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POSSIBLY EFFECTIVE

• Generalized anxiety disorder (GAD). Oral ashwagandha may modestly improve symptoms of anxiety in patients with GAD. Details: Clinical practice guidelines from the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) provisionally recommend ashwagandha root extract at doses of 300-600 mg, standardized to 5% withanolides, daily as monotherapy or adjunctive therapy in patients with GAD. This recommendation is based on a review of three preliminary clinical trials with consistent results (110318). Two of these studies are described below. A small clinical trial in patients with GAD who are taking selective serotonin reuptake inhibitors (SSRIs) shows that taking ashwagandha 1 gram daily for 6 weeks reduces symptoms of anxiety by 48%, compared with a 27% reduction in patients taking placebo. Furthermore, by the end of treatment, 72% of patients taking ashwagandha were determined to have mild symptoms of GAD, compared with only 32% of those taking placebo (102687). Another preliminary clinical trial in patients aged 16 years and older with GAD shows that taking ashwagandha root powder granules 4 grams three times daily for 60 days moderately improves anxious mood in 58% of patients, compared with no moderate improvement in the placebo group. Mild improvement occurred in 82% of patients in the placebo group and 40% of patients in the ashwagandha group (90654).
• Insomnia. Oral ashwagandha may modestly improve sleep in patients with insomnia or non-restorative sleep. Details: A small meta-analysis in patients with insomnia and healthy patients shows that taking a specific ashwagandha root extract (KSM-66, Ixoreal Biomed) 250-600 mg daily or a specific root and leaf extract (Shoden, Arjuna Natural) 120 mg daily for 6-12 weeks modestly improves overall sleep, as well as sleep quality, sleep latency, total sleep time, wake time after sleep onset, and sleep efficiency, when compared with placebo. Effects were more pronounced in those with insomnia, with doses of at least 600 mg daily, and with treatment durations of at least 8 weeks (106784). These findings may be limited by heterogeneity of the included studies. In patients with non-restorative sleep, clinical research shows that taking a specific ashwagandha extract (Shoden, Arjuna Natural Private Ltd) 125 mg daily for 6 weeks increases sleep quality by 72%, compared with an improvement of 29% in patients taking placebo. Small to moderate improvements also occurred in total sleep time, sleep latency, and number of times awake (103476).
• Stress. Oral ashwagandha seems to help reduce stress and may also reduce stress-related weight gain. Details: A meta-analysis of seven small clinical studies in healthy adults, patients with chronic stress, or patients with psychiatric conditions shows that taking ashwagandha 240-1000 mg daily for 8-12 weeks improves stress when compared with placebo (109587). Clinical studies included in this meta-analysis that evaluated adults with chronic stress show that taking specific ashwagandha root extracts 240 mg daily (Shoden, Arjuna Natural Ltd.) or 300 mg twice daily (KSM-66, Ixoreal Biomed) for 60 days reduces perceived stress levels by 30% to 44% and decreases cortisol levels by 22% to 28% when compared with baseline. These improvements remain significant when compared with the changes seen for patients treated with placebo (90652,95617,101816,102682). In adults reporting moderate to high stress levels, clinical research shows that treatment with specific slow-release capsules containing another ashwagandha root extract (Prolanza), 300 mg daily for 90 days, lowers perceived stress scores and cortisol levels when compared with placebo (107371). In healthy college students, clinical research also shows that taking ashwagandha root extract 350 mg twice daily for 30 days improves qualitative perceptions of stress management, but not stress scores, when compared with placebo (109589,109590). Other clinical research shows that taking ashwagandha root extract 500 mg twice daily may prevent stress-related weight gain when compared with placebo (95617).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. A small clinical study suggests that oral ashwagandha may modestly improve well-being, sleep, and alertness in elderly patients. Details: A small clinical trial in individuals aged 65-80 years shows that taking ashwagandha root extract (KSM-66, Ixoreal Biomed) 600 mg daily for 12 weeks improves overall well-being, sleep quality, and mental alertness by small to moderate amounts when compared with placebo (102684).
• Antipsychotic-induced metabolic side effects. It is unclear if ashwagandha is beneficial for attenuating the metabolic side effects of antipsychotic agents. Details: One preliminary clinical trial shows that taking a specific ashwagandha extract (Cap Strelaxin, M/s Pharmanza Herbal Pvt. Ltd.) 400 mg three times daily for one month reduces serum triglycerides by 12% and fasting blood glucose by 15% when compared with baseline levels. Patients were taking atypical antipsychotics and had modestly elevated triglycerides and fasting blood glucose levels at baseline (90649). The validity of these findings is limited by the lack of a comparator group.
• Anxiety. It is unclear if oral ashwagandha is beneficial for reducing anxiety. Details: One small clinical study shows that taking ashwagandha root (Swiss Herbals) 300 mg twice daily for 12 weeks, in combination with standard psychotherapy interventions, including dietary counseling, deep breathing exercise instruction, and a multivitamin, reduces anxiety scores when compared with standard psychotherapy interventions and placebo (19271). However, other clinical research in young adults shows that a specific ashwagandha root and leaf extract (NooGandha, Specnova LLC) 225 mg or 400 mg daily for 30 days produces similar improvements in self-reported anxiety, stress, and depression scores when compared with placebo (107370).
• Asthma. Although there has been interest in using oral ashwagandha for asthma, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Athletic performance. It is unclear if ashwagandha is beneficial for improving athletic performance. Details: A meta-analysis of four small clinical trials shows that taking ashwagandha increases aerobic capacity in athletes and non-athletes based on the measurement of maximum oxygen consumption. Effective doses ranged from 500-1000 mg daily for up to 12 weeks (102683). Another meta-analysis shows that taking ashwagandha in doses of 120-1250 mg daily, as a single dose or divided twice daily, for up to 6 months seems to improve muscle strength, speed, time to exhaustion, recovery time, and cardiorespiratory fitness in athletes and non-athletes (105824). However, the validity of this analysis is reduced by the lack of a control group, the varied training levels of the subjects, and the wide range of outcomes assessed. More research is needed to determine whether taking ashwagandha can improve athletic performance.
• Attention deficit-hyperactivity disorder (ADHD). Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In a preliminary clinical trial, children with ADHD were given a combination herbal extract formula (Nurture & Clarity), containing ashwagandha, white peony root, gotu kola, blue-green algae, bacopa, and sage, 3 mL three times daily for 4 months. Measures of attention, cognition, and impulse control improved significantly in children receiving ashwagandha when compared with placebo (19272). The dose of ashwagandha in the combination product was not reported, and the effect of ashwagandha alone in ADHD is unclear.
• Back pain. Although there has been interest in using oral or topical ashwagandha for back pain, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Bipolar disorder. It is unclear if oral ashwagandha is beneficial for improving cognitive function in adults with bipolar disorder. Details: Clinical research shows that taking ashwagandha extract (Sensoril, Natreon, Inc.) 250 mg daily for 1 week and then 250 mg twice daily for 7 weeks, improves some, but not all, measures of cognition by a small-to-moderate amount when compared with placebo (90653).
• Bronchitis. Although there has been interest in using oral ashwagandha for bronchitis, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Cerebellar ataxia. It is unclear if oral ashwagandha is beneficial for improving balance in patients with cerebellar ataxia. Details: A small, open-label study evaluating ashwagandha 500 mg three times daily in combination with Ayurvedic therapy for one month showed improvement in balance indices in subjects with cerebellar ataxia when compared with baseline (19273). The validity of this finding is limited by the lack of a comparator group. Additionally, it is unclear if this effect is due to ashwagandha, other ingredients, or the combination.
• Chemotherapy-related fatigue. Evidence is limited to one small clinical study in patients with breast cancer. Details: In preliminary clinical research in patients with breast cancer, taking ashwagandha powdered root extract 2 grams (Himalaya Drug Co) three times daily through six cycles of chemotherapy decreases chemotherapy-related fatigue when compared with no treatment. Fatigue scores were 16% to 52% higher in the control group when compared to the ashwagandha group (90651).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral ashwagandha is beneficial in patients with COPD. Details: A small clinical study in patients with stable COPD shows that taking ashwagandha root extract 250 mg twice daily for 12 weeks, along with conventional therapy, improves measures of lung function and exercise tolerance, but not quality of life, when compared with conventional therapy alone (109588).
• Cognitive function. Although there has been interest in using oral ashwagandha for cognitive function, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Constipation. Oral ashwagandha 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 constipation shows that taking a combination product containing ashwagandha root and ambrette fruit extracts 300 mg or 500 mg daily for 14 days improves bowel movement frequency and abdominal, rectal, and stool symptoms when compared with placebo (112114). It is unclear if these effects are due to ashwagandha, ambrette, or the combination. The validity of these effects is limited by the small sample size.
• Coronavirus disease 2019 (COVID-19). Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults hospitalized with COVID-19 shows that taking a specific combination product, (Artovid-20, Bioved Pharmaceuticals) containing ashwagandha, ginger, turmeric, and Boswellia, 1,776 mg orally twice daily for 14 days shortens the duration of symptoms by 0.9 days when compared with placebo. Taking the combination product also modestly reduced the severity ratings of some symptoms, such as sore throat and cough, however, these improvements are unlikely to be clinically relevant (109899). Another small clinical study in adults with mild to moderate COVID-19 shows that taking ashwagandha 500 mg and ginger 1000 mg twice daily for 15 days reduces time to recovery by around 6 days and increases the rate of clinical cure 14-fold and 2.6-fold at days 5 and 7, respectively, when compared with a control. However, taking this combination does not appear to improve the proportion of patients with a negative COVID-19 test, viral clearance, serum antibodies, chest findings, or disease progression when compared with control (112094). The validity of these findings is limited by a lack of blinding, and the study may have been inadequately powered to detect a difference between groups. Additionally, it is unclear if these effects are due to ashwagandha, ginger, or the combination.
• Diabetes. It is unclear if oral ashwagandha is beneficial for type 2 diabetes. Details: In patients with type 2 diabetes, preliminary clinical research shows that ashwagandha 3 grams daily for 30 days decreases blood glucose to a degree similar to oral hypoglycemic drugs (19274). However, this study did not compare ashwagandha directly to a group taking oral hypoglycemic drugs.
• Fibromyalgia. Although there has been interest in using oral ashwagandha for fibromyalgia, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Hiccups. Although there has been interest in using oral ashwagandha for hiccups, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Hypercholesterolemia. It is unclear if ashwagandha is beneficial for hypercholesterolemia. Details: A very small clinical study in subjects with hypercholesterolemia shows that ashwagandha 3 grams daily for 30 days decreases serum cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, and very low-density lipoprotein (VLDL) cholesterol levels when compared with baseline (19274). The validity of these findings is limited by the lack of a comparator group.
• Hypothyroidism. It is unclear if ashwagandha is beneficial for hypothyroidism. Details: Preliminary clinical research in adults with subclinical hypothyroidism shows that taking a specific ashwagandha root extract (KSM-66, Ixoreal Biomed) 300 mg twice daily for 8 weeks increases triiodothyronine (T3) and thyroxine (T4) levels by 42% and 20%, respectively, and reduces serum TSH levels by 17% from baseline. These changes are significant when compared with placebo (97292). However, the effects of ashwagandha on thyroid hormone levels in patients with overt hypothyroidism, or in patients taking prescription thyroid hormones, is unknown.
• Infertility. Although there has been interest in using oral ashwagandha for infertility in females, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Male infertility. It is unclear if oral ashwagandha is beneficial for male infertility. Details: Preliminary clinical research in males with infertility shows that taking ashwagandha root powder for approximately 3 months modestly improves hormone levels, as well as sperm count and motility, when compared with baseline (19275,90650). The validity of these findings is limited by the lack of a comparator group. One study used a specific ashwagandha root extract (KSM-66 Ashwagandha, Ixoreal Biomed) 225 mg three times daily; another study provided doses of 5 grams daily (19275,90650).
• Menopausal symptoms. Oral ashwagandha may be beneficial for menopausal symptoms. Details: A small clinical study in healthy adults in perimenopause shows that taking a specific ashwagandha root extract (KSM-66, Ixoreal Biomed) 300 mg twice daily for 8 weeks improves menopausal symptom severity by 24%, compared with 11% in those receiving placebo. Quality of life and hot flashes also were improved in those taking ashwagandha (106785).
• Obsessive-compulsive disorder (OCD). It is unclear if ashwagandha is beneficial for OCD. Details: Preliminary clinical research shows that taking ashwagandha root extract 120 mg after meals for 6 weeks, in conjunction with prescribed selective-serotonin reuptake inhibitors (SSRIs), might reduce OCD symptom severity when compared with prescribed SSRIs alone. The dose was initiated at 30 mg daily and increased by 30 mg every 4 days. Although OCD scores were significantly reduced when compared with placebo, it should be noted that scores were already significantly lower in the placebo group at baseline (95618).
• Osteoarthritis. Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In patients with osteoarthritis, taking a specific combination supplement, containing ashwagandha 450 mg, Ayurvedic zinc complex 50 mg, guggul 100 mg, and turmeric 50 mg (Articulin-F) two capsules three times daily for 3 months reduces symptoms of pain and swelling when compared with placebo. However, there were no radiological improvements (19276). It is unclear if this effect is due to ashwagandha, other ingredients, or the combination.
• Parkinson disease. Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In patients with Parkinson disease, a small clinical study shows that taking a product containing ashwagandha 14.5 grams, cowhage 4.5 grams, Hyoscyamus reticulantus 0.75 grams, and Sida cordifolia 14.5 grams in lukewarm milk twice daily for 56 days improves symptoms like tremor, stiffness, and cramps when compared with baseline. The therapy followed 28 days of cleansing or eliminative therapy using Ayurvedic remedies (6899). The validity of these findings is limited by the lack of a comparator group. Also, it is unclear if these effects are due to ashwagandha, other ingredients, or the combination. Cowhage contains levodopa, which may contribute to any benefit seen with this combination product.
• Psychological well-being. It is unclear if oral ashwagandha is beneficial for improving psychological well-being in college students. Details: A small clinical study in healthy college students shows that taking ashwagandha root extract 350 mg twice daily for 30 days improves perceptions of well-being, including improvements in energy, mental clarity, food cravings, and sleep quality, when compared with placebo. Qualitative analysis also suggests these students had improvements in stress management, but stress scores were not reduced when compared with placebo (109589,109590).
• Rheumatoid arthritis (RA). It is unclear if ashwagandha is beneficial for improving symptoms of RA. Details: Preliminary clinical research shows that taking ashwagandha powder 5 grams twice daily for 3 weeks, followed by 4 weeks of sidh makardhwaj (a mixture of gold, mercury, and sulfur) 100 mg with honey daily, modestly improves symptoms in about 50% of males and 60% of females with RA when compared with baseline (95620). The lack of a control group limits the validity of this finding. Additionally, the effect of ashwagandha powder alone is unclear.
• Sexual dysfunction. Small clinical studies suggest that oral ashwagandha root extract may help improve sexual arousal and sexual desire in some females and males with sexual dysfunction. Details: Two, small clinical studies in adult females with sexual dysfunction show that taking ashwagandha root extract (KSM-66, Ixoreal Biomed) 300 mg twice daily with food for 8 weeks in conjunction with or without counseling increases the number of successful sexual encounters and improves orgasms, satisfaction, lubrication, and arousal when compared with placebo or counseling alone (95619,110492). Also, a small clinical study in adult males with low sexual desire shows that taking the same ashwagandha root extract 300 mg twice daily after meals for 8 weeks improves subjective sexual functioning scores, including measures of sexual arousal, sexual desire, sexual behavior, and orgasm, when compared with placebo (109586).
• Smoking cessation. Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with a history of smoking 5 or more cigarettes daily for at least 3 years shows that taking a specific combination product containing ashwagandha 100 mg, Indian gooseberry, tribulus, bacopa, Albizia lebbeck, licorice, clove, ginger, cowhage, holy basil, and turmeric (Smotect, Smotect India) daily for 3 months reduces the number of cigarettes smoked daily and levels of alveolar carbon monoxide and carboxyhemoglobin but does not improve lung capacity when compared with placebo (112115). It is unclear if these effects are due to ashwagandha, other ingredients, or the combination.
• Tuberculosis. Although there has been interest in using oral ashwagandha for tuberculosis, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Vitiligo. Although there has been interest in using oral ashwagandha for vitiligo, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Wrinkled skin. It is unclear if topical ashwagandha is beneficial in individuals with wrinkled skin. Details: A small clinical study in healthy adults with photoaged skin shows that applying ashwagandha root extract 8% lotion daily for 60 days improves physician-rated scores for skin wrinkles, hydration, brightness, tone, and pigmentation and improves other measures of skin elasticity and hydration when compared with placebo. However, changes in melanin content did not differ between treatment groups (111538).
• Wound healing. Although there has been interest in using topical ashwagandha for healing of skin ulcers and skin sores, there is insufficient reliable information about the clinical effects of ashwagandha for this condition. More evidence is needed to rate ashwagandha for these uses.

(Read more about ASHWAGANDHA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. It is unclear if oral bacopa is beneficial in patients with Alzheimer disease. Details: A small clinical study in patients with Alzheimer disease or mild cognitive impairment shows that taking bacopa 300 mg daily for 12 months does not improve measures of cognitive function or memory when compared with donepezil or baseline measures (109623).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral bacopa is beneficial in children with ADHD. Details: A small clinical study in boys 6-14 years of age with symptoms consistent with ADHD but without an official diagnosis shows that taking a specific bacopa supplement (KeenMind - CDRI 08, Flordis) for 14 weeks does not improve symptoms of ADHD but improves some cognitive outcomes including error-making, cognitive flexibility, executive functioning, and sleep when compared with placebo. Bacopa 160 mg was given once daily in those weighing 20-35 kg and twice daily in those over 35 kg (109625). However, another small, open-label study in children aged 6-12 years with ADHD shows that taking a different bacopa supplement (BacoMind, Natural Remedies), 225 mg daily for 6 months, improves symptoms such as restlessness, impulsivity, learning problems, and attention deficit when compared to baseline (97603). The validity of these findings is limited by the lack of blinding or comparator group.
• Back pain. Although there is interest in using oral bacopa for back pain, there is insufficient reliable information about the clinical effects of bacopa for this condition.
• Cognitive function. Bacopa seems to improve some measures of cognitive function, but data are conflicting. Details: A meta-analysis of 9 small clinical studies, along with more recent clinical research, shows that taking bacopa 300-600 mg daily for at least 12 weeks is not associated with improved measures of cognition including working memory, learning rate, recognition of pictures and words, reaction time, or attention when compared with placebo. However, subgroup analysis of this meta-analysis and another small clinical study show some evidence of improved reaction times, verbal learning, total recall, retention, memory, and information processing in healthy adults when compared with placebo (10058,17946,33287,97605,109624,111520). In children aged 6-8 years old, a very small clinical study shows that taking a syrup containing bacopa extract 350 mg three times daily for 3 months improves visual motor function and immediate memory when compared to baseline (33304). The validity of this finding is limited by the lack of a statistical comparison to the placebo group. Bacopa has also been studied in combination with other ingredients. A study in healthy adults aged 18-60 years shows that taking a single dose of a combination of bacopa 300 mg, American ginseng 100 mg, and coffee fruit extract 100 mg (Bacognize) improves some measures of working memory and attention by a small amount at 45 minutes when compared with placebo (103375). It is unclear if these effects are due to bacopa, other ingredients, or the combination. In contrast, a moderate-sized study in healthy, middle-aged adults shows that taking a combination product containing whole plant bacopa 7.5 grams, gingko biloba, and group B vitamins for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo. Subgroup analysis shows a possible benefit of bacopa supplementation on measures of attention in those with an optimal diet at baseline (111334).
• Cognitive impairment. It is unclear if oral bacopa is beneficial in patients with cognitive impairment. Details: A small clinical study in patients with mild cognitive impairment or Alzheimer disease shows that taking bacopa 300 mg daily for 12 months does not improve measures of cognitive function or memory when compared with donepezil or baseline (109623).
• Congestive heart failure (CHF). Although there is interest in using oral bacopa for CHF, there is insufficient reliable information about the clinical effects of bacopa for this condition.
• Depression. It is unclear if oral bacopa is beneficial in patients with depression. Details: Preliminary clinical research in adults with depression who have not responded to citalopram 40 mg daily shows that adding bacopa extract 300 mg twice daily for 4 weeks improves scores on depression rating scales when compared with citalopram alone (103378).
• Hypertension. Although there is interest in using oral bacopa for hypertension, there is insufficient reliable information about the clinical effects of bacopa for this condition.
• Insomnia. Although there is interest in using oral bacopa for insomnia, there is insufficient reliable information about the clinical effects of bacopa for this condition.
• Irritable bowel syndrome (IBS). Bacopa has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with diarrhea-predominant IBS shows that taking a combination of bacopa and bael (Aegel marmalos) reduces symptoms in 65% of patients, compared with 78% of patients taking clidinium bromide, chlordiazepoxide, and blond psyllium, and 33% taking placebo. Neither treatment is more effective than placebo for preventing relapses (10059).
• Parkinson disease. It is unclear if oral bacopa is beneficial in patients with Parkinson disease. Details: A very small study in older adults with Parkinson disease taking levodopa shows that taking a specific bacopa extract (Cognitus, Herbarium) 225 mg or 450 mg daily for 90 days does not improve Parkinsonian or systemic symptoms, motor activity, emotional function, or social outcomes when compared with placebo (111523). The validity of these findings is limited by a small sample size and lack of randomization.
• Rheumatoid arthritis (RA). Although there is interest in using oral bacopa for RA, there is insufficient reliable information about the clinical effects of bacopa for this condition.
• Sexual dysfunction. Although there is interest in using oral bacopa for sexual dysfunction, there is insufficient reliable information about the clinical effects of bacopa for this condition.
• Smoking cessation. Oral bacopa has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with a history of smoking 5 or more cigarettes daily for at least 3 years shows that using a specific combination product containing bacopa 100 mg, ashwagandha, Indian gooseberry, tribulus, albizia lebbeck, licorice, clove, ginger, cowhage, holy basil, turmeric (Smotect , Smotect India) twice daily for 3 months reduces the number of cigarettes smoked daily and alveolar carbon monoxide and carboxyhemoglobin levels but does not improve lung capacity when compared with placebo (112115). It is unclear if these effects are due to bacopa, other ingredients, or the combination. More evidence is needed to rate bacopa for these uses.

(Read more about BACOPA)

POSSIBLY EFFECTIVE

• Aging skin. Oral collagen peptides seem to improve skin hydration and elasticity in older adults. However, it is unclear if any improvements related to wrinkles are cosmetically important. Details: Meta-analyses of the available research, as well as multiple individual clinical studies, show that collagen peptide products, taken in doses of 372 mg to 12 grams daily for 4-12 weeks, improve skin hydration and elasticity in older adults. Studied products include Peptan-F or Peptan-P (Rousselot), Wellnex (Nitta Gelatin), Gold Collagen Active (Minerva Research Labs), VERISOL (Gelita AG), and Nippi peptide FCP-EX (Nippi/Shizuoka) (97632,100703,101597,104647,107460,112457). Pooled study results also suggest that hydrolyzed collagen sourced from fish improves skin hydration and elasticity, while collagen peptides originating from chickens seems to modestly improve skin elasticity but not hydration. Collagen peptides derived from bovine do not seem to improve skin hydration or elasticity (112457). Despite research showing improvement in skin hydration and elasticity, it is unclear if collagen peptides reduce skin wrinkles to a cosmetically significant degree, as most studies have not evaluated this outcome. In one clinical study, taking a freshwater fish-derived collagen peptide (Vinh Wellness Collagen, Vinh Hoan Corporation) 10 grams every morning reduced wrinkle count in the nasolabial region of the right side, but not the left side, of the face by 24% when compared with placebo. Collagen peptides did not improve participant-reported measures of wrinkles, elasticity, hydration, and others, when compared with placebo (104639). Another clinical study shows that taking a specific fish scale-derived collagen peptide (Wellnex, Nitta Gelatin) with either a high or low ratio of prolyl-hydroxyproline and hydroxylpropyl-glycine as 5 grams orally daily for 8 weeks modestly improves wrinkle depth and roughness, but not wrinkle volume, when compared with placebo. The product with a high ratio of dipeptides had a larger effect (97632). Also, one clinical study shows that taking a specific product containing porcine collagen type I peptides (VERISOL, Gelita AG) 2.5 grams daily for 8 weeks reduces eye wrinkle volume by 20% when compared with placebo (101648). Two similar moderate-size clinical studies in middle-aged adults with crow's feet wrinkles and dry skin show that taking specific low-molecular-weight fish-derived collagen peptide products (Geltech Co.; CPNS) at doses of 2000 mg or 1650 mg, respectively, daily for 12 weeks improves eye wrinkles, skin hydration, and elasticity when compared with placebo (110729,110730). While investigator satisfaction scores regarding wrinkle reduction were modestly improved, participant satisfaction was not improved (110729). Small clinical studies have shown contradictory findings when collagen peptides are taken in combination with other ingredients. In one clinical trial, a specific drink (Diva Luxe) providing fish collagen peptides 5.5 grams plus Chenopodium formosanum extract 1 gram daily for 8 weeks improved some measures of skin brightness and hydration, but not wrinkles and crow's feet, when compared with placebo (104646). Another small clinical study shows that taking collagen peptides 4 grams daily in combination with coenzyme Q10 50 mg, vitamin C, vitamin A, and biotin for 12 weeks reduces wrinkles and improves skin smoothness by a small amount when compared with placebo. However, there was no difference in skin elasticity or hydration (104638). A clinical study in older females shows that taking collagen peptides 9 grams in combination with zinc and vitamins A, C, and E daily for 90 days increases stratum corneum water content and skin viscoelasticity when compared with placebo. However, it is unclear if the improvement from baseline differed between groups. Small improvements in dermal echogenicity, wrinkles, or skin pores were noted in some facial regions, but the lack of statistical comparison to placebo limits the validity of these findings (107464). Some small clinical studies have shown mixed effects with low doses of collagen peptides from preliminary clinical research using BioCell Collagen (BioCell Technology, LLC) or Celergen (Laboratories-Dom) (28681,97930). It is unclear if any improvements from these studies are due to collagen peptides, other ingredients, or the combinations. Topical application of collagen peptides has been minimally evaluated. A very small observational study in older adults has found that application of a carbopol gel containing collagen peptides 1% to the periorbital area twice daily for 8 weeks is associated with increased skin hydration and elasticity and reduced transepidermal water loss, skin roughness, and wrinkles when compared with baseline (107459). The validity of these findings is limited by poor study methodology, lack of statistical comparison to baseline, and lack of a comparator group.
• Dry skin. Oral collagen peptides seem to improve skin hydration and elasticity in adults with dry skin. However, their effect on other measures of dry skin is unclear. Details: A meta-analysis of 19 clinical studies, along with several small and moderate-sized individual studies, some of which are included in the meta-analysis, show that taking collagen peptides 372 mg to 12 grams daily for 4-12 weeks improves skin hydration and elasticity when compared with placebo in healthy adults (107461,110729,110730,112457,112458). Some studies show that collagen peptides improve skin roughness (107461), decrease peeling (110729,110730), and increase stratum corneum and epidermis water content (107462) but not skin gloss (107461) or elasticity (107462). Some research shows that collagen peptides reduce transepidermal water loss (107462), while another study shows no change (107461). Subgroup analysis of the meta-analysis suggests that hydrolyzed collagen sourced from fish improves skin hydration and elasticity the most, while collagen peptides originating from chicken seem to modestly improve skin elasticity but not hydration. Collagen peptides from bovine do not seem to improve skin hydration or elasticity (112457). Studied products include FCP-Z (Nippi Co., Ltd), Geltech Co., CPNS, and GPVGPS Collagen (Daehan Chemtech) (107462,110729,110730,112458). Collagen peptides have also been evaluated in combination with other ingredients. A small clinical study in healthy adults with low skin moisture shows that drinking 30 mL of a beverage containing fish scale-derived collagen peptides 10 grams and ornithine 400 mg (FUJIFILM) daily for 8 weeks does not improve skin moisture but seems to improve skin elasticity and reduce water loss when compared with placebo (101607). Another very small clinical study in a mixed population of patients with dry skin and mild atopic dermatitis shows that twice daily application of an emollient containing collagen peptides, soluble proteoglycan, and hyaluronic acid for 4 weeks reduces itching severity from moderate at baseline to mild or almost none. Transepidermal water loss and skin hydration also improved when compared to baseline (107465). The validity of these findings is limited by the lack of a comparator group. Both of these studies are limited by their small size, and it is unclear if any improvements are due to collagen peptides, other ingredients, or the combination.

POSSIBLY INEFFECTIVE

• Muscle strength. Most research suggests that oral collagen peptides do not improve leg strength. However, they may improve hand-grip strength and fat-free mass. Details: Small clinical studies in healthy male and female athletes or non-athletes undergoing resistance or other training show that taking collagen peptides 15-30 grams daily or after training sessions for up to 15 weeks, with or without vitamin C, does not improve leg strength (i.e. squat strength, knee extension, or flexor strength) when compared with placebo (101608,104641,107457,110668,110669). Similarly, 2 very small clinical studies in healthy adults show that taking a specific oral collagen peptide product (Bodybalance, Gelita AG) 5-15 grams daily while completing a resistance training program for 14-15 weeks increases patellar tendon cross-sectional area but does not improve most measures of tendinous tissue remodeling including patellar tendon size, vastus lateralis aponeurosis size, patellar tendon mechanical properties, tendon stiffness, maximal knee extension strength, or rectus femoris muscle cross-sectional area when compared with placebo (112452,112454). However, a small clinical study with the same product in untrained females aged 18-50 years shows that taking 15 grams daily in addition to resistance training three times weekly for 12 weeks improves hand-grip strength when compared with resistance training and placebo (101608). In untrained males aged 30-60 years, taking the same dose of this collagen peptide product along with resistance training for 12 weeks improves fat-free mass by 3 kg, compared with 2 kg with resistance training and placebo. A post-hoc exploratory analysis suggests that the effects seen in males are similar to those seen with whey protein (107457).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there has been interest in using oral collagen peptides for acne, there is insufficient reliable information about the clinical effects of collagen peptides for this condition.
• Androgenic alopecia. Oral collagen peptides have only been evaluated in combination with other ingredients, their effect when used alone is unclear. Details: A moderate-sized clinical study in adults with androgenic alopecia or telogen effluvium shows that taking a combination product containing hydrolyzed collagen 300 mg, taurine, cysteine, methionine, iron, and selenium (GFM Oral, Cantabria Labs) daily along with conventional therapy, consisting primarily of finasteride or minoxidil, for 12 weeks improves hair loss when compared with conventional therapy alone (111636). It is unclear if this effect is due to collagen peptides, other ingredients, or the combination.
• Athletic performance. It is unclear if oral collagen peptides improve performance in most athletes. Details: In recreationally active female runners undergoing resistance and endurance training 3 times weekly, clinical research shows that taking collagen peptides 7.5 grams twice daily for 12 weeks increases running distance by approximately 1,034 meters, compared with an increase of 703 meters in those taking placebo, although there was no effect on speed (104641). A clinical study in healthy young male athletes undergoing heavy strength and power training shows that taking collagen peptides 20 grams and vitamin C 50 mg daily for 3 weeks improves squat performance and countermovement jump performance when compared with placebo. However, removal of a single outlier negated the statistical significance of most of these findings (107456). Also, it is unclear if any improvements from this study are due to collagen peptides, vitamin C, or the combination.
• Atopic dermatitis (eczema). It is unclear if oral or topical collagen peptides are beneficial for improving the severity of eczema. Details: A small clinical study in patients with atopic dermatitis shows that taking a porcine skin-derived collagen peptide with a high ratio of tripeptides with glycine-X-Y sequences, 3.9 grams daily for 12 weeks, improves symptoms and severity of eczema when compared to baseline. There was no improvement in the group taking the same dose of porcine skin-derived collagen peptide without the high ratio of tripeptides (101605). Another very small clinical study in a mixed population of patients with atopic dermatitis and dry skin shows that twice daily application of an emollient containing collagen peptides, soluble proteoglycan, and hyaluronic acid for 4 weeks reduces itching severity from moderate at baseline to mild or almost none. Transepidermal water loss and skin hydration also improved when compared to baseline (107465). It is unclear if any improvements are due to collagen peptides, the other ingredients, or the combination. Both of these studies are limited by their small size and lack of comparator groups.
• Burns. Some preliminary clinical research suggests that oral collagen peptides might reduce the time needed for burn healing. Details: In male patients with 20% to 30% body surface area burns, a small clinical trial shows that taking a collagen-based supplement providing collagen peptides (Amutiya, Qom) 36 grams daily for 4 weeks improves wound healing when compared with taking an isocaloric supplement containing the same amount of soy protein. Complete wound healing occurred in 50% and 100% of patients taking collagen for 2 and 4 weeks, respectively, compared with 7% and 40% of those taking the isocaloric product. The duration of hospital stay was not significantly different between the two groups (104642). A small clinical study in hospitalized adults with 20-45% body surface area 2nd or 3rd degree burns shows that consuming a beverage containing collagen peptides 40 grams daily for 4 weeks shortens the time to wound healing, improves scar scores, and reduces the duration of hospital stays but does not limit wound infections when compared with placebo. Adding fish oil 3 grams daily did not further improve outcomes (110667).
• Brittle nails. One small clinical study suggests that oral collagen peptides may improve nail health in people with brittle nails. Details: A small clinical study shows that taking a specific porcine type I collagen peptide product (VERISOL, Gelita AG) 2.5 grams daily for 6 months improves overall symptoms of brittle nail syndrome, increases nail growth rate by 12%, and reduces broken nail frequency by 42% when compared with baseline (101606). This study was limited by its small size and lack of a comparator group.
• Cellulite. One small clinical study suggests that oral collagen peptides may reduce cellulite. Details: In people with cellulite, a small clinical study shows that taking specific collagen peptides (VERISOL by Gelita AG) 2.5 grams daily for 6 months seems to reduce cellulite, skin waviness, and dermal density by a small amount when compared with placebo (101619).
• Cognitive function. It is unclear if oral collagen peptides are beneficial for improving memory. Details: In healthy adults, preliminary clinical research shows that taking collagen peptides 5 grams daily for 4 weeks improves some measures of memory and verbal learning when compared to baseline (104643). This study was limited by its small size and lack of a comparator group.
• Dermatoporosis. One small clinical study suggests that using oral or topical collagen peptides does not improve this condition. Details: A small clinical study in post-menopausal patients aged 70 years on average with mild dermatoporosis shows that taking collagen peptides 5 grams daily, applying a collagen peptides 2.5% serum 3 pumps nightly to each forearm, or using these in combination for 6 months does not improve skin lesions, epidermal thickness, collagen or elastin density, or patient perception of skin improvement when compared with placebo (110731). However, it is unclear if these results apply to patients with more severe dermatoporosis.
• Diabetes. Some preliminary clinical research suggests that oral collagen peptides might have a small effect on glycemic indices. Details: Preliminary clinical research in patients with type 2 diabetes shows that taking fish-derived collagen peptides 6.5 grams orally twice daily for 3 months, in addition to treatment with antidiabetes drugs, may modestly reduce levels of fasting blood glucose, glycated hemoglobin, and fasting blood insulin and may increase levels of insulin sensitivity when compared with antidiabetes drugs and placebo (101626,101627).
• Erythema. It is unclear if oral collagen peptides are beneficial for erythema. Details: A moderate-sized clinical study in adults with dry and wrinkled eye skin shows that taking low-molecular weight collagen peptides (GPVGPS Collagen, Daehan Chemtech) 2000 mg daily for 12 weeks reduces erythema index when compared with placebo (112458).
• Exercise-induced gastrointestinal (GI) symptoms. It is unclear if oral collagen peptides prevent GI symptoms due to exercise. Details: A small crossover study in moderately well-trained young adults shows that taking collagen peptides 10 grams daily for 7 days prior to rigorous treadmill exercise does not limit GI symptoms but may attenuate some markers of GI distress when compared with placebo (110665).
• Exercise-induced muscle soreness. It is unclear if oral collagen peptides prevent muscle soreness after exercise. Details: Preliminary clinical research in a small number of healthy, recreationally active adults shows that taking collagen peptides (Peptan, Rousselot BVBA, Collagen Peptides, Vital Proteins) 10-15 grams twice daily, starting 7 days prior to strenuous exercise and continuing for 2-5 days after, does not reduce muscle soreness when compared with placebo (100700,104648). However, there was a small benefit on the recovery of countermovement jump ability within 24 hours (104648). Furthermore, another small clinical study in adults unaccustomed to exercise shows that taking collagen peptides 10 grams daily for 33 days modestly reduces muscle soreness and fatigue immediately after the exercise load, but not 2 hours after exercise or the next morning, when compared with placebo (111639). Also, a small clinical study in active middle-aged adults shows that taking specific collagen peptides (SOLUGEL Collagen Peptides, PB Leiner) 10 grams daily for 6 months improves pain in those who exercise frequently (>188 minutes weekly) when compared with placebo. However, collagen peptides do not seem to improve pain in low frequency exercisers (<188 minutes weekly) (112455). Collagen peptides have also been evaluated in combination with other ingredients. One preliminary clinical study in healthy, recreationally active adults shows that taking a specific product (BioCell Collagen, BioCell Technology, LLC) containing collagen peptides from chicken collagen type II, hyaluronic acid, and chondroitin sulfate 1.5 grams twice daily for 6 weeks prior to two bouts of intense resistance exercise attenuates increases in biomarkers of muscle damage and decreases delayed onset muscle soreness when compared with placebo (96301). It is unclear if these benefits are due to collagen peptides, other ingredients or the combination.
• Gingivitis. It is unclear if oral collagen peptides are beneficial for patients with gingivitis. Details: A small clinical study in patients with mild-to-moderate chronic gingivitis shows that taking a specific collagen peptide product (Verisol B, Gelita AG) 5 grams daily for 90 days following mechanical plaque removal reduces bleeding and inflammation but does not improve plaque scores when compared with placebo (110666).
• Hypertension. Limited research suggests that oral collagen peptides may lower systolic or diastolic blood pressure. However, results are inconsistent. Details: One preliminary clinical study in patients with hypertension and type 2 diabetes shows that taking fish-derived collagen peptides 6.5 grams twice daily for 3 months modestly reduces diastolic, but not systolic, blood pressure when compared with placebo (101626). Another small clinical study in patients with mildly elevated blood pressure shows that taking a test food containing chicken leg-derived collagen peptides 2.9 grams daily for 12 weeks lowers systolic, but not diastolic, blood pressure when compared with placebo (101610). An additional small clinical study in patients with mild hypertension shows that taking chicken leg-derived collagen peptides 5.2 grams daily 4 weeks reduces systolic blood pressure by 12 mmHg when compared with baseline (101618). This study was limited by its small size and lack of a comparator group. The reasons for conflicting data are unclear.
• Insomnia. It is unclear if oral collagen peptides are beneficial for insomnia. Details: A very small clinical study in physically active males with difficulty sleeping shows that taking collagen peptides 15 grams before bedtime for 7 nights reduces the frequency of nocturnal awakenings and improves cognitive accuracy but does not improve objective measures of total sleep time, latency, efficiency, stage changes, waking after sleep onset, other cognitive function measures, or subjective measures of sleepiness, fatigue, and sleep quality when compared with placebo (112459).
• Joint pain. Most research shows that oral collagen peptides might moderately reduce joint pain in young athletes. However, evidence in elderly patients is conflicting. Details: Preliminary clinical research in student athletes with joint pain shows that taking a specific collagen peptide product (FORTIGEL, Gelita AG) 10 grams in 25 mL of liquid daily for 24 weeks modestly improves pain during movement and at rest when compared with placebo (101601). Other clinical research in young adults exercising or participating in sports at least 3 hours weekly with activity-related knee pain shows that taking this same product 5 grams daily for 12 weeks reduces pain intensity during activity by 38% to 41%, compared with a 26% to 28% reduction in those taking placebo. However, there was no improvement in pain at rest or after the activity when compared with placebo (97623,107454). Furthermore, it is not clear if these effects are clinically significant. Research on the use of collagen peptides in older patients is conflicting. A small clinical study in otherwise healthy patients aged 40-65 years with joint discomfort shows that taking a specific collagen peptides product (AVC-H2, Avicenna) 1.25 grams twice daily for 8 weeks improves overall Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scores by 37% at 4 weeks, compared with 14% in those receiving placebo. However, this difference in improvement was no longer significant at 8 weeks. Collagen peptides also improved the physical activity and stiffness subdomains, but not the pain subdomain, at 4 and 8 weeks when compared with placebo (107455). A larger clinical study in patients 50 years or older with general joint pain shows that taking a specific collagen peptides product (Genacol) 1200 mg daily for 6 months does not reduce pain or improve function when compared with placebo (97657). However, collagen peptides used in combination with other ingredients have shown benefit. Preliminary clinical research in patients 51-70 years of age shows that taking a specific combination product (Gold Collagen Active, Minerva Research Labs) containing fish collagen peptides 4 grams, glucosamine hydrochloride 1000 mg, chondroitin sulfate 500 mg, L-carnitine 200 mg, and other ingredients daily for 90 days reduces joint pain by 43% when compared with baseline, while patients taking placebo saw negligible improvement in pain. A greater percentage of patients taking this product also perceived improvements in joint discomfort, flexibility, mobility, and rigidity when compared with placebo (100703). It is unclear if these effects are due to collagen peptides, other ingredients, or the combination.
• Obesity. It is unclear if oral collagen peptides are beneficial for weight loss. Details: A preliminary clinical study in adults with overweight shows that taking skate skin-derived collagen peptides 2 grams daily for 12 weeks modestly reduces body fat mass by 1.2 kg, compared with an increase of 0.3 kg in the placebo group (101621). It is unclear if collagen peptides improve weight loss or reduce body fat mass in the long-term.
• Osteoarthritis. Most research suggests that oral collagen peptides improve pain in patients with knee osteoarthritis; however, any improvement is modest and may not be considered clinically significant. Details: A meta-analysis of 3 clinical studies, all of which are included below, in adults with knee osteoarthritis shows that taking collagen peptides or hydrolyzed collagen reduces pain when compared with placebo (112456). Clinical research shows that taking specific collagen peptides (Colnatur, Protein SA) 10 grams daily for 5 months increases the number of patients who experience at least a 30% improvement in pain by approximately 42% when compared with placebo. However, there is no difference between groups when the Western Ontario and McMaster Universities (WOMAC) scale is used. Patients with the greatest joint deterioration at baseline, as well as those with the lowest dietary meat intake, seemed most likely to experience benefit from collagen peptides (97635). Another small clinical study shows that taking collagen peptides isolated from pork skin and bovine bone (Nitta Gelatin Inc.) 5 grams dissolved in 250 mL water or milk twice daily after food for 13 weeks modestly improves pain when compared with placebo (101611). Another small clinical study in patients over 40 years old shows that taking collagen peptides (Colatech) 10 grams daily for 90 days reduces pain by about 2 points on a 100-point scale, compared with a 0.9-point reduction with glucosamine sulfate 1.5 grams. Ibuprofen use was not affected (101622). One multicenter clinical study shows that taking collagen peptides 10 grams daily for 6 months does not relieve pain or improve joint function when compared with placebo, although a trend towards reduced pain and improved joint function was observed in patients with severe symptoms at baseline (7704). Collagen peptides have also been evaluated in combination with other ingredients. Clinical research in patients with osteoarthritis of the knee, hip, or hand shows that taking a specific product (BioCell Collagen, BioCell Technology, LLC) containing collagen peptides from chicken collagen type II, hyaluronic acid, and chondroitin sulfate 1 gram twice daily for up to 10 weeks reduces pain and the need for rescue analgesics and increases physical activity when compared with placebo (28678,28680). Similarly, a moderate-size clinical study in patients aged 45-75 years with mild to moderate knee osteoarthritis undergoing resistance exercise twice weekly shows that taking a specific product (Suntory Beverage and Food Asia) containing collagen peptides from chicken collagen type II, hyaluronic acid, and chondroitin sulfate 2 grams daily for 24 weeks does not improve WOMAC scores when compared with glucosamine 1.5 grams daily or placebo, but may modestly improve pain scores when compared with placebo. However, the use of rescue analgesics was not assessed. Adding essence of chicken 5.81 grams daily to collagen peptides did not improve WOMAC or pain scores (110670). Also, preliminary clinical research in patients with knee osteoarthrosis shows that taking a specific product (Ialoral 1500, PharmaSuisse Laboratories Srl) containing collagen peptides, chondroitin sulfate, hyaluronic acid, and keratin peptides for 4 weeks improves pain and function by a moderate amount when compared with baseline (104645). However, the validity of these findings is limited by the lack of statistical comparison to the control group. It is unclear if these effects are due to collagen peptides, other ingredients, or the combination.
• Osteopenia. It is unclear if oral collagen peptides prevent loss of bone mineral density (BMD) in postmenopausal adults. Details: A large clinical study in patients with reduced BMD after menopause shows that taking specific collagen peptides (Fortibone, Gelita AG) 5 grams daily for 12 months increases BMD of the spine and the femoral neck by 3% and 7%, respectively, compared with losses of 1% with placebo (101609). In a very small observational extension of this study, BMD continued to increase over an additional 4 years when compared with baseline. However, the validity of these findings is limited by the lack of a comparator group (107340). Collagen peptides have also been evaluated in combination with calcium and vitamin D. In patients with osteopenia after menopause, a small clinical study shows that taking collagen peptides calcium chelate 5 grams, containing elemental calcium 500 mg and vitamin D3 200 IU, daily for 12 months does not affect total hip, total body, or vertebral BMD when compared with calcium 500 mg and vitamin D 200 IU (101604). The validity of these results is limited by a high dropout rate and insufficient power to detect smaller effects. Conversely, another small study in this population shows that taking specific collagen peptides (Fortibone, Gelita AG) in combination with elemental calcium (as calcium lactate) 500 mg and vitamin D3 400 IU daily for 12 months improves trabecular bone mineral content, trabecular volumetric BMD, and cortical volumetric BMD, but not cortical bone mineral content, when compared with a combination tablet containing equivalent doses of elemental calcium (as calcium carbonate) and vitamin D (107453). It is unclear if these effects are due to collagen peptides, other ingredients, or the combination.
• Osteoporosis. It is unclear if oral collagen peptides improve bone mineral density (BMD) in adults with osteoporosis after menopause. Details: In patients with osteoporosis after menopause, clinical research shows that taking collagen peptides 10 grams daily in addition to twice weekly intramuscular calcitonin for 6 months does not improve BMD in the forearm when compared with calcitonin alone (104649). It is unclear if supplementation with collagen peptides improves BMD in the femoral neck or lumbar spine.
• Pressure ulcers. Oral collagen peptides might help to improve ulcer size and healing. Details: A small clinical study in patients with Stage II, III, or IV pressure ulcers shows that taking collagen peptides 5 grams orally three times daily for 8 weeks in addition to standard care improves ulcer size and exudate when compared with placebo and standard care (101612). This study was limited because it only used one scale to assess healing of the pressure ulcer. Another small clinical study in patients with stage II or III pressure ulcers shows that receiving standard care and collagen peptides with high levels of prolyl-hydroxyproline 5 grams twice daily for 16 weeks improves ulcer exudate, healing, and wound size when compared with standard care plus placebo (101620).
• Sarcopenia. Oral collagen peptides might help to increase fat-free mass. However, it is unclear if collagen peptides are more beneficial than other types of protein. Details: A small clinical study in elderly males with sarcopenia shows that taking collagen peptides from type I collagen 15 grams daily for 12 weeks along with three resistance training sessions weekly modestly increases fat-free mass and power when compared with resistance training and placebo (101624). It is unclear if supplementation with collagen peptides is more beneficial than supplementation with protein.
• Sprains. It is unclear if oral collagen peptides improve ankle instability after a previous sprain. Details: A small clinical study in athletes with chronic ankle instability from an ankle sprain shows that taking collagen peptides 5 grams daily for 6 months improves subjective ankle instability when compared with placebo. However, ankle stiffness, which is a more objective measure of ankle instability, is not improved when compared with placebo (101603).
• Tendinopathy. It is unclear if oral collagen peptides improve tendon pain. Details: A small clinical study in patients with Achilles tendinopathy shows that taking a specific collagen peptides supplement (TENDOFORTE, Gelita AG) 2.5 grams daily for 3 months in addition to a calf-strengthening program improves pain when compared with baseline (101615). The validity of this finding is limited by the lack of a comparator group.
• Wound healing. It is unclear if oral collagen peptides improve wound healing. Details: A small clinical study in healthy volunteers with wounds after photothermolysis shows that taking collagen peptides 3 grams daily for 4 weeks improves erythema, skin hydration, and skin elasticity when compared with placebo (101599). This study was limited by small size, short duration, and no direct measurement of wound healing or scar formation.
• Wrinkled skin. Some small clinical studies suggest that oral collagen peptides might help to reduce lines and wrinkles from sun damage. Details: Preliminary clinical research in females with photodamaged skin shows that taking a specific low molecular weight collagen peptide product (Evercollagen, Newtree Co.) 1000 mg daily for 12 weeks modestly improves most measures of skin wrinkling, hydration, and elasticity when compared with placebo. This specific collagen peptide product is standardized to contain more than 15% glycine-containing tripeptides, including 3% glycyl-prolyl-hydroxyproline (100702). Another moderate-sized clinical study in adults with dry and wrinkled eye skin shows that taking low-molecular weight collagen peptides (GPVGPS Collagen, Daehan Chemtech) 2000 mg daily for 12 weeks reduces skin wrinkling parameters including facial skin roughness, peak-to-valley values, maximum wrinkle height, and eye wrinkle volume and improves skin hydration and skin elasticity when compared with placebo. However, there was no improvement in maximum wrinkle depth (112458). Another preliminary clinical study shows that taking a specific combination product (BioCell Collagen, BioCell Technology, LLC) containing collagen peptides from chicken collagen type II 600 mg, low molecular weight hyaluronic acid 100 mg, and chondroitin sulfate 200 mg daily for 12 weeks reduces lines and wrinkles associated with both natural aging and photoaging by about 13% when compared to baseline (28681). This study was limited by the lack of a comparator group. Additionally, it is unclear if these effects are due to collagen peptides, other ingredients, or the combination. More evidence is needed to rate collagen peptides for these uses.

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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). 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). 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. A very large clinical trial in adults with moderate acute ischemic stroke shows that an intravenous infusion of GDLM 25 mg initiated within 48 hours of symptom onset for 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 (111693). 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). Higher quality studies are still needed to confirm these results.
• 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 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: 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.
• 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).
• 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).
• 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)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. It is unclear if oral lion's mane mushroom is beneficial in patients with Alzheimer disease. Details: Preliminary clinical research in patients over 50 years of age with mild Alzheimer disease shows that taking lion's mane mushroom mycelia (standardized to contain 5 mg/gram of erinacrine A) 1.05 grams daily for 49 weeks improves performance of activities of daily living when compared with placebo. It also improves scores on the Mini-Mental State Examination when compared with baseline (105546). The validity of these findings is reduced by the lack of an intention to treat analysis, and the comparison of some outcomes to baseline instead of placebo.
• Anxiety. Although there is interest in using oral lion's mane mushroom for anxiety, there is insufficient reliable information about the clinical effects of lion's mane mushroom for this condition.
• Athletic performance. Although there is interest in using oral lion's mane mushroom for improving athletic performance, there is insufficient reliable information about the clinical effects of lion's mane mushroom for this purpose.
• Cancer. Although there is interest in using oral lion's mane mushroom for cancer, there is insufficient reliable information about the clinical effects of lions mane mushroom for this purpose.
• Cognitive function. Small clinical trials suggest that lion's mane mushroom does not improve cognitive function. Details: A small clinical trial shows that taking lion's mane mushroom 3.2 grams daily for 12 weeks does not improve most measures of cognitive function when compared with placebo in middle aged to older adults (101770). Additional clinical research in younger adults shows that taking lion's mane mushroom 10 grams daily for 4 weeks does not improve markers of cognition during a period of exercise-induced fatigue when compared with taking placebo. The lion's mane product is 50% dried mushroom and 50% extract (111932). These studies were small and may have been underpowered to detect differences.
• Cognitive impairment. It is unclear if oral lion's mane mushroom is beneficial in patients with mild cognitive impairment. Details: One clinical study in Japanese patients aged 50-80 years old with mild cognitive impairment shows that taking lion's mane mushroom powder 1 gram three times daily for 16 weeks increases cognitive function when compared with placebo. However, cognitive function regresses within 4 weeks of treatment termination (91999).
• Coronavirus disease 2019 (COVID-19). Although there has been interest in using oral lion's mane mushroom for COVID-19, there is insufficient reliable information about the clinical effects of lion's mane mushroom for this purpose.
• Dementia. Although there is interest in using oral lion's mane mushroom for dementia, there is insufficient reliable information about the clinical effects of lion's mane mushroom for this condition.
• Depression. It is unclear if oral lion's mane mushroom is beneficial in patients with depression. Details: Preliminary clinical research in perimenopausal patients without a formal diagnosis of depression shows that eating 4 cookies daily, each containing 0.5 grams powdered lion's mane mushroom, for 4 weeks is similarly effective to placebo cookies for reducing scores on a depression scale (105547).
• Diabetes. Although there is interest in using oral lion's mane mushroom for diabetes, there is insufficient reliable information about the clinical effects of lion's mane mushroom for this condition.
• Gastritis. It is unclear if oral lion's mane mushroom is beneficial in patients with chronic atrophic gastritis. Details: Preliminary clinical research in patients with chronic atrophic gastritis shows that taking lion's mane mushroom (unknown dose) before meals daily for 3 months improves upper abdominal pain in about 27% more patients, improves dyspepsia in about 39% more patients, and reduces inflammatory infiltration in about 23% more patients when compared with placebo (92630).
• Hyperlipidemia. Although there is interest in using oral lion's mane mushroom for hyperlipidemia, there is insufficient reliable information about the clinical effects of lion's mane mushroom for this condition.
• Memory. Although there is interest in using oral lion's mane mushroom for memory, there is insufficient reliable information about the clinical effects of lion's mane mushroom for this purpose.
• Multiple sclerosis (MS). Although there is interest in using oral lion's mane mushroom for MS, there is insufficient reliable information about the clinical effects of lion's mane mushroom for this condition.
• Obesity. Although there is interest in using oral lion's mane mushroom for obesity, there is insufficient reliable information about the clinical effects of lion's mane mushroom for this condition.
• Parkinson disease. Although there is interest in using oral lion's mane mushroom for Parkinson disease, there is insufficient reliable information about the clinical effects of lion's mane mushroom for this condition.
• Peptic ulcers. Although there is interest in using oral lion's mane mushroom for peptic ulcers, there is insufficient reliable information about the clinical effects of lion's mane mushroom for this condition.
• Wound healing. Although there is interest in using topical lion's mane mushroom for wound healing, there is insufficient reliable information about the clinical effects of lion's mane mushroom for this condition. More evidence is needed to rate lion's mane mushroom for these uses.

(Read more about LION'S MANE MUSHROOM)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Ashwagandha has been used with apparent safety in doses of up to 1250 mg daily for up to 6 months (3710,11301,19271,90649,90652,90653,97292,101816,102682,102683) (102684,102685,102687,103476,105824,109586,109588,109589,109590). ...when used topically. Ashwagandha lotion has been used with apparent safety in concentrations up to 8% for up to 2 months (111538).

PREGNANCY: LIKELY UNSAFE
when used orally. Ashwagandha has abortifacient effects (12).

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about ASHWAGANDHA)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Bacopa has been used safely in clinical trials at a dose of up to 600 mg daily for up to 12 weeks (10058,10059,17946,97605).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. Clinical research suggests bacopa extract might be safe to use at a dose of 225 mg daily for up to 6 months or 320 mg daily for up to 14 weeks in children aged 6-14 years (33304,97603,109625).

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

(Read more about BACOPA)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Collagen peptides have been used with apparent safety at doses up to 10 grams daily for up to 6 months and in doses up to 40 grams daily for up to 4 weeks (97632,97635,101615,101621,104638,104643,104644,104647,101622,110667). PREGNANCY &

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about COLLAGEN PEPTIDES)

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)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking ashwagandha with antidiabetes drugs might increase the risk of hypoglycemia.  Details There is preliminary clinical evidence suggesting that ashwagandha might lower blood glucose levels. Theoretically, ashwagandha might have additive effects when used with antidiabetes drugs and increase the risk of hypoglycemia (19274,90649,102685).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha with antihypertensive drugs might increase the risk of hypotension.  Details Animal research suggests that ashwagandha might lower systolic and diastolic blood pressure (19279). Theoretically, ashwagandha might have additive effects when used with antihypertensive drugs and increase the risk of hypotension.

BENZODIAZEPINES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha might increase the sedative effects of benzodiazepines.  Details There is preliminary evidence that ashwagandha might have an additive effect with diazepam (Valium) and clonazepam (Klonopin) (3710). This may also occur with other benzodiazepines.

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha might increase the sedative effects of CNS depressants.  Details Ashwagandha seems to have sedative effects. Theoretically, this may potentiate the effects of barbiturates, other sedatives, and anxiolytics (3710).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha might decrease the effects of immunosuppressants.  Details Ashwagandha has demonstrated immunostimulant effects in humans (3710,3711,4114,11301,106786). Animal research has shown that ashwagandha can attenuate the immunosuppression caused by cyclophosphamide (3711,4114).

THYROID HORMONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Ashwagandha might increase the effects and adverse effects of thyroid hormone.  Details Concomitant use of ashwagandha with thyroid hormones may cause additive therapeutic and adverse effects. Preliminary clinical research and animal studies suggest that ashwagandha boosts thyroid hormone synthesis and secretion (19281,19282,97292). In one clinical study, ashwagandha increased triiodothyronine (T3) and thyroxine (T4) levels by 41.5% and 19.6%, respectively, and reduced serum TSH levels by 17.4% from baseline in adults with subclinical hypothyroidism (97292).

(Read more about ASHWAGANDHA)

ANTICHOLINERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concurrent use might decrease the effectiveness of both agents.  Details Bacopa seems to inhibit acetylcholinesterase and might increase acetylcholine levels, which could counteract the effects of anticholinergic drugs (17946). Similarly, anticholinergic drugs might counteract the cholinergic effects of bacopa.

CEVIMELINE (Evoxac) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bacopa might increase the effects and adverse effects of cevimeline.  Details In one case, a 58-year-old female taking cevimeline long-term for Sjogren syndrome experienced hyperhidrosis, malaise, nausea, and tachycardia shortly after taking a single dose of bacopa. Symptoms resolved after two days. Cevimeline is metabolized by cytochrome P450 (CYP) 2D6 and CYP3A4, and researchers theorize that bacopa may have inhibited these isoenzymes (109627). However, it is unclear if bacopa causes clinically significant inhibition of either CYP2D6 or CYP3A4.

CHOLINERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concurrent use of bacopa with other cholinergic drugs might have additive effects.  Details Bacopa seems to inhibit acetylcholinesterase and might increase acetylcholine levels (17946). Theoretically, this could result in additive cholinergic effects when used with cholinergic drugs.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bacopa might increase the levels and adverse effects of CYP1A2 substrates.  Details Research on the effects of bacopa extracts on CYP1A2 enzymes is conflicting. Some in vitro evidence shows that bacopa extract can moderately and non-competitively inhibit CYP1A2, while other in vitro evidence suggests that any effect is unlikely to be clinically significant (97269,97606).

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bacopa might increase the levels and adverse effects of CYP2C19 substrates.  Details In vitro evidence suggests that bacopa extract can moderately and non-competitively inhibit CYP2C19 enzymes (97606). It is not known whether this is clinically significant.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bacopa might increase the levels and adverse effects of CYP2C9 substrates.  Details Research on the effect of bacopa extracts on CYP2C9 enzymes is conflicting. Some in vitro evidence suggests that bacopa extract can moderately and non-competitively inhibit CYP2C9, while other in vitro evidence suggests that any effect is unlikely to be clinically significant (97269,97606).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bacopa might increase the levels and adverse effects of CYP3A4 substrates.  Details Research on the effects of bacopa extracts on CYP3A4 enzymes is conflicting. Some in vitro evidence suggests that bacopa extract can moderately and competitively inhibit CYP3A4, while other in vitro evidence suggests that any effect is unlikely to be clinically significant (97269,97606).

THYROID HORMONE Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, bacopa might have additive effects when used with thyroid hormone.  Details Animal research suggests that bacopa increases thyroxine (T4) levels in mice by about 40% (33286).

(Read more about BACOPA)

(Read more about COLLAGEN PEPTIDES)

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).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, lion's mane mushroom may increase the risk of bleeding when used with anticoagulant/antiplatelet drugs.  Details In vitro research suggests that lion's mane mushroom extracts can inhibit platelet aggregation (92619).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, lion's mane mushroom may have additive effects when used with antidiabetes drugs.  Details Animal research suggests that an aqueous extract of lion's mane mushroom can reduce serum glucose and increase serum insulin (91996).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concurrent use of lion's mane mushroom might interfere with immunosuppressive therapy.  Details In animal and in vitro research, lion's mane mushroom polysaccharides stimulate the immune system (91933,111933).

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General ...Orally, ashwagandha seems to be well-tolerated. Topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal upset, nausea, and vomiting. However, these adverse effects do not commonly occur with typical doses.
Serious Adverse Effects (Rare):
Orally: Some case reports raise concerns about acute liver failure, hepatic encephalopathy, and the need for liver transplantation with ashwagandha treatment.

Dermatologic ...Orally, dermatitis has been reported in three of 42 patients in a clinical trial (19276).

Endocrine ...A case report describes a 73-year-old female who had taken an ashwagandha root extract (unspecified dose) for 2 years to treat hypothyroidism which had been previously managed with levothyroxine. The patient was diagnosed with hyperthyroidism after presenting with supraventricular tachycardia, chest pain, tremor, dizziness, fatigue, irritability, hair thinning, and low thyroid stimulating hormone (TSH) levels. Hyperthyroidism resolved after discontinuing ashwagandha (108745).

Gastrointestinal ...Orally, large doses may cause gastrointestinal upset, diarrhea, and vomiting secondary to irritation of the mucous and serous membranes (3710). When taken orally, nausea and abdominal pain (19276,110490) and gastritis and flatulence (90651) have been reported.

Genitourinary ...In one case report, a 28-year-old male with a decrease in libido who was taking ashwagandha 5 grams daily over 10 days subsequently experienced burning, itching, and skin and mucous membrane discoloration of the penis, as well as an oval, dusky, eroded plaque (3 cm) with erythema on the glans penis and prepuce (32537).

Hepatic ...Orally, ashwagandha in doses of 154-1350 mg daily has played a role in several case reports of liver injury. In most of these cases, other causes of liver injury were excluded, and liver failure did not occur. Symptoms included jaundice, pruritus, malaise, fatigue, lethargy, weight loss, nausea, diarrhea, abdominal pain, stool discoloration, and dark urine. Symptom onset was typically 5-180 days from first intake, although in some cases onset occurred after more than 12 months of use (102686,107372,110490,110491,111533,111535,112111). Laboratory findings include elevated aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, and serum bilirubin (112111). In most cases, liver enzymes normalized within 1-5 months after discontinuation of ashwagandha (102686,107372,110491,111535,112111). However, treatment with corticosteroids, lactulose, ornithine, ursodeoxycholic acid, and plasmapheresis, among other interventions, was required in one case (111533). Rarely, use of oral ashwagandha has been reported to cause hepatic encephalopathy and liver failure requiring liver transplantation (110490).

Neurologic/CNS ...Orally, ashwagandha has been reported to cause drowsiness (110492). Headache, neck pain, and blurry vision have been reported in a 47-year-old female taking ashwagandha, cannabis, and venlafaxine. Imaging over the course of multiple years and hospital admissions indicated numerous instances of intracranial hemorrhage and multifocal stenosis of intracranial arteries, likely secondary to reversible cerebral vasoconstriction syndrome (RCVS) (112113). It is unclear whether the RCVS and subsequent intracranial hemorrhages were precipitated by ashwagandha, cannabis, or venlafaxine.

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General ...Orally, bacopa is generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal cramps, diarrhea, dry mouth, headache, nausea.

Cardiovascular ...Orally, bacopa has been reported to cause palpitations (10058).

Gastrointestinal ...Orally, bacopa has been reported to cause abdominal cramps, abdominal pain, bloating, decreased appetite, diarrhea, dry mouth, excessive thirst, flatulence, indigestion, nausea, and increased stool frequency. Rates of adverse gastrointestinal events have ranged from 12% to 30% (10058,17946,33295,97605,109623,111520).

Musculoskeletal ...Orally, bacopa has been reported to cause arthralgia, muscle fatigue, and myopathy (10058,109623,111522). In one case, a 21-year-old male experienced progressive proximal weakness, muscle atrophy, weight loss, dark urine, and elevated serum markers of myopathy, with muscle biopsy showing immune-mediated necrotizing myopathy, after taking a supplement containing bacopa for 5 years (111522).

Neurologic/CNS ...Orally, bacopa has been reported to cause drowsiness, headache, insomnia, and vivid dreams (10058,10059,17946,109623).

Other ...Orally, bacopa has been reported to cause flu like symptoms and fatigue (10058,97605,111520).

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General ...Orally, collagen peptides seem to be well tolerated.

Dermatologic ...Orally, a case of a mild skin rash has been reported for a patient who used a specific collagen peptide-containing product (BioCell Collagen) (28680).

Gastrointestinal ...Orally, collagen peptides may cause nausea, dyspepsia, diarrhea, and flatulence, but these adverse effects are rare (101622,104639).

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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).
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 in one patient (87858).

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), 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 extract may cause tinnitus is some patients, although the incidence is rare (8543).
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.

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General ...Orally, lion's mane mushroom is generally well tolerated.
Most Common Adverse Effects:
Orally: Gastrointestinal discomfort, nausea, skin rash.

Dermatologic ...Orally, lion's mane mushroom may cause skin rash (105546).

Gastrointestinal ...Orally, lion's mane mushroom may cause gastrointestinal discomfort and nausea (91999,105546).

(Read more about LION'S MANE MUSHROOM)