the elderly. However, the FDA has determined that there is very little scientific evidence supporting this claim (102363).
• Depression. It is unclear if oral phosphatidylserine is beneficial for depression. Details: One very small clinical study in elderly adults with depression shows that taking phosphatidylserine 300 mg daily for 30 days modestly improves depression scores when compared to baseline (7113).
• Exercise-induced muscle soreness. It is unclear if oral phosphatidylserine is beneficial for exercise-induced muscle soreness. Details: One small clinical study in athletes shows that taking soybean-derived phosphatidylserine 800 mg daily for 2 weeks during periods of over-training reduces muscle soreness post-exercise when compared with those not taking phosphatidylserine (2264). More evidence is needed to rate phosphatidylserine for these uses.

(Read more about PHOSPHATIDYLSERINE)

LIKELY SAFE ...when used orally and appropriately. Acetyl-L-carnitine has been used safely in doses up to 3 grams daily in clinical trials lasting up to 33 months (42,1589,1594,1595,1596,1597,1598,1599,3600,3601) (9105,9791,10076,12743,12745,58375,90755,90756,90759,90761)(90766,90767,90768,95063,95067,111862).

POSSIBLY SAFE ...when used parenterally and appropriately under medical supervision (1591,1592,12743).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. Acetyl-L-carnitine has been safely used orally in children for up to 6 weeks (90754).

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

(Read more about ACETYL-L-CARNITINE)

LIKELY SAFE ...when used orally and appropriately. Choline is safe in adults when taken in doses below the tolerable upper intake level (UL) of 3.5 grams daily (3094) ...when used intravenously and appropriately. Intravenous choline 1-4 grams daily for up to 24 weeks has been used with apparent safety (5173,5174).

POSSIBLY UNSAFE ...when used orally in doses above the tolerable upper intake level (UL) of 3. 5 grams daily. Higher doses can increase the risk of adverse effects (3094).

CHILDREN: LIKELY SAFE
when used orally and appropriately (3094). Choline is safe in children when taken in doses below the tolerable upper intake level (UL), which is 1 gram daily for children 1-8 years of age, 2 grams daily for children 9-13 years of age, and 3 grams daily for children 14-18 years of age (3094).

CHILDREN: POSSIBLY UNSAFE
when used orally in doses above the UL. High doses can increase the risk of adverse effects (3094).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Choline is safe when taken in doses below the tolerable upper intake level (UL), which is 3 grams daily during pregnancy and lactation in those up to 18 years of age and 3.5 grams daily for those 19 years and older (3094,92114). There is insufficient reliable information available about the safety of choline used in higher doses during pregnancy and lactation.

(Read more about CHOLINE)

LIKELY SAFE ...when used orally and appropriately, short-term. Eleuthero root extract 300-2000 mg has been used safely in clinical trials lasting up to 3 months (730,1427,2574,7522,11099,15586,91509). There is insufficient reliable information available about the safety of eleuthero when used long-term.

CHILDREN: POSSIBLY SAFE
when used orally in adolescents aged 12-17 years, short-term. Eleuthero 750 mg three times daily was used for 6 weeks with apparent safety in one clinical trial (75028). There is insufficient reliable information available about the safety of eleuthero in children or adolescents when used long-term.

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

(Read more about ELEUTHERO)

LIKELY SAFE ...when used orally and appropriately. Standardized ginkgo leaf extracts have been used safely in trials lasting for several weeks up to 6 years (1514,1515,3461,5717,5718,6211,6212,6213,6214,6215)(6216,6222,6223,6224,6225,6490,14383,14499,16634,16635)(16636,16637,17402,17716,17718,87794,87819,87826,87848,87864)(87888,87897,87901,87904,89701,89707,107359,107360). There have been some reports of arrhythmias associated with ginkgo leaf extract. However, it is not yet clear if ginkgo might cause arrhythmia (105253,105254). There is some concern about toxic and carcinogenic effects seen in animals exposed to a ginkgo leaf extract containing 31.2% flavonoids, 15.4% terpenoids, and 10.45 ppm ginkgolic acid, in doses of 100 to 2000 mg/kg five times per week for 2 years (18272). However, the clinical relevance of this data for humans, using typical doses, is unclear. The content of the extract used is not identical to that commonly used in supplement products, and the doses studied are much higher than those typically used by humans. A single dose of 50 mg/kg in rats is estimated to be equivalent to a single dose of about 240 mg in humans (18272).

POSSIBLY SAFE ...when used intravenously, short-term. A standardized ginkgo leaf extract called EGb 761 ONC has been safely administered intravenously for up to 14 days (9871,9872,107360,107452). A Chinese preparation containing ginkgo leaf extract and dipyridamole has been safely administered intravenously for up to 30 days (102881,102882). ...when applied topically, short-term. There was no dermal irritation during a 24-hour patch test using the leaf extract, and no sensitization with repeat applications (112946). When used topically in cosmetics, extracts of ginkgo leaves are reported to be safe, but there is insufficient data to determine the safety of nut and root extracts, and isolated biflavones and terpenoids (112946).

POSSIBLY UNSAFE ...when the roasted seed or crude ginkgo plant is used orally. Consuming more than 10 roasted seeds per day can cause difficulty breathing, weak pulse, seizures, loss of consciousness, and shock (8231,8232). Crude ginkgo plant parts can exceed concentrations of 5 ppm of the toxic ginkgolic acid constituents and can cause severe allergic reactions (5714).

LIKELY UNSAFE ...when the fresh ginkgo seed is used orally. Fresh seeds are toxic and potentially deadly (11296).

PREGNANCY: POSSIBLY UNSAFE
when used orally. There is concern that ginkgo might have labor-inducing and hormonal effects. There is also concern that the antiplatelet effects of ginkgo could prolong bleeding time if taken around the time of labor and delivery (15052). Theoretically, ginkgo might adversely affect pregnancy outcome; avoid using during pregnancy.

LACTATION:
Insufficient reliable information available; avoid using.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term (87790,89708). A specific ginkgo dried extract (Ginko T.D., Tolidaru Pharmaceuticals), has been safely used in doses of 80-120 mg daily for 6 weeks in children aged 6-14 years (17112,95669). Another specific combination product containing ginkgo leaf extract and American ginseng extract (AD-FX, CV Technologies, Canada) has also been safely used in children aged 3-17 years for up to 4 weeks (8235).

CHILDREN: LIKELY UNSAFE
when ginkgo seed is used orally. The fresh seeds have caused seizures and death in children (8231,11296).

(Read more about GINKGO)

POSSIBLY SAFE ...when used orally and appropriately. Phosphatidylserine has been used with apparent safety at dose of up to 300 mg daily for up to 6 months (2255,2437,2438,2439,2440,2441,7118,15539,68855).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term (7117). Phosphatidylserine has been used with apparent safety in clinical research in doses of 200-300 mg daily for up to 4 months in children aged 4-18 years (7117,89498).

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

(Read more about PHOSPHATIDYLSERINE)

ACENOCOUMAROL (Sintrom) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, acetyl-L-carnitine might increase the anticoagulant effects of acenocoumarol.  Details L-carnitine, the parent compound of acetyl-L-carnitine, might enhance the anticoagulant effects of acenocoumarol, an oral anticoagulant that is similar to warfarin, but shorter-acting (9878,12165). There are at least two case reports of INR elevation when L-carnitine was taken with acenocoumarol. In one case, a 33-year-old male with a previously stable INR had an elevated INR of 4.65 after L-carnitine was started and continued for 10 weeks. INR normalized after discontinuation of the L-carnitine-containing product (12165). It is unclear if such an interaction would also occur with acetyl-L-carnitine.

SEROTONERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, acetyl-L-carnitine might increase the risk of serotonergic side effects, including serotonin syndrome and cerebral vasoconstrictive disorders, when taken with serotonergic drugs.  Details Animal research shows that acetyl-L-carnitine can increase levels of serotonin in the brain (95065).

THYROID HORMONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, acetyl-L-carnitine might decrease the effectiveness of thyroid hormone replacement.  Details L-carnitine appears to act as a peripheral thyroid hormone antagonist by inhibiting entry of thyroid hormone into the nucleus of cells (12761). Taking L-carnitine also seems to diminish some of the symptoms of hyperthyroidism (8047). It is unclear if such an interaction would occur with acetyl-L-carnitine.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, acetyl-L-carnitine might increase the anticoagulant effects of warfarin.  Details L-carnitine, the parent compound of acetyl-L-carnitine, might increase the anticoagulant effects of acenocoumarol, a shorter-acting oral anticoagulant similar to warfarin (9878,12165). There is not enough information to know whether this interaction occurs with acetyl-L-carnitine and warfarin.

(Read more about ACETYL-L-CARNITINE)

ATROPINE Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, choline might decrease the effects of atropine in the brain.  Details Animal research shows that administering choline one hour before administering atropine can attenuate atropine-induced decreases in brain levels of acetylcholine (42240). Theoretically, concomitant use of choline and atropine may decrease the effects of atropine.

(Read more about CHOLINE)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, eleuthero may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In vitro and animal research shows that a constituent of eleuthero, dihydroxybenzoic acid, appears to inhibit platelet aggregation (7592,74976). Concomitant use with anticoagulant or antiplatelet drugs might increase the risk of bleeding. This effect has not been reported in humans.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, eleuthero might have additive effects when used with antidiabetes drugs.  Details Animal research suggests that certain constituents of eleuthero have hypoglycemic activity in both healthy and diabetic animals (7591,73535,74932,74956,74988,74990). A small study in adults with type 2 diabetes also shows that taking eleuthero for 3 months can lower blood glucose levels (91509). However, one very small study in healthy individuals shows that taking powdered eleuthero 3 grams, 40 minutes prior to a 75-gram oral glucose tolerance test, significantly increases postprandial blood glucose levels when compared with placebo (12536). These contradictory findings might be due to patient-specific variability and variability in active ingredient ratios.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, eleuthero might increase levels of drugs metabolized by CYP1A2.  Details In vitro and animal research suggest that standardized extracts of eleuthero inhibit CYP1A2 (7532). This effect has not been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, eleuthero might increase levels of drugs metabolized by CYP2C9.  Details In vitro and animal research suggest that standardized extracts of eleuthero might inhibit CYP2C9 (7532). This effect has not been reported in humans.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, eleuthero might increase levels of drugs metabolized by CYP2D6.  Details In vitro and animal research suggest that standardized extracts of eleuthero might inhibit CYP2D6. However, research in healthy human volunteers has found that taking eleuthero 485 mg twice daily for 14 days does not inhibit CYP2D6 drug metabolism (7532,10400).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, eleuthero might increase levels of drugs metabolized by CYP3A4.  Details In vitro and animal research suggest that standardized extracts of eleuthero might inhibit CYP3A4. However, research in healthy human volunteers has found that taking eleuthero 485 mg twice daily for 14 days does not inhibit CYP3A4 drug metabolism (7532,10400).

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Eleuthero might increase serum digoxin levels and increase the risk of side effects.  Details In one case report, a 74-year-old male who was stabilized on digoxin presented with an elevated serum digoxin level after starting an eleuthero supplement, without symptoms of toxicity. After stopping the supplement, serum digoxin levels returned to normal (543). It is not clear whether this was due to a pharmacokinetic interaction or to interference with the digoxin assay (15585). Although the product was found to be free of digoxin and digitoxin (543), it was not tested for other contaminants (797).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, eleuthero might interfere with immunosuppressive drugs because of its immunostimulant activity.  Details Animal and in vitro research shows that eleuthero extracts have immunomodulatory effects, including increasing cellular and humoral activity (74887,74915).

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, eleuthero might decrease levels of drugs metabolized by OATP.  Details In vitro research suggests that eleuthero inhibits OATP2B1, which might reduce the bioavailability of oral drugs that are substrates of OATP2B1 (35450). Due to the weak inhibitory effect identified in this study, this interaction is not likely to be clinically significant.

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, eleuthero might increase levels of P-glycoprotein substrates.  Details In vitro research suggests that eleuthero can inhibit the multi-drug transporter protein, P-glycoprotein (22639,91509). However, it is too soon to tell if this is clinically important. This interaction has not been reported in humans.

(Read more about ELEUTHERO)

ALPRAZOLAM (Xanax) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, ginkgo might decrease the levels and clinical effects of alprazolam.  Details In clinical research, ginkgo extract (Ginkgold) 120 mg twice daily seems to decrease alprazolam levels by about 17%. However, ginkgo does not appear to decrease the elimination half-life of alprazolam. This suggests that ginkgo is more likely to decrease absorption of alprazolam rather than induce hepatic metabolism of alprazolam (11029).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = A Ginkgo has been shown to increase the risk of bleeding in some people when taken with warfarin. Theoretically, ginkgo might increase the risk of bleeding if used with other anticoagulant or antiplatelet drugs.  Details Several pharmacodynamic studies suggest that ginkgo inhibits platelet aggregation. It is thought that the ginkgo constituent, ginkgolide B, displaces platelet-activating factor (PAF) from its binding sites, decreasing blood coagulation (6048,9760). Several case reports have documented serious bleeding events in patients taking ginkgo (244,578,579,8581,13002,13135,13179,13194,14456,87868). However, population and clinical studies have produced mixed results. Some evidence shows that short-term use of ginkgo leaf does not significantly reduce platelet aggregation and blood clotting (87732). A study in healthy males who took a specific ginkgo leaf extract (EGb 761) 160 mg twice daily for 7 days found no change in prothrombin time (12114). An analysis of a large medical record database suggests that ginkgo increases the risk of a bleeding adverse event by 38% when taken concurrently with warfarin (91326). It has been suggested that ginkgo has to be taken for at least 2-3 weeks to have a significant effect on platelet aggregation (14811). However, a meta-analysis of 18 studies using standardized ginkgo extracts, 80-480 mg daily for up to 32 weeks, did not find a significant effect on platelet aggregation, fibrinogen concentration, or PT/aPTT (17179). In addition, a single dose of ginkgo plus clopidogrel (14811) or ticlopidine does not seem to significantly increase bleeding time or platelet aggregation (17111,87846). Also, taking ginkgo leaf extract daily for 8 days in conjunction with rivaroxaban does not affect anti-factor Xa activity; however, this study did not evaluate bleeding time (109526).

ANTICONVULSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might reduce the effectiveness of anticonvulsants.  Details Ginkgo seeds contain ginkgotoxin. Large amounts of ginkgotoxin can cause neurotoxicity and seizure. Ginkgotoxin is present in much larger amounts in ginkgo seeds than leaves (8232). Ginkgo leaf extract contains trace amounts of ginkgotoxin. The amount of ginkgotoxin in ginkgo leaf and leaf extract seems unlikely to cause toxicity (11296). However, there are anecdotal reports of seizure occurring after use of ginkgo leaf both in patients without a history of seizure disorder and in those with previously well-controlled epilepsy (7030,7090).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking ginkgo with antidiabetes drugs might alter the response to antidiabetes drugs.  Details Ginkgo leaf extract seems to alter insulin secretion and metabolism, and might affect blood glucose levels in people with type 2 diabetes (5719,14448,103574). The effect of ginkgo seems to differ depending on the insulin and treatment status of the patient. In diet-controlled diabetes patients with hyperinsulinemia, taking ginkgo does not seem to significantly affect insulin or blood glucose levels. In patients with hyperinsulinemia who are treated with oral hypoglycemic agents, taking ginkgo seems to decrease insulin levels and increase blood glucose following an oral glucose tolerance test. Researchers speculate that this could be due to ginkgo-enhanced hepatic metabolism of insulin. In patients with pancreatic exhaustion, taking ginkgo seems to stimulate pancreatic beta-cells, resulting in increased insulin and C-peptide levels, but with no significant change in blood glucose levels in response to an oral glucose tolerance test (14448).

ATORVASTATIN (Lipitor) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, ginkgo might decrease the levels and clinical effects of atorvastatin.  Details In humans, intake of ginkgo extract appears to increase atorvastatin clearance, reducing the area under the curve of atorvastatin by 10% to 14% and the maximum concentration by 29%. However, this interaction does not appear to affect cholesterol synthesis and absorption (89706). Further, a model in rats with hyperlipidemia suggests that administering ginkgo extract does not impact blood levels of atorvastatin and leads to lower total cholesterol, low-density lipoprotein cholesterol, and triglycerides when compared with rats given atorvastatin alone (111331).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, ginkgo might increase levels of drugs metabolized by CYP1A2.  Details Laboratory research suggests that ginkgo leaf extract can mildly inhibit CYP1A2 enzymes (1303,6423,6450). However, clinical research suggests ginkgo might not affect CYP1A2 (10847). Until more is known, use ginkgo cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, ginkgo might decrease levels of drugs metabolized by CYP2C19.  Details Some clinical research shows that a specific ginkgo leaf extract (Remembrance, Herbs Product LTD) 140 mg twice daily can induce CYP2C19 enzymes and potentially decrease levels of drugs metabolized by these enzymes (13108). However, other clinical research shows that taking ginkgo 120 mg twice daily for 12 days has no effect on levels of drugs metabolized by CYP2C19 (87824).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might increase levels of drugs metabolized by CYP2C9.  Details In vitro, a specific standardized extract of ginkgo leaf (EGb 761) inhibits CYP2C9 activity (11026,12061,14337). The terpenoid (ginkgolides) and flavonoid (quercetin, kaempferol, etc.) constituents seem to be responsible for this effect. Most ginkgo extracts contain some amount of these constituents. Therefore, other ginkgo leaf extracts might also inhibit the CYP2C9 enzyme. However, clinical research suggests that ginkgo might not have a significant effect on CYP2C9 in humans. Ginkgo does not seem to significantly affect the pharmacokinetics of CYP2C9 substrates diclofenac or tolbutamide.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, ginkgo might decrease levels of drugs metabolized by CYP3A4.  Details There is conflicting evidence about whether ginkgo induces or inhibits CYP3A4 (1303,6423,6450,11026,87800,87805,111330). Ginkgo does not appear to affect hepatic CYP3A4 (11029). However, it is not known if ginkgo affects intestinal CYP3A4. Preliminary clinical research suggests that taking ginkgo does not significantly affect levels of donepezil, lopinavir, or ritonavir, which are all CYP3A4 substrates (11027,87800,93578). Other clinical research also suggests ginkgo does not significantly affect CYP3A4 activity (10847). However, there are two case reports of decreased efavirenz concentrations and increased viral load in patients taking ginkgo. It is suspected that terpenoids from the ginkgo extract reduced drug levels by inducing cytochrome P450 3A4 (CYP3A4) (16821,25464).

EFAVIRENZ (Sustiva) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might decrease the levels and clinical effects of efavirenz.  Details There are two case reports of decreased efavirenz concentrations and increased viral load in patients taking ginkgo. In one case, an HIV-positive male experienced over a 50% decrease in efavirenz levels over the course of 14 months while taking ginkgo extract. HIV-1 RNA copies also increased substantially, from less than 50 to more than 1500. It is suspected that terpenoids from the ginkgo extract reduced drug levels by inducing cytochrome P450 3A4 (CYP3A4) (16821). In another case report, a patient stable on antiviral therapy including efavirenz for 10 years, had an increase in viral load from <50 copies/mL to 1350 copies/mL after 2 months of taking a combination of supplements including ginkgo. After stopping ginkgo, the viral load was again controlled with the same antiviral therapy regimen (25464).

IBUPROFEN (Advil, others) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might increase the risk of bleeding when used with ibuprofen.  Details Ginkgo might have antiplatelet effects and has been associated with several case reports of spontaneous bleeding. In one case, a 71-year-old male had taken a specific ginkgo extract (Gingium, Biocur) 40 mg twice daily for 2.5 years. About 4 weeks after starting ibuprofen 600 mg daily he experienced a fatal intracerebral hemorrhage (13179). However, the antiplatelet effects of ginkgo have been questioned. A meta-analysis and other studies have not found a significant antiplatelet effect with standardized ginkgo extracts, 80 mg to 480 mg taken daily for up to 32 weeks (17179).

NIFEDIPINE (Procardia) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking ginkgo with oral, but not intravenous, nifedipine might increase levels and adverse effects of nifedipine.  Details Animal research and some clinical evidence suggests that taking ginkgo leaf extract orally in combination with oral nifedipine might increase nifedipine levels and cause increased side effects, such as headaches, dizziness, and hot flushes (87764,87765). However, taking ginkgo orally does not seem to affect the pharmacokinetics of intravenous nifedipine (87765).

OMEPRAZOLE (Prilosec) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking ginkgo with omeprazole might decrease the levels and clinical effects of omeprazole.  Details Clinical research shows that a specific ginkgo leaf extract (Remembrance, Herbs Product LTD) 140 mg twice daily can induce cytochrome P450 (CYP) 2C19 enzymes and decrease levels of omeprazole by about 27% to 42% (13108).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking ginkgo with P-glycoprotein substrates might increase the levels and adverse effects of these substrates.  Details A small clinical study in healthy volunteers shows that using ginkgo leaf extract 120 mg orally three times daily for 14 days can increase levels of the P-glycoprotein substrate, talinolol, by 36% in healthy male individuals. However, single doses of ginkgo do not have the same effect (87830).

RISPERIDONE (Risperdal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ginkgo with risperidone might increase the levels and adverse effects of risperidone.  Details A single case of priapism has been reported for a 26-year-old male with schizophrenia who used risperidone 3 mg daily along with ginkgo extract 160 mg daily (87796). Risperidone is metabolized by cytochrome P450 (CYP) 2D6 and CYP3A4. CYP3A4 activity might be affected by ginkgo. Theoretically, ginkgo may inhibit the metabolism of risperidone and increase the risk of adverse effects.

ROSIGLITAZONE (Avandia) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might decrease the levels and clinical effects of rosiglitazone.  Details Animal research shows that ginkgo leaf extract orally 100 or 200 mg/kg daily for 10 days alters the pharmacodynamics of rosiglitazone in a dose-dependent manner. The 100 mg/kg and 200 mg/kg doses reduce the area under the concentration time curve (AUC) of rosiglitazone by 39% and 52%, respectively, and the half-life by 28% and 39%, respectively. It is hypothesized that these changes may be due to induction of cytochrome P450 2C8 by ginkgo (109525).

SEIZURE THRESHOLD LOWERING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ginkgo with drugs that lower the seizure threshold might increase the risk for convulsions.  Details Ginkgo seeds contain ginkgotoxin. Large amounts of ginkgotoxin can cause neurotoxicity and seizure. Ginkgotoxin is present in much larger amounts in ginkgo seeds than leaves (8232). Ginkgo leaf extract contains trace amounts of ginkgotoxin. The amount of ginkgotoxin in ginkgo leaf and leaf extract seems unlikely to cause toxicity (11296). However, there are anecdotal reports of seizure occurring after use of ginkgo leaf both in patients without a history of seizure disorder and in those with previously well-controlled epilepsy (7030,7090,14281).

SIMVASTATIN (Zocor) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, ginkgo might decrease the levels and clinical effects of simvastatin.  Details Clinical research shows that taking ginkgo extract can reduce the area under the curve and maximum concentration of simvastatin by 32% to 39%. However, ginkgo extract does not seem to affect the cholesterol-lowering ability of simvastatin (89704).

SOFOSBUVIR (Sovaldi) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might increase the levels and clinical effects of sofosbuvir.  Details Animal research in rats shows that giving a ginkgo extract 25 mg/kg orally daily for 14 days increases the area under the concentration time curve (AUC) after a single sofosbuvir dose of 40 mg/kg by 11%, increases the half-life by 60%, and increases the plasma concentration at 4 hours by 38%. This interaction appears to be related to the inhibition of intestinal P-glycoprotein by ginkgo (109524).

TACROLIMUS (Prograf) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might increase the blood levels of tacrolimus.  Details In vitro evidence suggests that certain biflavonoids in ginkgo leaves (i.e. amentoflavone, ginkgetin, bilobetin) may inhibit the metabolism of tacrolimus by up to 50%. This interaction appears to be time-dependent and due to inhibition of cytochrome P450 (CYP) 3A4 by these bioflavonoids. In rats given tacrolimus 1 mg/kg orally, amentoflavone was shown to increase the area under the concentration time curve (AUC) of tacrolimus by 3.8-fold (111330).

TALINOLOL Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Taking ginkgo with talinolol seems to increase blood levels of talinolol.  Details There is some evidence that using ginkgo leaf extract 120 mg orally three times daily for 14 days can increase levels of talinolol by 36% in healthy male individuals. However, single doses of ginkgo do not seem to affect talinolol pharmacokinetics (87830).

TRAZODONE (Desyrel) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might increase the levels and clinical effects of trazodone.  Details In a case report, an Alzheimer patient taking trazodone 20 mg twice daily and ginkgo leaf extract 80 mg twice daily for four doses became comatose. The coma was reversed by administration of flumazenil (Romazicon). Coma might have been induced by excessive GABA-ergic activity. Ginkgo flavonoids are thought to have GABA-ergic activity and act directly on benzodiazepine receptors. Ginkgo might also increase metabolism of trazodone to active GABA-ergic metabolites, possibly by inducing cytochrome P450 3A4 (CYP3A4) metabolism (6423).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Ginkgo has been shown to increase the risk of bleeding in some people when taken with warfarin.  Details Several pharmacodynamic studies suggest that ginkgo inhibits platelet aggregation. It is thought that the ginkgo constituent, ginkgolide B, displaces platelet-activating factor (PAF) from its binding sites, decreasing blood coagulation (6048,9760). Several case reports have documented serious bleeding events in patients taking ginkgo (244,576,578,579,8581,13002,13135,13179,13194,14456,87868). Information from a medical database suggests that when taken concurrently with warfarin, ginkgo increases the risk of a bleeding adverse event by 38% (91326). There is also some evidence that ginkgo leaf extract can inhibit cytochrome P450 2C9, an enzyme that metabolizes warfarin. This could result in increased warfarin levels (12061). However, population and clinical research has produced mixed results. Clinical research in healthy people suggests that ginkgo has no effect on INR, or the pharmacokinetics or pharmacodynamics of warfarin (12881,15176,87727,87889). A meta-analysis of 18 studies using standardized ginkgo extracts, 80 mg to 480 mg daily for up to 32 weeks, did not find a significant effect on platelet aggregation, fibrinogen concentration, or PT/aPTT (17179). There is also some preliminary clinical research that suggests ginkgo might not significantly increase the effects of warfarin in patients that have a stable INR (11905).

(Read more about GINKGO)

ANTICHOLINERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, phosphatidylserine might decrease the effectiveness anticholinergic drugs.  Details Phosphatidylserine is thought to increase acetylcholine levels (2437,8857,8858), which could theoretically interfere with the activity of anticholinergic agents.

CHOLINERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, phosphatidylserine might have additive effects with cholinergic drugs.  Details Phosphatidylserine is thought to increase acetylcholine levels (2437,8857,8858), which could theoretically lead to additive cholinergic effects when used with cholinergic drugs.

(Read more about PHOSPHATIDYLSERINE)

General ...Orally, acetyl-L-carnitine is generally well tolerated.
Most Common Adverse Effects:
Orally: Agitation, dry mouth, headache, insomnia, and reduced appetite. A metabolite of acetyl-L-carnitine has been reported to cause a fishy odor of the urine, breath, and sweat.

Cardiovascular ...Orally, one patient in a pharmacokinetic study reported high blood pressure 8 hoursafter taking acetyl-L-carnitine 500 mg; however, it is unclear if this was due to acetyl-L-carnitine or another factor (95061).

Dermatologic ...Orally, a combination of acetyl-L-carnitine and alpha-lipoic acid may cause rash (90441).

Gastrointestinal ...Orally, acetyl-L-carnitine may cause nausea, vomiting, diarrhea, constipation, hiccups, abdominal distension and gastrointestinal upset or pain. However, gastrointestinal symptoms do not usually occur more often in patients receiving acetyl-L-carnitine than in patients receiving placebo (1596,1599,12743,13007,58922,90755,95063,95067,111889,111894). Acetyl-L-carnitine may also cause dry mouth and anorexia (58342). When taken orally, a combination of acetyl-L-carnitine and alpha-lipoic acid may cause diarrhea, constipation, and dyspepsia (90441).

Neurologic/CNS ...Orally, acetyl-L-carnitine may cause headache and insomnia (90760,90767,95063). In one clinical trial, two patients with antiretroviral toxic neuropathy reported paresthesia, pain, and neuropathy after taking acetyl-L-carnitine 1000 mg daily (58342). A case of mania has been reported for a patient with bipolar I disorder currently in remission. The patient presented with symptoms after taking multiple supplements for the past 4 weeks including acetyl-L-carnitine 1000 mg twice daily. The symptoms appeared 3 days after beginning to take acetyl-L-carnitine and worsened over the next week. The patient had increased speech rate and volume and reported increased energy levels and racing thoughts. The patient's parent reported irritability and an increase in loud behaviors at home, similar to a previous episode of mania. The patient was advised to discontinue acetyl-L-carnitine, and the manic symptoms disappeared 3 days later (95062).

Psychiatric ...Orally, acetyl-L-carnitine may cause agitation (restlessness and motor overactivity) (1596,1599,12743,13007). Side effects reported in people with Alzheimer disease include psychiatric disturbances such as depression, mania, confusion and aggression, but it is not clear whether these are due to acetyl-L-carnitine or the condition itself (1594,1595,1596,1597,1598,1599,9105,10391).

Other ...One of the metabolites of acetyl-L-carnitine can cause the urine, breath, and sweat to have a fishy odor (12756). Also, foul smelling urine has been reported following oral use of a combination of acetyl-L-carnitine and alpha-lipoic acid (90441).

(Read more about ACETYL-L-CARNITINE)

General ...Orally, choline is well tolerated when used appropriately. Adverse effects have been reported with doses exceeding the tolerable upper intake level (UL) of 3.5 grams daily.
Most Common Adverse Effects:
Orally: Fishy body odor. At high doses of at least 9 grams daily, choline has been reported to cause diarrhea, nausea, salivation, sweating, and vomiting.

Cardiovascular ...Orally, doses of choline greater than 7. 5 grams daily may cause low blood pressure (94648).

Gastrointestinal ...Orally, large doses of choline can cause nausea, vomiting, salivation, and anorexia (42275,91231). Gastrointestinal discomfort has reportedly occurred with doses of 9 grams daily, while gastroenteritis has reportedly occurred with doses of 32 grams daily (42291,42310). Doses of lecithin 100 grams standardized to 3.5% choline have reportedly caused diarrhea and fecal incontinence (42312).

Genitourinary ...Orally, large doses of choline greater than 9 grams daily have been reported to cause urinary incontinence (42291).

Neurologic/CNS ...Orally, high intake of choline may cause sweating due to peripheral cholinergic effects (42275).

Oncologic ...In one population study, consuming large amounts of choline was associated with an increased risk of colorectal cancer in females, even after adjusting for red meat intake (14845). However, more research is needed to confirm this finding.

Psychiatric ...Orally, large doses of choline (9 grams daily) have been associated with onset of depression in patients taking neuroleptics. Further research is needed to clarify this finding (42270).

Other ...Orally, choline intake may cause a fishy body odor due to intestinal metabolism of choline to trimethylamine (42285,42275,42310,92111,92112).

(Read more about CHOLINE)

General ...Orally, eleuthero root is generally well tolerated when used short-term.
Most Common Adverse Effects:
Orally: Diarrhea, dyspepsia, gastrointestinal upset, headache, nausea, and urticaria.

Cardiovascular ...Orally, increased blood pressure has been reported in children with hypotension taking eleuthero in one clinical study (74980). Eleuthero has been reported to cause tachycardia, hypertension, and pericardial pain in patients with rheumatic heart disease or atherosclerosis. It is unclear if these effects were caused by eleuthero, or by the cardioglycoside-containing herb, silk vine (Periploca sepium), which is a common adulterant found in eleuthero products (12,797,6500).

Dermatologic ...Orally, eleuthero has been reported to cause rash in some clinical studies (75013,75028).

Gastrointestinal ...Orally, eleuthero has been reported to cause dyspepsia, nausea, diarrhea, and gastrointestinal upset in some patients (74938,75028,91510).

Genitourinary ...Orally, mastalgia and uterine bleeding were reported in 7. 3% of females taking eleuthero 2 grams daily in one clinical study (6500,11099). These adverse effects seem to be more likely with higher doses.

Neurologic/CNS ...Orally, headaches have been reported in 9. 8% of people taking eleuthero in one clinical study (11099).
In one case report, a 53-year-old female developed spontaneous subarachnoid hemorrhage associated with the use of an herbal supplement containing red clover, dong quai, and eleuthero (70419). It is unclear if this event was related to the use of eleuthero, the other ingredients, the combination, or another cause entirely.

Psychiatric ...Orally, nervousness has been reported in 7. 3% of people taking eleuthero in one clinical study (11099). Eleuthero has also been reported to cause slight anxiety, irritability, and melancholy in some patients (6500,11099). These adverse effects seem to be more likely to occur with higher doses.

(Read more about ELEUTHERO)

General ...Orally, ginkgo leaf extract is generally well tolerated when used for up to 6 years. However, the seed and crude plant contain toxic constituents and should be avoided.
Intravenously, ginkgo leaf extract seems to be well tolerated when used for up to 30 days.
Topically, no adverse effects have been reported with ginkgo as a single ingredient. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Dizziness, gastrointestinal symptoms, headache.
Serious Adverse Effects (Rare):
Orally: Arrhythmia, bleeding, Stevens-Johnson syndrome.

Cardiovascular ...Cardiac arrhythmias suspected to be related to ginkgo have been reported. Internationally, there are at least 162 reports from 18 countries, with 34% of cases considered serious, involving five deaths and four life-threatening events. Additionally, a report from Canada found that 10 out of 15 cases of arrhythmia were considered serious. Ginkgo was the only suspect ingredient in 57% of all international reports, with symptoms generally presenting within days of initiation. The most common symptoms included palpitations, tachycardia, bradycardia, syncope, and loss of consciousness. Most cases were reported to be related to oral use of ginkgo leaf products; however, some cases were associated with oral use of the seed, and others with intravenous or intramuscular use of the leaf. Documented discontinuation of ginkgo led to recovery in approximately 84% of cases where ginkgo was the sole suspect. Despite these findings, ginkgo cannot be confirmed as the causal agent. It is possible that these reports are confounded by underlying co-morbidities. Of the reported cases, the main reason for ginkgo use was tinnitus, a symptom commonly associated with pre-existing arrhythmias (105253,105254). Despite this large number of reports, only three cases of cardiac arrhythmia have been published in the literature (105253,105254). In one case, frequent nocturnal episodes of paroxysmal atrial fibrillation were reported for a 35-year-old female taking ginkgo extract 240 mg daily orally for 2 months. Arrythmias ceased following discontinuation of ginkgo (87884).
Increases in blood pressure were commonly reported with ginkgo in a safety database analysis; however, information on the magnitude of the increase was limited, and reports included both oral and intravenous administration (115628).
In one clinical trial, the rate of ischemic stroke and transient ischemic attacks was significantly higher in patients taking ginkgo extract orally when compared with placebo (16635). It is unclear if these events were due to ginkgo, other factors, or a combination.

Dermatologic ...Topically, ginkgo fruit pulp can cause contact dermatitis, with intense itching, edema, papules, and pustules which take 7-10 days to resolve after stopping contact (112946).

Gastrointestinal ...Orally, ginkgo extract may cause mild gastrointestinal discomfort or pain (3965,8543,17112,87818,87858), nausea and vomiting (8543,17112,87728,87844,87858), diarrhea (87844), dry mouth (17112), and constipation (5719,87787). However, post-market surveillance suggests that the incidence of these events is relatively low, occurring in less than 2% of patients (88007).
Fresh ginkgo seeds can cause stomach ache, nausea, vomiting, or diarrhea. Ingesting roasted seeds in amounts larger than the normal food amounts of 8-10 seeds per day, or long-term, can also cause these same adverse reactions (8231,8232).

Genitourinary ...Orally, ginkgo extract has been reported to cause blood in the urine (87858,115628).

Hematologic ...Spontaneous bleeding is one of the most concerning potential side effects associated with ginkgo. There are several published case reports linking ginkgo to episodes of minor to severe bleeding; however, not all case reports clearly establish ginkgo as the cause of bleeding. In most cases, other bleeding risk factors were also present including taking other medications or natural medicines, old age, liver cirrhosis, recent surgery, and other conditions. In most cases, bleeding occurred after several weeks or months of taking ginkgo (13135). Large-scale clinical trials and a meta-analysis evaluating standardized ginkgo leaf extracts show that the incidence of bleeding in patients taking ginkgo is not significantly higher than in those taking placebo (16634,16635,17179,17402).
There are several case reports of intracerebral bleeding. Some of these cases resulted in permanent neurological damage and one case resulted in death (244,578,8581,13135,13179,14456,87868,87977).
There are at least 4 cases of ocular bleeding including spontaneous hyphema (bleeding from the iris into the anterior part of the eye) and retrobulbar hemorrhage associated with ginkgo use (579,10450,13135).
There are also cases of surgical and post-surgical complications in patients using ginkgo. Retrobulbar hemorrhage (bleeding behind the eye) during cataract surgery has been associated with ginkgo use (10450). Excessive postoperative bleeding requiring transfusion has also occurred following laparoscopic surgery in a patient who had been taking ginkgo leaf extract (887). There have also been two cases of excessive bleeding during surgery and post-surgical hematoma in patients undergoing rhytidoplasty and blepharoplasty (13002). In another case, an elderly patient taking ginkgo experienced excessive postoperative bleeding following total hip arthroplasty (13194). In another case, use of ginkgo following liver transplantation surgery was associated with subphrenic hematoma requiring evacuation by laparotomy. The patient also subsequently experienced vitreous hemorrhage (14315). In another case, an elderly patient who had taken ginkgo chronically experienced excessive post-operative bleeding following an ambulatory surgical procedure (14453).
In another case, an elderly man experienced nose bleeds and ecchymosis following use of ginkgo. One case of diffuse alveolar hemorrhage in a female taking ginkgo and ginseng for over one year has been reported (95670). These instances of bleeding stopped when ginkgo was discontinued, and recurred when the patient started taking ginkgo again (13135).
Persistent bleeding has also occurred following dental surgery (87862) and laparoscopic cholecystectomy (88000). Nosebleed has also been reported as an adverse effect in a clinical trial (87813).

Immunologic ...Orally, ginkgo leaf extract can cause allergic skin reactions in some patients (14449,15578,112946). In one case, a patient developed acute generalized exanthematous pustulosis 48 hours after taking a single-ingredient ginkgo product. The rash resolved within 10 days after discontinuing ginkgo (14449). In another case, progressive erythema of the face, neck, trunk, and extremities occurred after two 60 mg oral doses of ginkgo extract (112946). There is also a case of Stevens-Johnson syndrome following a second administration of a preparation containing ginkgo leaf extract, choline, vitamin B6, and vitamin B12 (208). In another case, systemic edema and severe arthralgia was reported after contact with a ginkgo tree nut and manifested as multifocal lymphadenopathy associated with an allergic reaction on PET/CT scan imaging (95672).

Musculoskeletal ...Edema has been reported for three patients treated with ginkgo extract 40 mg orally three times daily (87818).

Neurologic/CNS ...Orally, ginkgo extract may cause headache (6220,8543,87818), dizziness (5719,87818), increased desire to sleep (87839,115628), and sedation (10893) in some patients. In addition, although ginkgo leaf and ginkgo leaf extract contain only small amounts of ginkgotoxin, there are anecdotal reports of seizure occurring after use of ginkgo leaf preparations both in patients without a history of seizure disorder and in those with previously well-controlled epilepsy (7030,7090,11296,14281).

Ocular/Otic ...Orally, ginkgo may cause tinnitus is some patients (8543,115628).
Topically, eye drops containing ginkgo extract and hyaluronic acid may cause stinging sensations in some people (87829).

Psychiatric ...Orally, ginkgo has been associated with a single case of mood dysregulation. A 50-year-old female with schizophrenia developed irritability, difficulty controlling anger, and agitation after one week of taking ginkgo 80 mg twice daily. The mood changes resolved within 2-3 days of discontinuation. When ginkgo was re-trialed at a later date, the same symptoms reappeared, and again dissipated after discontinuation of the ginkgo product. The relationship between ginkgo and mood dysregulation was considered to be "probable" based on the Naranjo adverse drug reaction probability scale (96763); however, the exact mechanism by which ginkgo may have affected mood regulation is unknown.

(Read more about GINKGO)

General ...Orally, phosphatidylserine is generally well tolerated.
Most Common Adverse Effects:
Orally: Flatulence, gastrointestinal upset, headache, insomnia, and nausea.

Gastrointestinal ...Orally, phosphatidylserine can cause gastrointestinal upset such as flatulence or nausea. Gastrointestinal upset can occur at doses of 200-300 mg/day (7116,7121,15539,68862,90711).

Neurologic/CNS ...Orally, phosphatidylserine can cause insomnia. Insomnia is more likely to occur with a higher dose of 600 mg (7121,68844). Headache has also been reported (90711).

(Read more about PHOSPHATIDYLSERINE)