TrueZs by NatureCity

POSSIBLY EFFECTIVE

• Anxiety. Small clinical studies suggest that oral ashwagandha might reduce anxiety. Details: One small clinical study in postal workers reporting moderate or severe anxiety 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). Additionally, two small clinical studies in adults with mild to moderate anxiety, depression, or stress show that taking a specific ashwagandha root extract standardized to contain 2.5% withanolides (Shagandha, Sabinsa Corp.) 500 mg with piperine 5 mg daily for 60-90 days reduces anxiety symptoms and perceived stress and improves sleep and quality of life when compared with placebo (113608,113609). However, another clinical study in young adults shows that taking a specific ashwagandha root and leaf extract (NooGandha, Specnova LLC) 225 mg or 400 mg daily for 30 days does not improve anxiety, stress, and depression scores when compared with placebo (107370).
• 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, some of which are included in the meta-analysis mentioned above, evaluating adults with chronic stress show that taking specific ashwagandha root extracts 240 mg daily (Shoden, Arjuna Natural Ltd.), 300 mg twice daily (KSM-66, Ixoreal Biomed), or 500 mg daily (Shagandha, Sabinsa Corp.) with piperine 5 mg for 60 days, or a specific slow-release capsule containing ashwagandha root extract (Prolanza) 300 mg daily for 90 days reduces perceived stress and cortisol levels when compared with baseline and placebo (90652,95617,101816,102682,107371,113608). Additionally, a small clinical study in adults with stress and a related comorbidity, such as anxiety or depression, shows that taking ashwagandha root and leaf extract (Sensoril, Kerry Group) 125-500 mg orally daily for 8 weeks improves stress scores in a dose-dependent manner when compared with placebo (114112). In contrast, a moderate-sized study in adults with overweight or mild obesity with moderate-to-high levels of stress and fatigue shows that taking ashwagandha root extract (Witholytin, Verdure Sciences Inc) 200 mg twice daily for 12 weeks reduces stress when compared to baseline, but not when compared with placebo (113611).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).
• Androgenic alopecia. It is unclear if topical ashwagandha is beneficial for androgenic alopecia. Details: A small clinical study in adults with mild to moderate hair loss, including androgenic alopecia, shows that applying ashwagandha root extract serum (KSM-66, Ixoreal Biomed) 1-2 drops to the scalp daily for 75 days reduces hair shedding and increases hair density, growth, and thickness when compared with placebo (113613).
• 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.
• 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). Additionally, a moderate-sized clinical study in adults with functional constipation shows that using the same combination of ashwagandha and ambrette 300 mg or 500 mg daily for 60 days moderately improves constipation symptom scores and bowel movement scores when compared with placebo (114115). It is unclear if these effects are due to ashwagandha, ambrette, or the combination.
• 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. Other clinical research in adults hospitalized with mild to moderate COVID-19 shows that taking a specific combination product (Coroprotect) containing ashwagandha, pomegranate, turmeric, bacopa, licorice, and other ingredients, twice daily for 10 days improved cough, breathlessness, and fatigue symptoms when compared with placebo (114114). It is unclear if any effects are due to ashwagandha, other ingredients, or the combination.
• Depression. It is unclear if oral ashwagandha is beneficial for depression. Details: A small clinical study in adults with mild to moderate depression, anxiety, or stress shows that taking a specific ashwagandha root extract standardized to contain 2.5% withanolides (Shagandha, Sabinsa) 500 mg with piperine 5 mg daily for 90 days reduces the severity of depressive symptoms, improves sleep and quality of life, and increases serum serotonin levels when compared with placebo (113609).
• 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.
• Fatigue. It is unclear if oral ashwagandha is beneficial for fatigue. Details: A moderate-sized clinical study in adults with overweight or obesity and moderate-to-high levels of fatigue and stress shows that taking ashwagandha root extract (Witholytin, Verdure Sciences Inc.) 200 mg twice daily for 12 weeks reduces self-reported fatigue when compared with placebo (113611).
• 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)

POSSIBLY EFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about SAFFRON)

POSSIBLY EFFECTIVE

• Cognitive function. Oral L-theanine may improve some aspects of cognitive function. It is unclear if using L-theanine in conjunction with caffeine can enhance the effects of either ingredient. Details: A single dose of L-theanine 100 mg seems to improve vigilant attention, reducing error rates in cognitive tests when compared with placebo (91747). However, taking L-theanine (Suntheanine, Taiyo Kagaku) 200 mg daily for 4 weeks does not improve verbal fluency, memory, motor speed, or executive function in an adult population, although it may moderately improve verbal fluency in a subgroup of people with lower cognitive function at baseline (101986). When L-theanine is combined with caffeine, a meta-analysis and multiple individual clinical studies show that the combination improves alertness, as well as accuracy during a test that requires switching attention between different tasks, but does not improve reaction time (38116,91750,96335,96336). Some research also shows that L-theanine plus caffeine improves cognitive performance and reduces task-induced fatigue when compared with baseline and placebo. However, it is unclear if this is due to the individual ingredients or the combination (38116,96335,96336). Some research suggests that the combination is no better than either individual ingredient alone (91747,96335,96336).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral L-theanine, taken continuously or as a single dose, improves cognition in older adults. Details: A small clinical study in healthy, Japanese adults aged 50-69 years shows that taking a specific product (Suntheanine; Taiyo International.) containing L-theanine 101 mg daily after breakfast for 12 weeks does not improve mini-mental state exam (MMSE) scores when compared with placebo. However, a single-dose analysis from this study shows that administration of L-theanine 101 mg may improve the quality of working memory and reaction times during a cognitive function test when compared with placebo (108553). Patients were permitted to consume polyphenol-rich beverages during the study period; however, consumption was not documented, limiting the validity of this finding.
• Alzheimer disease. Although there is interest in using oral theanine for Alzheimer disease, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Anxiety. It is unclear if oral L-theanine is beneficial in patients with anxiety. Results of clinical research are conflicting. Details: A preliminary clinical study shows that taking a single dose of a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg does not reduce experimentally-induced anticipatory anxiety when compared with placebo (12188). However, another preliminary clinical study in healthy adults with stress-related anxiety shows that taking L-theanine 200 mg daily for 4 weeks reduces anxiety scale scores and sleep disturbance when compared with placebo (101986).
• Attention. It is unclear if oral theanine improves attention. Details: A small clinical study in healthy males shows that taking a single dose of L-theanine 200 mg improves selective attention similar to a single dose of caffeine 160 mg (96337). However, other small clinical studies in adults show that taking L-theanine 100-400 mg does not improve most measures of attention, especially sustained attention or attention in executive control tasks, but doses of 100-200 mg may improve performance in simple attentional tasks when compared with placebo (96338,111396). Some of these studies suggest that taking L-theanine with caffeine appears to provide more benefit than either individual ingredient alone (96337,96338).
• Attention deficit-hyperactivity disorder (ADHD). Oral L-theanine seems to improve some aspects of ADHD, including cognition and sleep. Details: Some preliminary clinical research in children with ADHD shows that taking a one-time dose of L-theanine 2.5 mg/kg increases cognition scores, but does not improve results on sustained attention or inhibitory control tests, when compared with placebo. Taking L-theanine with caffeine 2 mg/kg also increases cognition scores and improves performance on a sustained attention test, but does not improve inhibitory control, when compared with placebo (104141). Other preliminary clinical research in males aged 8-12 years with ADHD shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg orally twice daily for 6 weeks increases the percent of time spent in restful sleep by about 5% and decreases the number of bouts of nocturnal activity by about 6 when compared with placebo (91744).
• Cancer. Although there is interest in using oral theanine for cancer, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Chemotherapy-induced diarrhea. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with colon cancer shows that taking L-cystine 700 mg and L-theanine 280 mg (Ajinomoto Co. Inc.) orally once daily, starting one week before chemotherapy with TS-1 (Taiho Pharmaceutical) and continuing for 28 days, increases the rate of therapy completion by 49%, reduces the incidence of diarrhea by 37%, reduces appetite loss by 33%, and improves the reported tolerability of chemotherapy when compared with chemotherapy alone (96334). However, this combination does not appear to be beneficial in patients with gastric cancer, or in those with colorectal cancer receiving 4 courses of capecitabine-based adjuvant chemotherapy. (96334,101985).
• Cognitive impairment. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One very small clinical study in adults with mild cognitive impairment shows that taking a product containing L-theanine 120 mg and green tea extract 720 mg (LGNC-07, LG Household & Health Care, Ltd) orally twice daily after meals for 16 weeks modestly improves memory and attention when compared with baseline. However, taking this product does not appear to improve memory and attention when patients with self-reported memory problems, but without mild cognitive impairment, are also considered (96339).
• Depression. It is unclear if oral L-theanine is beneficial in patients with depression. Details: A small clinical study shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku Co. Ltd.) 250 mg at bedtime for 8 weeks reduces symptoms and improves sleep quality when compared to baseline in individuals with mild major depressive disorder (MDD) (96331). The validity of these findings is limited by the lack of a comparator group. Another small clinical study in adults with MDD shows that taking L-theanine 200 mg daily with sertraline for 6 weeks reduces depression symptoms and increases remission rates but does not improve treatment response rates when compared with sertraline and placebo (112278). The validity of these effects is limited by the small sample size and short study duration. Additionally, it is unclear if the reduction in depressive symptoms is clinically significant.
• Erythema. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy females with self-perceived skin sensitivity shows that taking a specific supplement containing L-theanine, ashwagandha, and saffron (InnerCalm, Arbonne) daily for 8 weeks reduces facial pigmentation when compared to baseline (111399). The validity of this finding is limited by a lack of a placebo group. It is unclear if these effects are due to L-theanine, other ingredients, or the combination.
• Generalized anxiety disorder (GAD). It is unclear if oral L-theanine is beneficial for reducing anxiety in people with GAD. Details: One small clinical study in adults with GAD shows that taking L-theanine 225 mg twice daily for 4 weeks, then 450 mg twice daily for 4 weeks, in conjunction with prescribed antidepressants, does not reduce anxiety scores when compared with antidepressants and placebo (104976).
• Hypertension. Although there is interest in using oral theanine for hypertension, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Influenza. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of green tea catechins (THEA-FLAN 90S, Ito-en Co.) 378 mg, standardized to contain epigallocatechin gallate 270 mg and L-theanine (Suntheanine, Taiyo Kagaku) 210 mg daily for 5 months reduces the risk of developing clinically diagnosed influenza when compared with placebo. However, the combination does not seem to prevent laboratory-confirmed influenza infection (54021).
• Insomnia. It is unclear if oral L-theanine is beneficial for insomnia. Details: A very small clinical study in young healthy adults with sleep quality worsened by caffeine intake shows that taking L-theanine 50 mg (Suntheanine, Taiyo Kagaku Co. Ltd) once 10 minutes before bedtime suppresses caffeine-induced elevations in wake after sleep onset time but does not improve parameters of sleep quality including sleep onset latency, sleep time, or number of times waking after sleep onset when compared with placebo (112275). L-theanine has also been studied in combination with other ingredients. A small clinical study in adults with insomnia or disturbed sleep patterns shows that a specific product (RLX2; LiveLife Biosciences AG) containing L-theanine 50 mg and a specific casein peptide, alpha-s1-casein tryptic hydrolysate, 150 mg, taken one hour before bedtime for 4 weeks, increases sleep duration by 45 minutes and improves habitual sleep efficiency and daytime dysfunction when compared with baseline (108556). Another very small clinical study in healthy adults shows that taking a combination product containing tryptophan, glycine, magnesium, tart cherry powder, and L-theanine 2 hours before bedtime decreases sleep onset latency and increases total sleep duration, leading to better sleep efficiency and reduced morning sleepiness, when compared with placebo (111184). Another combination product containing L-theanine, ashwagandha, and saffron (InnerCalm, Arbonne), taken daily for 8 weeks, seems to improve sleep quality when compared to baseline (111399). However, the validity of this finding is limited by a lack of a control group. It is unclear if the effects described above are due to L-theanine, other ingredients, or the combination.
• Obsessive-compulsive disorder (OCD). It is unclear if oral L-theanine is beneficial for OCD. Details: A small clinical study in adults with OCD shows that taking L-theanine 100 mg twice daily for 10 weeks with fluvoxamine reduces OCD symptoms, particularly obsessive symptoms, and increases the proportion of patients with a complete response to treatment but does not improve compulsive symptoms, partial response rates, or remission rates when compared with placebo and fluvoxamine (112276).
• Postoperative recovery. Oral theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study of adults with esophageal cancer undergoing esophagectomy shows that taking theanine 280 mg and cystine 700 mg daily, staring 4 days before surgery and continued for 13 days after surgery, does not improve measures of physical activity but does improve exercise tolerance and some measures of quality of life when compared with placebo (111400). It is unclear if these findings are due to theanine, cystine, or the combination.
• Schizophrenia. It is unclear if oral L-theanine is beneficial in patients with schizophrenia; the available evidence is limited and conflicting. Details: One small preliminary clinical study in adults with schizophrenia or schizoaffective disorder shows that taking L-theanine (Biosynergy) 200 mg orally twice daily for 8 weeks along with antipsychotic medications improves positive symptoms, anxiety, and general psychopathology symptoms, such as poor impulse control and disorientation, when compared with placebo. However, theanine does not improve general disease severity, negative symptoms, depression, cognitive function, extrapyramidal side effects, or quality of life (96341). In contrast, two small clinical studies show that taking L-theanine 400 mg (Suntheanine, BioSynergy Health Alternatives) with antipsychotics and with or without pregnenolone 50 mg daily for 8 weeks reduces negative symptoms, general psychopathology symptoms, and anxiety when compared with placebo in patients with schizophrenia or schizoaffective disorder. However, there were no improvements in positive schizophrenia symptoms, extrapyramidal side effects, or symptoms of depression (97923,112277). The inconsistency of results might be due to the small study sizes and the subjectivity of the outcomes measured.
• Stress. It is unclear if oral L-theanine is beneficial in patients with stress. Details: One very small clinical study shows that taking L-theanine 200 mg prior to a stress-inducing exam reduces tension-anxiety and may prevent blood pressure increases caused by psychological stress when compared with placebo (91746). Other preliminary clinical research in pharmacy students shows that taking theanine 200 mg twice daily for one week prior, and then for the first 10 days of a pharmacy practice period, decreases subjective stress scores when compared with placebo (91745). Another small clinical study in healthy young adults shows that drinking a beverage containing L-theanine 200 mg alone or combined with L-arginine 50 mg after a psychological stressor reduces stress, as measured by salivary alpha-amylase activity, when compared with placebo. The combination of L-arginine and L-theanine did not differ from L-theanine alone, suggesting that the combination does not act synergistically to reduce markers of stress (110393). However, not all research has been positive. A small clinical study shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg induces subjective feelings of tranquility in relaxed people, but not those with experimentally-induced anticipatory anxiety, when compared with placebo (12188). Also, a small, clinical crossover study in healthy, moderately stressed adults shows that taking a single dose of a specific product (Alphawave; Ethical Naturals) containing L-theanine 200 mg prior to a stress-inducing exam does not improve anxiety at any time point when compared with placebo (108554). Due to the single-dose nature of this study, the effects of continued administration of this product are unclear. L-theanine has also been evaluated in combination with other ingredients. A small clinical study in adults with stress shows that taking a specific combination product (Mg-Teadiola, Sanofi-Aventis Group), containing green tea extract 125 mg (providing 50 mg L-theanine), magnesium 150 mg, vitamin B6 0.2 mg, vitamin B9 0.1 mg, vitamin B12 1.25 mcg, and rhodiola 222 mg, orally once daily for 28 days modestly improves stress and anxiety scores when compared with placebo. Improvements in stress scores, but not anxiety scores, appear to persist at 28 days after treatment completion (108672). It is unclear if any effects are due to L-theanine, other ingredients, or the combination.
• Tourette syndrome. It is unclear if oral L-theanine is beneficial in children with Tourette syndrome. Details: A small, nonblinded clinical study in children aged 4-17 years with untreated Tourette syndrome or with chronic tic disorder and associated symptoms of anxiety shows that taking a liquid nutritional supplement providing L-theanine 200 mg and vitamin B6 2.8 mg daily for 2 months improves scores on the Yale Global Tic Severity Scale, but does not reduce anxiety, when compared with patients receiving psychoeducation (108555). This study may have been inadequately powered to detect a difference between groups. More evidence is needed to rate theanine for these uses.

(Read more about THEANINE)

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)

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

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

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

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

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about SAFFRON)

POSSIBLY SAFE ...when used orally and appropriately, short-term. L-theanine has been used safely in clinical research in doses of up to 900 mg daily for 8 weeks (12188,36439,96331,96332,96334,96341,97923,101986,104976). There is insufficient reliable information available about the safety of L-theanine when used long-term.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. A specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg twice daily has been used safely in males aged 8-12 years for up to 6 weeks (91744).

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

(Read more about THEANINE)

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).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, ashwagandha might decrease the levels and clinical effects of CYP1A2 substrates.  Details In vitro research shows that ashwagandha extract induces CYP1A2 enzymes (111404).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, ashwagandha might decrease the levels and clinical effects of CYP3A4 substrates.  Details In vitro research shows that ashwagandha extract induces CYP3A4 enzymes (111404).

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha with hepatotoxic drugs might increase the risk of liver damage.  Details Ashwagandha has been linked to cases of acute hepatitis, liver failure, hepatic encephalopathy, autoimmune hepatitis, the need for liver transplantation, and death due to liver failure (102686,107372,110490,110491,111533,111535,112111,113610).

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)

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

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

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

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

(Read more about SAFFRON)

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theanine might lower blood pressure, potentiating the effects of antihypertensive drugs.  Details Animal research shows that theanine can lower blood pressure in spontaneously hypertensive animals (7687,77354). Theoretically, concomitant use of theanine and antihypertensive drugs might potentiate the antihypertensive activity.

CNS DEPRESSANTS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, theanine might have additive sedative effects when used in conjunction with CNS depressants. However, it is unclear if this concern is clinically relevant.  Details Theoretically, theanine may compete with glutamate and/or increase plasma gamma-aminobutyric acid (GABA) levels, which could cause CNS depression (96334). In one clinical study, some subjects taking oral theanine reported drowsiness (96331).

(Read more about THEANINE)

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 hepatitis, acute liver failure, hepatic encephalopathy, the need for liver transplantation, and death due to liver failure 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). Additionally, an otherwise healthy adult who was taking ashwagandha extract orally for 2 months experienced clinical and laboratory-confirmed thyrotoxicosis. Thyrotoxicosis resolved 50 days after discontinuing ashwagandha, without other treatment (114111).

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 (19276,110490,113609) 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 mg to 20 grams daily has played a role in several case reports of cholestatic, hepatocellular, and mixed liver injuries. 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 and distension, 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 (102686,107372,110490,110491,111533,111535,112111,113610,114113). Laboratory findings include elevated aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, serum bilirubin, and international normalized ratio (INR) (112111,113610,114113). In most cases, liver enzymes normalized within 1-5 months after discontinuation of ashwagandha (102686,107372,110491,111535,112111,114113). 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, liver failure requiring liver transplantation, and acute-on-chronic liver failure resulting in death (110490,113610).

Neurologic/CNS ...Orally, ashwagandha has been reported to cause drowsiness (110492,113609). 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.

(Read more about ASHWAGANDHA)

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

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

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

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

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

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

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

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

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

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

(Read more about SAFFRON)

General ...Orally, L-theanine seems to be well tolerated.
Most Common Adverse Effects:
Orally: Drowsiness, headaches.

Neurologic/CNS ...Orally, L-theanine may cause headaches (36439). Patients have also reported drowsiness, increased duration of sleep, and increased dream activity after oral L-theanine use (96331).
A case of subtle facial tic starting within 4 days of taking L-theanine 400 mg daily has been reported for a pediatric patient. Although the tics reportedly ceased once theanine was discontinued, the child had exhibited tics in the past. Therefore, the adverse effect was not thought to be related to L-theanine (91744).

(Read more about THEANINE)