Glucostat by Maharishi Ayurveda Products

POSSIBLY EFFECTIVE

• Anxiety. Small clinical studies suggest that oral ashwagandha might reduce anxiety. Details: A meta-analysis of small randomized controlled trials in adults with anxiety and/or insomnia shows that taking ashwagandha 600-12,000 mg orally daily for 6-10 weeks moderately improves anxiety scores when compared with placebo. However, the validity of this study is limited by high heterogeneity (114787). 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). Another small clinical trial in adults with general anxiety disorder shows that taking ashwagandha, standardized to 35% withanolides, 60-120 mg orally daily for 60 days improves anxiety scores by about 60% when compared with placebo (114792).
• 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. A meta-analysis of 2 small randomized controlled trials in adults with anxiety and/or insomnia shows that taking ashwagandha 600 mg orally daily for 8-10 weeks modestly improves sleep onset latency, total sleep time, sleep efficiency, and sleep quality scores, but not wake after sleep onset or total time in bed, when compared with placebo. However, the validity of this study is limited by moderate heterogeneity (114787). 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). Ashwagandha has also been evaluated as part of a combination treatment. A very small clinical trial in adults with poor quality sleep shows that taking milk fortified with ashwagandha 250-600 mg, or ashwagandha 250 mg and tryptophan, orally daily for 90 days moderately improves sleep quality scores when compared with placebo (114791). Additional data are needed to determine if the addition of tryptophan improves results more than ashwagandha alone.
• 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. A moderate-sized clinical trial in active adults shows that taking a specific ashwagandha root extract (KSM-66, Ixoreal Biomed) 300 mg orally twice daily, in addition to resistance training, for 8 weeks improves the maximum rate of oxygen consumption (VO2 max) as a measure of cardiorespiratory endurance, but not muscle strength when compared with placebo (114788). 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.Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in adults with back pain shows that taking a specific combination product (Berelief, Monteloeder S.L.) containing ashwagandha 66%, rosemary, and sesame seed, 200-400 mg orally daily for 12 weeks moderately improves pain scores and reduces the need for adjunct pain medication when compared with placebo (114793). It is unclear if this effect is due to ashwagandha, other ingredients, or the combination.
• 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 oral 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. Another small study in adults with RA shows that taking a combination product containing ashwagandha, ginger, black pepper, and colchicum luteum orally twice daily for 4 weeks does not improve RA disease scores when compared with celecoxib 100 mg orally twice daily (114785). However, the interpretation of these results is limited by poor methodology, and the study may have been inadequately powered to detect a difference between groups.
• 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

• Asthma. Clinical research in patients with asthma shows that taking 100 mg of a specific product (AlvioLife) containing a 1:1 combination of bael fruit and boswellia gum resin extracts twice daily for 8 weeks improves activity, asthma symptoms, and emotions compared with placebo. The improvement in the maximum speed of expiration was approximately double that of placebo. The amount of air exhaled during a forced breath was not improved (99299). It is unclear if these effects are due to bael, boswellia, or the combination.
• Shigellosis. Preliminary clinical research shows that taking dried bael fruit powder 6 grams daily for 3 days does not reduce the number of stools in patients with diarrhea due to shigellosis (33330). More evidence is needed to rate bael for these uses.

(Read more about BAEL)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Diabetes. Clinical research shows that drinking jambolan tea 2 grams, prepared with jambolan leaves in one liter of water, does not improve fasting blood glucose in patients with type 2 diabetes when compared with placebo (13092). Clinical research in patients with prediabetes and those with newly-diagnosed type 2 diabetes shows that taking a combination product (GlycaCare-II, Sami-Sabinsa Group Ltd.) providing jambolan dried fruit extract 20 mg orally twice daily for 120 days is associated with similar decreases in glycated hemoglobin levels, and fasting and postprandial glucose levels, to metformin orally 500 mg twice daily. The combination product also contains cassia cinnamon bark extract, bitter melon fruit extract, heartwood extract, gymnema leaf extract, and Salacia bark extract (112762). It is not clear whether the changes are due to jambolan, other ingredients, or the combination. The validity of the results is also reduced by compliance issues and the lack of a per-protocol analysis.
• Venous leg ulcers. Clinical research in patients with venous leg ulcers shows that applying hydrocolloid gel dressings containing an extract of jambolan flowers, seeds, and bark for about 6 months does not improve the overall healing rate or speed of healing when compared with the hydrocolloid dressing alone (112763). More evidence is needed to rate jambolan for these uses.

(Read more about JAMBOLAN)

POSSIBLY EFFECTIVE

• Dental plaque. Topical neem mouth rinses and gel extracts may reduce dental plaque. It is unclear if neem is as effective as chlorhexidine for this purpose. Details: Clinical research shows that using neem topically as a mouth rinse or gel extract twice daily for 3 weeks to 3 months can reduce dental plaque in some patients (12824,64845,94567,97926,104182). Neem leaf extracts, including one at a concentration of 2.5%, have been applied to the teeth and gums twice daily for up to 3 months (12824,64845,104182). Rinsing with 5 mL of neem solution (concentration unknown) or 15 mL of neem 2% solution twice daily for up to 30 days has also been used (94567,97926). It is unclear how neem compares to chlorhexidine for this purpose. One small clinical trial shows that applying neem gel shows similar improvements in plaque index when compared with chlorhexidine 0.2% gel (104182), while another small study shows that rinsing with a neem solution may not be as effective as chlorhexidine 0.2% solution for reducing dental plaque (97926). Reasons for these disparate findings are unclear, but may be related to differences in patient populations, formulations used, and study length.
• Gingivitis. Topical neem mouth rinses and gel extracts may reduce gingivitis, but neem may not be effective in patients with chronic gingivitis. It is unclear if neem is as effective as chlorhexidine for this purpose. Details: Clinical research shows that using neem topically as a mouth rinse or gel extract twice daily for 3 weeks to 3 months appears to improve gingivitis in some patients (12824,64845,94567,104182). However, neem may not be effective in patients with chronic gingivitis (64850). Neem leaf extracts, including one at a concentration of 2.5%, have been applied to the teeth and gums twice daily for up to 3 months (12824,64845,104182). Rinsing with 15 mL of neem 2% solution twice daily for 3 weeks has also been used (94567). It is unclear how neem compares to chlorhexidine for this purpose. One small clinical trial shows that applying neem gel shows similar improvements in gingival index when compared with chlorhexidine 0.2% gel (104182), while other small studies show that rinsing with neem solution may not be as effective as chlorhexidine 0.2% solution for reducing gingivitis (97926,97927). Reasons for these disparate findings are unclear, but may be related to differences in patient populations, formulations used, and study length.
• Lice. Topical neem extract shampoo may treat lice in children. Details: Clinical research in children 2-11 years of age with head lice shows that applying a single application of neem extract shampoo (Licener Pronovo Laboratories) 100 mL to dry hair for 10 minutes followed by rinsing with warm water eradicates 100% of head lice. A single application of neem extract shampoo appears to be slightly more effective than dimethicone (silicone oil) shampoo (97928).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Topical neem extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An observational study in adults who have mild to moderate acne or those without current lesions who are prone to acne, shows that using a specific face wash containing unknown amounts of neem extract and turmeric extract (Himalaya's Purifying Neem Face Wash; Himalaya Drug Company) twice daily for 28 days reduces new inflammatory and non-inflammatory acne lesions by 45% and 69%, respectively, when compared with baseline (107883). The validity of these findings is limited by the lack of a comparator group and short duration of treatment; additionally, it is unclear if this effect is due to neem extract, other ingredients, or the combination.
• Abortion. Although there has been interest in using oral neem to induce abortion, there is insufficient reliable information available about the clinical effects of neem for this purpose.
• Asthma. Although there has been interest in using oral neem for asthma, there is insufficient reliable information available about the clinical effects of neem for this purpose.
• Cardiovascular disease (CVD). Although there has been interest in using oral neem for CVD, there is insufficient reliable information available about the clinical effects of neem for this purpose.
• Contraception. Although there has been interest in using oral and intravaginal neem for contraception, there is insufficient reliable information available about the clinical effects of neem for this purpose.
• Coronavirus disease 2019 (COVID-19). There is limited evidence on the oral use of a neem leaf extract in preventing COVID-19 in high-risk individuals. Details: A clinical study in adults at high risk for COVID-19 infection (e.g. healthcare workers and relatives of patients with COVID-19) shows that taking a specific capsule formulation of neem leaf extract (Nisarga's Neem; Nisarga Biotech) 50 mg twice daily for 28 days decreases the rate of COVID-19 infections by day 29 to 4%, compared with 10% of patients in the placebo group. This suggests that 17 patients would need to take this product to prevent one infection (107882). The validity of this study is limited by the short duration of treatment and unclear reporting. Additionally, patients were only tested for COVID-19 at baseline, day 29, or if symptoms were present; therefore, asymptomatic COVID-19 infections may have been underreported.
• Cough. Although there has been interest in using oral neem for cough, there is insufficient reliable information available about the clinical effects of neem for this purpose.
• Diabetes. It is unclear if oral neem extract is beneficial in patients with diabetes. Details: One small clinical trial in patients with type 2 diabetes who are taking metformin shows that taking a specific neem leaf and twig extract (PhytoBGS; Natreon Inc) 125 mg, 250 mg, or 500 mg twice daily for 12 weeks improves glycemic control in a dose-dependent manner. When compared with placebo, reductions in fasting plasma glucose with neem extract ranged from 8-22 mg/dL and reductions in glycated hemoglobin ranged from 0.18% to 1.47%. Postprandial glucose and measures of insulin resistance and endothelial function were also improved (104181).
• Dyspepsia. Although there has been interest in using oral neem for dyspepsia, there is insufficient reliable information available about the clinical effects of neem for this purpose.
• Hemorrhoids. Although there has been interest in using topical neem for hemorrhoids, there is insufficient reliable information available about the clinical effects of neem for this purpose.
• Insect repellent. Although there has been interest in using topical neem as an insect repellent, there is insufficient reliable information available about the clinical effects of neem for this purpose.
• Intestinal parasite infection. Although there has been interest in using oral neem for intestinal parasite infections, there is insufficient reliable information available about the clinical effects of neem for this purpose.
• Metabolic syndrome. It is unclear if oral neem leaf and twig extract is beneficial in patients with metabolic syndrome. Details: One clinical trial in patients with metabolic syndrome shows that taking a specific neem leaf and twig extract (PhytoBGS; Natreon Inc) 250 mg or 500 mg twice daily for 12 weeks improves glycemic control in a dose-dependent manner when compared with placebo. In the treatment group, reductions in fasting plasma glucose, postprandial plasma glucose, and glycated hemoglobin (HbA1c) ranged from 3-6 mg/dL, 0.7-5.4 mg/dL, and 0.6% to 1.7%, respectively (107881). However, there was no improvement in lipid parameters, and a lower dose of 125 mg twice daily did not affect any measurements (107881). The validity of this study is limited due to unclear reporting.
• Mosquito repellent. Small clinical studies suggest that topical creams containing neem oil may provide moderate to high-level protection against mosquitos. Details: Several small clinical studies show that topical application of a cream containing neem oil 1%, 2%, or 5% provides 37.5% to 100% protection against mosquitoes when compared with a placebo cream. Effectiveness seems to vary depending on mosquito species and geographic location (64876,64878,64882).
• Osteoarthritis. Although there has been interest in using topical neem for osteoarthritis, there is insufficient reliable information available about the clinical effects of neem for this condition.
• Peptic ulcers. It is unclear if oral neem is beneficial in patients with peptic ulcers. Details: One small, uncontrolled clinical study in six patients with peptic ulcers shows that taking neem bark extract 30-60 mg twice daily for 10 weeks reduces gastric secretions when compared to baseline and might aid in the healing of gastroduodenal ulcers. All patients treated with neem bark extract experienced at least 80% healing of gastroduodenal ulcers (12822). The validity of these findings is limited by the very small study size and the lack of a control group.
• Psoriasis. It is unclear if oral neem is beneficial in patients with psoriasis. Details: One small clinical trial in patients with uncomplicated psoriasis shows that taking neem extract by mouth daily in combination with daily sun exposure and application of a Vaseline-based cream containing crude coal tar and salicylic acid for 12 weeks reduces psoriasis symptom severity by approximately 50% when compared with placebo (64892).
• Scleroderma. Topical neem has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research in patients with systemic sclerosis has found that topical application of a specific cream (Holoil, RI.MOS. SRL) containing neem oil and St. John's wort extract seems to improve the healing of skin ulcers, decrease pain, reduce the need for surgical removal of lesions, and reduce the risk of infections and need for antibiotic therapy when compared with a control group (102867). It is unknown if these effects are due to neem, St. John's wort, or the combination. Additionally, the validity of these results is limited by a lack of randomization, blinding, and placebo-control.
• Tungiasis. It is unclear if topical neem oil is beneficial for the treatment of tungiasis. Details: One small clinical trial in children aged 6-15 years with tungiasis shows that topical application of an oil mixture containing neem seed oil 20% and virgin coconut oil 80%, 1 drop on days 1 and 3, kills about 40% of sand fleas within 7 days, a rate similar to standard treatment with a potassium permanganate 0.05% foot bath (104258).
• Urinary tract infections (UTIs). Although there has been interest in using oral neem for UTIs, there is insufficient reliable information available about the clinical effects of neem for this purpose.
• Wound healing. Topical neem has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-size clinical study in adults with dehisced post-surgical wounds shows that applying a specific aerosol product (1PWD, Kerecis AG) containing neem oil and St. John's wort to wounds during dressing changes does not improve wound healing scores at day 28 but may reduce pain scores when compared with silver-based dressings (alginates or polyurethane foam) (111592). However, this study may have been inadequately powered to detect a difference between groups. It is also unclear if these affects are due to neem, St. John's wort, or the combination. More evidence is needed to rate neem for these uses.

(Read more about NEEM)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. Oral shilajit has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small preliminary clinical trial in adults with probable Alzheimer disease shows that taking shilajit 200 mg, in combination with folate and vitamins B6 and B12, daily for 24 weeks modestly prevents cognitive deterioration based on some measures compared with placebo (112637). This study lacks a complete description of methodology and findings. Also, it is not clear if these effects are due to shilajit, the other ingredients, or the combination.
• Athletic performance. Although there is interest in using oral shilajit for improving athletic performance, there is insufficient reliable information about the clinical effects of shilajit for this purpose.
• Benign prostatic hyperplasia (BPH). Although there is interest in using oral shilajit for BPH, there is insufficient reliable information about the clinical effects of shilajit for this condition.
• Diabetes. Although there is interest in using oral shilajit for diabetes, there is insufficient reliable information about the clinical effects of shilajit for this condition.
• Fractures. It is unclear if oral shilajit is beneficial for fracture repair. Details: Clinical research in adults shows that taking shilajit 500 mg twice daily for 28 days following surgery for a new tibia fracture results in a mean time to bone union of 129 days compared with 153 days in those taking placebo (112616). This study is limited by the large attrition rate, leaving only 62 patients X-rayed for the primary outcome.
• Hyperlipidemia. Although there is interest in using oral shilajit for hyperlipidemia, there is insufficient reliable information about the clinical effects of shilajit for this condition.
• Hypertension. Although there is interest in using oral shilajit for hypertension, there is insufficient reliable information about the clinical effects of shilajit for this condition.
• Male infertility. It is unclear if oral shilajit is beneficial for male infertility. Details: Preliminary clinical research in adults with oligospermia shows that taking shilajit 100 mg twice daily for 90 days increases total sperm count by 61% and motility by at least 12% when compared to baseline. Normal sperm count was increased by 19% and white blood cell counts were reduced by 55% (112621). The validity of this study is limited by the lack of a comparator group.
• Muscle strength. It is unclear if oral shilajit is beneficial for muscle strength. Details: A small clinical trial in recreationally-active adults with baseline maximal strength above the 50^th percentile shows that taking shilajit (PrimaVie, Natreon Inc., New Brunswick, NJ) 500 mg daily for 8 weeks modestly prevents a decline in this muscle strength after a fatiguing protocol when compared with taking shilajit 250 mg daily or placebo. However, there was no effect in the adults below the 50th percentile for maximal strength at baseline (112614). This study is limited by the inclusion of only male participants.
• Osteopenia. It is unclear if oral shilajit is beneficial for osteopenia. Details: A small clinical trial in postmenopausal adults with osteopenia or osteoporosis shows that taking shilajit (PrimaVie, Natreon Inc., New Brunswick, NJ) 250 mg or 500 mg daily, in a dose-responsive manner, for 48 weeks modestly increases bone density at the lumbar spine and femoral neck when compared with placebo (112613). The study is limited by the inclusion only of patients within 5 years of menopause lacking conventional hormonal therapy or anti-resorptive medication. It is unclear if these results are generalizable to other populations, including males or premenopausal or older females.
• Osteoporosis. It is unclear if oral shilajit is beneficial for osteoporosis. Details: A small clinical trial in postmenopausal adults with osteopenia or osteoporosis shows that taking shilajit (PrimaVie, Natreon Inc., New Brunswick, NJ) 250 mg or 500 mg daily, in a dose-responsive manner, for 48 weeks modestly increases bone density at the lumbar spine and femoral neck when compared with placebo (112613). The study is limited by the inclusion only of patients within 5 years of menopause lacking conventional hormonal therapy or anti-resorptive medication. It is unclear if these results are generalizable to other populations, including males or premenopausal or older females.
• Sexual desire. Although there is interest in using oral shilajit for increasing sexual desire, there is insufficient reliable information about the clinical effects of shilajit for this purpose.
• Sexual dysfunction. Although there is interest in using oral shilajit for sexual dysfunction, there is insufficient reliable information about the clinical effects of shilajit for this purpose. More evidence is needed to rate shilajit for these uses.

(Read more about SHILAJIT)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Angina. It is unclear if oral Terminalia arjuna is beneficial in patients with angina. Details: Low-quality clinical research in patients with angina shows that taking Terminalia arjuna extract 500-2000 mg orally daily for 3 months reduces the frequency of angina symptoms by 50% to 71% when compared with baseline. These results were similar to taking conventional therapy (2502,2503). Other preliminary research in adults with chronic stable angina shows that taking Terminalia arjuna 500 mg orally three times daily for 7 days reduces the need for rescue treatment and improves exercise tolerance when compared with placebo. Improvements were similar to taking isosorbide mononitrate 20 mg twice daily (92833).
• Asthma. Although there has been interest in using oral Terminalia arjuna for asthma, there is insufficient reliable information about the clinical effects of Terminalia arjuna for this purpose.
• Athletic performance. It is unclear if oral Terminalia arjuna is beneficial for athletic performance. Details: A small clinical study in young regular exercising males shows that taking Terminalia arjuna extract (Oxyjun, Enovate Biolife Pvt Ltd, India) 400 mg daily for 8 weeks increases the time to exhaustion by approximately 117 seconds when compared with placebo. There were also modest improvements in feelings of perceived exertion and the left ventricular ejection fraction, a measure of blood pumped from the heart with each heartbeat (111093). It is unclear if oral Terminalia arjuna is beneficial other populations such as athletes and females.
• Coronary heart disease (CHD). It is unclear if oral Terminalia arjuna is beneficial in patients with CHD. Details: Preliminary clinical research in patients with CHD shows that taking Terminalia arjuna bark powder 500 mg orally daily for 30 days decreases levels of total cholesterol by about 10% and low-density lipoprotein (LDL) cholesterol by about 16% when compared with baseline. Taking Terminalia arjuna bark powder did not improve high-density lipoprotein (HDL) cholesterol levels (92832).
• Heart failure. The effects of Terminalia arjuna in patients with heart failure is unclear; evidence to date comes from small, short-term clinical studies, and results are conflicting. Details: Preliminary, low-quality clinical research in patients with severe, refractory congestive heart failure shows that taking Terminalia arjuna bark extract 500 mg orally three times daily for 2 weeks, as an adjunct to conventional therapy, improves left ventricular ejection fraction (LVEF) by 17% when compared with placebo (2504). However, other preliminary clinical research in adults with stage II heart failure shows that taking an extract of Terminalia arjuna bark 750 mg orally twice daily as an adjunct to conventional therapy for 12 weeks does not improve LVEF, functional class, or functional capacity when compared with placebo (96726). However, the validity of these trials is limited by short-term treatment and variation in the conventional therapies used to manage heart failure.
• Hyperlipidemia. It is unclear if oral Terminalia arjuna is beneficial for improving lipid levels. Details: Preliminary clinical research in patients with elevated cardiovascular risk factors, such as hypertension, dyslipidemia, or obesity, shows that taking Terminalia arjuna 5 grams orally twice daily for 60 days decreases levels of low-density lipoprotein (LDL) cholesterol and triglycerides by 17% and 35%, respectively, and increases high-density lipoprotein (HDL) cholesterol levels by 9%, when compared with baseline. Improvements in lipid parameters were similar to taking amlodipine 5 mg and atorvastatin 10 mg daily (109677). However, this study may have been inadequately powered to detect a difference between groups.
• Hypertension. It is unclear if oral Terminalia arjuna is beneficial for reducing blood pressure. Details: Preliminary clinical research in patients with elevated cardiovascular risk factors such as hypertension, dyslipidemia, or obesity, shows that taking Terminalia arjuna 5 grams orally twice daily for 60 days reduces systolic and diastolic blood pressure by 11% and 14%, respectively, when compared with baseline. Improvements in blood pressure were similar to taking amlodipine 5 mg and atorvastatin 10 mg daily (109677). However, this study may have been inadequately powered to detect a difference between groups.
• Obesity. It is unclear if oral Terminalia arjuna is beneficial for weight loss. Details: Preliminary clinical research in patients with elevated cardiovascular risk factors, such as hypertension, dyslipidemia, or obesity, shows that taking Terminalia arjuna 5 grams orally twice daily for 60 days reduces body mass index (BMI) by 6% when compared with baseline. Improvements in BMI were similar to taking amlodipine 5 mg and atorvastatin 10 mg daily (109677). This study may have been inadequately powered to detect a difference between groups. More evidence is needed to rate Terminalia arjuna for these uses.

(Read more about TERMINALIA ARJUNA)

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)

There is insufficient reliable information available about the safety of bael.

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

(Read more about BAEL)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Jambolan tea prepared from 2 grams of jambolan leaves per liter of water has been consumed in place of water with apparent safety in clinical research (13092).

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

(Read more about JAMBOLAN)

POSSIBLY SAFE ...when neem bark extract is used orally and appropriately, short-term. Neem bark extract has been used safely in clinical research at doses up to 60 mg daily for up to 10 weeks (12822). ...when neem leaf and twig extract is used orally and appropriately, short-term. Neem leaf and twig extract has been used safely in clinical research at doses up to 500 mg twice daily for up to 12 weeks (104181). ...when neem leaf extract gel is used intraorally for up to 6 weeks (12824,64845,64850,94567). ...when neem oil, cream, or face wash is used topically on the skin for up to 2 weeks (64876,64878,64882,102867,107883).

POSSIBLY UNSAFE ...when neem or neem oil is used orally in large amounts or long-term. Preliminary clinical research suggests neem might be toxic to the kidneys or liver with high-dose or chronic use. Cardiac arrest has also been reported (12835,64870,64873).

CHILDREN: POSSIBLY SAFE
when neem extract is used topically. It has been used with apparent safety as a shampoo, with one or two total applications (97928).

CHILDREN: LIKELY UNSAFE
when neem oil or seeds are used orally. There are reports of infants who were severely poisoned and died after oral use of neem (3473,3474,3476,64855,64875).

PREGNANCY: LIKELY UNSAFE
when neem oil or leaf is used orally. Neem oil and leaf have been used as abortifacients (12825,12835,64884,64889).

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about NEEM)

POSSIBLY SAFE ...when processed shilajit is used orally and appropriately. Processed shilajit has been used with apparent safety in doses of 2 grams daily for 45 days or up to 500 mg daily for up to 48 weeks (112613,112614,112615,112616,112617,112618,112619,112621). There is insufficient reliable information available about the safety of crude or unprocessed shilajit when used orally or shilajit when used topically.

PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of shilajit when used during pregnancy and lactation.

(Read more about SHILAJIT)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Several small studies have used Terminalia arjuna powdered bark or bark extract with apparent safely in doses up to 2000 mg or 400 mg daily, respectively, for 2 weeks to 3 months (2502,2503,2504,111012,111093); however, patients should avoid self-treatment with this product due to potentially significant cardiovascular effects. Further study is needed to determine the safety of Terminalia arjuna for long-term use.

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

(Read more about TERMINALIA ARJUNA)

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 = D Evidence from animal research suggests that extracts of bael seed and leaf can reduce blood glucose levels (33316,33325). Theoretically, bael might have additive effects with antidiabetes drugs and increase the risk of hypoglycemia. Monitor blood glucose levels closely. Dose adjustments might be necessary.  Details Some antidiabetes drugs include glimepiride (Amaryl), glyburide (DiaBeta, Glynase PresTab, Micronase), insulin, pioglitazone (Actos), rosiglitazone (Avandia), and others.

CHOLINERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Bael leaf extract shows acetylcholinesterase (AChE) inhibitory activity in vitro (99296). Theoretically, bael might have additive effects with cholinergic drugs and increase the risk of cholinergic side effects.  Details Cholinergic drugs include bethanechol (Urecholine), donepezil (Aricept), echothiophate (Phospholine Iodide), edrophonium (Enlon, Reversol, Tensilon), neostigmine (Prostigmin), physostigmine (Antilirium), pyridostigmine (Mestinon, Regonol), succinylcholine (Anectine, Quelicin), and tacrine (Cognex).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Bael extract and its constituent marmesinin inhibited cytochrome P450 1A2 (CYP1A2) activity in vitro (99300). So far, this interaction has not been reported in humans. Theoretically, bael might increase levels of drugs metabolized by CYP1A2.  Details Some drugs metabolized by CYP1A2 include amitriptyline (Elavil), haloperidol (Haldol), ondansetron (Zofran), propranolol (Inderal), theophylline (Theo-Dur, others), verapamil (Calan, Isoptin, others), and others. Use bael cautiously or avoid in patients taking these drugs.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Bael and its constituents marmelosin and marmesinin inhibited cytochrome P450 3A4 (CYP3A4) activity in vitro (99300). So far, this interaction has not been reported in humans. Theoretically, bael might increase levels of drugs metabolized by CYP3A4.  Details Some drugs metabolized by CYP3A4 include lovastatin (Mevacor), ketoconazole (Nizoral), itraconazole (Sporanox), fexofenadine (Allegra), triazolam (Halcion), and numerous others. Use bael cautiously or avoid in patients taking these drugs.

(Read more about BAEL)

(Read more about JAMBOLAN)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Neem might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Some clinical research shows that neem can lower blood glucose levels in adults with type 2 diabetes, including those already taking metformin (12823,104181).

CYTOCHROME P450 2C8 (CYP2C8) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, neem leaf extract might increase the levels and clinical effects of CYP2C8 substrates.  Details In vitro research shows that neem leaf methanol extract inhibits CYP2C8 enzymes (111593). So far, this reaction has not been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, neem leaf extract might increase the levels and clinical effects of CYP2C9 substrates.  Details In vitro research shows that neem leaf methanol extract inhibits CYP2C9 enzymes (111593). So far, this reaction has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, neem leaf extract might increase the levels and clinical effects of CYP3A4 substrates.  Details In vitro research shows that neem leaf methanol extract inhibits CYP3A4 enzymes (111593). So far, this reaction has not been reported in humans.

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, neem might decrease the effectiveness of immunosuppressants.  Details Animal research suggests that neem might have immunostimulant effects (12825).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, neem leaf extract might increase the levels and clinical effects of P-glycoprotein substrates.  Details In vitro research shows that neem leaf methanol extract inhibits renal P-glycoprotein transport activity (107850). So far, this reaction has not been reported in humans.

(Read more about NEEM)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Taking shilajit with antidiabetes drugs might increase the risk of hypoglycemia.  Details Most human and animal research shows that shilajit can decrease fasting plasma glucose levels (112621,112626,112627,112630,112638). In an animal model, shilajit 100 mg per kg daily enhanced the glucose-lowering ability of both glibenclamide and metformin when given in combination over a 4 week period (112638). Monitor blood glucose levels closely. Dose adjustments might be necessary.

(Read more about SHILAJIT)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of Terminalia arjuna with anticoagulant or antiplatelet drugs may increase the risk of bleeding in some patients.  Details In vitro, Terminalia arjuna bark extract inhibits platelet aggregation, decreases platelet activation, and shows antithrombotic properties (92831).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, use of Terminalia arjuna may increase the levels and clinical effects of CYP2C9 substrates.  Details In vitro research shows that Terminalia arjuna extract inhibits CYP2C9 enzymes and reduces CYP2C9 substrate metabolism (96729).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, use of Terminalia arjuna may increase the levels and clinical effects of CYP2D6 substrates.  Details In vitro research shows that Terminalia arjuna extract inhibits CYP2D6 enzymes and reduces CYP2D6 substrate metabolism (96729).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, use of Terminalia arjuna may increase the levels and clinical effects of CYP3A4 substrates.  Details In vitro research shows that Terminalia arjuna extract inhibits CYP3A4 enzymes and reduces CYP3A4 substrate metabolism (96729).

(Read more about TERMINALIA ARJUNA)

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). Another case report describes a 37-year-old female who presented with moderate symptomatic hyponatremia secondary to adrenal insufficiency after chronic consumption of ashwagandha for 2 years. This subject was effectively managed with oral hydrocortisone (114790).

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 ...Consuming large amounts of bael may cause gastrointestinal upset and constipation (18).

Gastrointestinal ...Orally, consuming large amounts of bael may cause gastrointestinal upset and constipation (18).

(Read more about BAEL)

General ...No adverse effects have been reported; however, a thorough evaluation of safety outcomes has not been conducted.

(Read more about JAMBOLAN)

General ...Orally, neem extracts seem to be well tolerated in adults. However, high-quality assessment of safety has not been conducted. In children, oral use of neem oil can cause serious adverse effects. Topically, neem seems to be well tolerated in children and adults.
Most Common Adverse Effects:
Topically: Contact dermatitis in sensitive individuals.
Serious Adverse Effects (Rare):
Orally: Cardiac arrest, nephrotoxicity, and ventricular fibrillation with neem leaf in adults. Encephalopathy, hematologic abnormalities, hepatotoxicity, and nephrotoxicity with neem oil in infants and young children.

Cardiovascular ...Orally, neem leaf has been reported to cause ventricular fibrillation and cardiac arrest after ingestion in humans (64873,64870).

Dental ...Topically, use of neem twigs to brush teeth, which is a traditional dental hygiene practice in India, has been associated with vitiligo of the lips. The limonoid constituents in neem, which have been shown to inhibit melanogenesis and have cytotoxic effects, combined with repeated, local trauma from this dental hygiene practice are thought to cause this leucodermic reaction. In a case series of seven patients experiencing vitiligo of the lips from neem twigs, use of toothpaste and topical tacrolimus along with avoidance of neem stopped the progression of depigmentation in all patients. Repigmentation was reported in four of the seven patients 12 months after discontinuing neem-based dental hygiene practices (100958).

Dermatologic ...Topically, neem products have been associated with dermatologic reactions. Some case reports have associated the use of topical neem oil with contact dermatitis (64851,94568,102867). In one case series, the topical application of neem seed extract shampoo was associated with skin irritation, red spots, and a burning feeling of the scalp (64848). Use of neem twigs to brush teeth, which is a traditional dental hygiene practice in India, has been associated with vitiligo of the lips. The limonoid constituents in neem, which have been shown to inhibit melanogenesis and have cytotoxic effects, combined with repeated, local trauma from this dental hygiene practice are thought to cause this leucodermic reaction. In a case series of seven patients experiencing vitiligo of the lips from neem twigs, use of toothpaste and topical tacrolimus along with avoidance of neem stopped the progression of depigmentation in all patients. Repigmentation was reported in four of the seven patients 12 months after discontinuing neem-based dental hygiene practices (100958).

Gastrointestinal ...Orally, neem oil has been reported to cause vomiting and loose stools in infants and small children (3473,3474,3476,64865).

Genitourinary ...Orally, neem leaf has been reported to cause oliguria and anuria in adults (12833,12834). After a single intrauterine instillation, purified neem oil has been reported to cause endometritis in healthy, tubectomised females (64886).

Hematologic ...Orally, neem leaf has been reported to cause hemolysis in adults (12835). In one case report, a 35-year-old male with diabetes and glucose-6-phosphate dehydrogenase (G6PD) deficiency developed hemolytic anemia and jaundice after drinking several liters of neem tea daily for 3 weeks. All symptoms resolved after discontinuation and supportive treatment (94571). Orally, neem oil has been reported to cause metabolic acidosis, anemia, and polymorphonuclear leukocytosis in infants and young children (3473,3474,3476,64865).
A single intrauterine instillation of purified neem oil has been reported to cause mild transient eosinophilia in healthy, tubectomised females (64886).

Hepatic ...Orally, neem oil has been associated with reports of hepatotoxicity in infants and children. These adverse effects occurred after single doses of neem oil ranging from a few drops to 60 mL. Pathologic findings on liver biopsy reports have been consistent with Reye-like syndrome (3473,3474,3475).

Immunologic ...Topically, a case of aggravated bullous pemphigoid requiring hospitalization is reported in a 47-year-old patient with this autoimmune condition after application of neem oil to blisters for an unknown duration (111715).

Neurologic/CNS ...Orally, single doses of neem oil ranging from a few drops to 60 mL have been associated with reports of encephalopathy in infants and small children. Symptoms include drowsiness, seizure, loss of consciousness, coma, cerebral edema, Reye-like syndrome, and death within hours of ingestion (3473,3474,3476,3476,64855,94750). There is also at least one case report of neurotoxicity in an adult after ingestion of a neem-based pesticide. A 35-year-old female experienced neurotoxicity requiring intensive medical care and ventilation after ingestion of a pesticide containing azadirachtin, a constituent of neem oil (64858).

Ocular/Otic ...In one case report, a 35-year-old female developed toxic optic neuropathy and vision loss in both eyes lasting for two days after consuming 150 mL of neem oil in a suicide attempt five days earlier (64856).

Renal ...Orally, neem leaf has been reported to cause oliguria, anuria, acute tubular necrosis, and nephrotoxicity in adults (12833,12834). There are some case reports of children developing Reye-like syndrome after ingestion of neem oil. Pathologic findings on renal biopsy reports have been consistent with Reye syndrome (3473,3474,3475).

(Read more about NEEM)

General ...Orally, processed shilajit seems to be well tolerated. Topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: A case report has raised concerns about pseudohyperaldosteronism.

Cardiovascular ...Orally, a case of hypertension related to mineralocorticoid-excess syndrome or pseudohyperaldosteronism is reported in a 37-year-old female following the use of shilajit for 6 months during pregnancy. Electrocardiographic findings were normal. Product discontinuation and treatment with intravenous and oral potassium led to restoration of blood pressure and potassium levels (112622). The role of shilajit in this adverse effect cannot be confirmed. The presence of other ingredients or contaminants in the product was not ruled out.

Endocrine ...Orally, a case of apparent mineralocorticoid excess, or pseudohyperaldosteronism, with edema, increased urinary potassium, calcium, and magnesium loss, hypokalemia, and metabolic alkalosis, is reported in a 37-year-old female following the use of shilajit for 6 months during pregnancy. Product discontinuation and treatment with intravenous and oral potassium led to restoration of potassium levels (112622). The role of shilajit in this adverse effect cannot be confirmed. The presence of other ingredients or contaminants in the product was not ruled out.

Immunologic ...Orally, a case of allergy to shilajit made worse by exercise is reported in a 43-year-old female. Although symptoms were lacking when shilajit 400 mg was taken daily with meals for 3 months, she developed hives within an hour of taking a single dose of shilajit 800 mg. With intramuscular corticosteroids, symptoms improved but did not resolve. The next day, following a meal and physical activity she developed anaphylaxis requiring adrenaline and intravenous corticosteroids (112620).

Neurologic/CNS ...Orally, headache is reported rarely following shilajit intake in clinical research (112616).

(Read more about SHILAJIT)

General ...There is currently a limited amount of information available on the adverse effects of oral Terminalia arjuna. A thorough evaluation of safety outcomes has not been conducted.

(Read more about TERMINALIA ARJUNA)