Stimuliv by Jarrow Formulas

POSSIBLY EFFECTIVE

• Common cold. Oral andrographis, taken alone or as part of a specific combination product (Kan Jang, Swedish Herbal Institute) also containing eleuthero, seems to improve symptoms of the common cold. It is unclear if oral andrographis is beneficial for preventing the common cold. Details: Most clinical research shows that taking andrographis alone or as part of a combination herbal supplement improves cold symptoms (2744,2773,2774,5784,10795,12380,12381,98222). Taking a specific combination product (Kan Jang, Swedish Herbal Institute) containing andrographis extract, standardized to andrographolides 4-5.6 mg, and eleuthero three times daily seems to improve symptoms of the common cold when started within 72 hours of symptom onset. Some symptoms can improve after 2 days of treatment, but it typically takes 4-5 days of treatment for maximal symptom relief (2744,2773,2774,5784,10795,12380). This combination also seems to relieve cold symptoms better than echinacea or placebo in children (12381). Other clinical research shows that taking a specific andrographis extract (KalmCold) 200 mg daily for 5 days reduces cold symptoms by approximately two-fold and increases the number of patients who respond to treatment when compared with placebo (31222). Preliminary clinical research shows that taking andrographis (Kan Jang, Swedish Herbal Institute) prophylactically might decrease the risk of developing a cold by about 50% after 2 months of continuous treatment (2772); however, more evidence is needed to confirm these results.
• Osteoarthritis. Oral andrographis extract has been evaluated for the treatment of osteoarthritis, with promising results. Details: In patients with mild to moderate osteoarthritis of the knee, clinical research shows that taking a specific brand of andrographis extract (ParActin, HP Ingredients) 300 mg and 600 mg daily for 12 weeks reduces pain and stiffness by approximately 40% and 46%, respectively, compared with changes of less than 10% with placebo (101116).
• Tonsillopharyngitis. Oral andrographis has been evaluated for the management of fever and sore throat associated with tonsillopharyngitis, with promising results. Details: Some clinical research shows that andrographis 6 grams daily is comparable to acetaminophen for reducing fever and sore throat associated with tonsillopharyngitis after 3 and 7 days of treatment (2748).
• Ulcerative colitis. Oral andrographis extract has been evaluated for the management of ulcerative colitis symptoms, with promising results. Details: Some clinical research shows that taking andrographis extract 1200-1800 mg daily for 8 weeks reduces symptoms of mild to moderate ulcerative colitis, but does not affect remission rates, when compared with placebo (31231). Additional clinical research also shows that taking andrographis extract 1200 mg daily for 8 weeks is as effective as mesalamine for reducing symptoms in patients with ulcerative colitis (31223).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute bronchitis. Although there has been interest in using oral andrographis for acute bronchitis, there is insufficient reliable information about the clinical effects of andrographis for this purpose.
• Cognitive impairment. Oral andrographis has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in a small number of patients with mild cognitive impairment shows that taking a combination product (Adaptra Forte, Europharma USA) containing andrographis extract 400 mg, standardized to andrographolides 40 mg, and ashwagandha extract 150 mg twice daily for 4 weeks modestly improves some measures of concentration and sleep quality when compared with placebo (104822).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral andrographis is beneficial in mild to moderate COVID-19. Details: A moderate-sized clinical study in adults with mild to moderate COVID-19 receiving standard of care conducted in India shows that taking andrographis raw plant part extract 200 mg twice daily for 14 days improves the time to clinical improvement by 2-points on the World Health Organization (WHO) scale to about 4 days compared with about 6 days in the control group (112920). However, the interpretation of this finding is limited by unbalanced groups with sicker patients in the control group. Additionally, a large observational study conducted in Thailand in unvaccinated hospitalized adults with mild COVID-19 suggests that taking andrographis, dosed as andrographolide 60 mg, three times daily for 5 days is not associated with a decrease in the risk of developing pneumonia when compared with standard of care (112919).
• Diabetes. Oral andrographis has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in adults with type 2 diabetes who are taking metformin 1000 mg daily shows that taking a combination product containing andrographis and Syzygium polyanthum leaf extracts, 900 mg daily for 8 weeks, does not improve fasting blood glucose levels, glycated hemoglobin (HbA1c), blood pressure, or blood lipid levels when compared with placebo (101117).
• Familial Mediterranean fever. Oral andrographis has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children 3-15 years of age shows that taking a combination product (ImmunoGuard, Inspired Nutritionals) containing andrographis 16 mg, eleuthero, schisandra, and licorice daily for 1 month reduces the duration, frequency, and severity of attacks of familial Mediterranean fever (12382).
• Hypertriglyceridemia. It is unclear if oral andrographis is beneficial in patients with hypertriglyceridemia. Details: A small clinical study in adults with hypertriglyceridemia shows that taking andrographis, standardized to contain andrographolide 119.64-120.36 mg, by mouth daily for 8 weeks decreases triglycerides by 42 mg/dL, demonstrating comparable effects to gemfibrozil. However, compared to baseline, total cholesterol was increased by 15 mg/dL and low-density lipoprotein (LDL) cholesterol was increased by 21 mg/dL, suggesting that the benefits of lower triglycerides may be offset by elevations in other lipid levels. Taking a lower daily dose of andrographis, standardized to contain andrographolide 71.64-72.36 mg, does not seem to affect lipid levels (91839).
• Impaired glucose tolerance (prediabetes). It is unclear if oral andrographis is beneficial in patients with prediabetes. Details: A small crossover clinical study in adults with prediabetes conducted in Indonesia shows that taking andrographis 550 mg for 14 days increases glucagon-like peptide 1 (GLP-1) levels but does not statistically improve measures of insulin resistance (i.e., fasting insulin, fasting glucose, 2-hour postprandial glucose, 2-hour postprandial insulin, homeostatic model assessment for insulin resistance [HOMA-IR]) when compared with placebo (112918). However, it is unclear whether this improvement is clinically significant. In addition, the frequency of andrographis dosing is unclear.
• Influenza. Oral andrographis has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that patients with influenza who take a specific product (Kan Jang, Swedish Herbal Institute) containing andrographis extract, standardized to andrographolides 4-5.6 mg, and eleuthero three times daily for 3-5 days have more rapid symptom relief when compared with patients taking amantadine. Taking this combination product also seems to reduce the risk of post-influenza complications such as rhinosinusitis or bronchitis when compared with amantadine (10441).
• Migraine headache. Oral andrographis has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Research has evaluated a combination product (Vivinor, Brain Therapeutics; Partena, FB Health) containing andrographis 100 mg, magnesium 281 mg, riboflavin 5 mg, feverfew 150 mg, and coenzyme Q10 20 mg. A nonblinded, clinical study in patients with episodic migraines shows that taking 1-2 tablets of this product daily for 3 months decreases monthly average migraine days, migraine severity, and the number of days an acute migraine medication is used when compared with baseline. In the third month of treatment, 57% of patients had at least a 50% reduction in average migraine days (107473). The validity of this study is limited by the lack of randomization and placebo-control; additionally, it is unclear if any effects are due to andrographis, the other ingredients, or the combination.
• Multiple sclerosis (MS). It is unclear if oral andrographis is beneficial in patients with MS. Details: A small clinical study in patients with relapsing-remitting MS currently receiving interferon-beta shows that taking andrographis dried extract (Innobioscience Spa) 170 mg, standardized to contain andrographolides 85 mg, twice daily for 12 months decreases fatigue by 44%, but does not affect relapse rate or disability, when compared with placebo (91838). Another small clinical study of patients with primary or secondary, but not active, progressive MS shows that taking andrographolide, a constituent of andrographis, 140 mg twice daily for 24 months slows the progression of disability when compared with placebo (104821).
• Rheumatoid arthritis (RA). It is unclear if oral andrographis is beneficial in patients with RA. Details: Preliminary clinical research shows that taking andrographis extract 90 mg daily for 14 weeks reduces symptoms of RA when compared to baseline, but not when compared with placebo (31220).
• Rhinosinusitis. Although there has been interest in using oral andrographis for rhinosinusitis, there is insufficient reliable information about the clinical effects of andrographis for this purpose.
• Upper respiratory tract infection (URTI). Oral andrographis has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in adults with uncomplicated URTI shows that a specific combination product (Kan Jang, Swedish Herbal Institute) containing andrographis 195 mg and eleuthero root 11.4 mg per capsule, taken as two capsules three times daily for 5 days, reduces the median number of sick leave days to 2 days, compared with 3 days in the placebo group. It also increases the total number of recovered patients on day 3 to 75%, compared with 55% of those taking placebo (107471). More evidence is needed to rate andrographis for these uses.

(Read more about ANDROGRAPHIS)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Topical black nightshade has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in young adults with facial acne suggests that application of a cream containing black nightshade leaf 0.8%, elecampane flower and leaf 0.8%, and red soapwort root 0.32%, 2 to 3 times daily for 6 weeks, reduces acne severity index scores by 55%, 85%, and 91% from baseline at 2, 5, and 6 weeks, respectively, compared with no change in the placebo group (105733). It is unclear if this effect is due to black nightshade, other ingredients, or the combination. The poor study methodology and lack of statistical comparison to the placebo group limit the validity of these findings.
• Cirrhosis. Although there is interest in using oral black nightshade for cirrhosis, there is insufficient reliable information about the clinical effects of black nightshade for this condition.
• Herpes zoster (shingles). Although there is interest in using topical black nightshade for shingles, there is insufficient reliable information about the clinical effects of black nightshade for this condition. More evidence is needed to rate black nightshade for these uses.

(Read more about BLACK NIGHTSHADE)

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)

POSSIBLY EFFECTIVE

• Vitiligo. Taking picrorhiza orally for up to 1 year, in combination with oral and topical methoxsalen, seems to help treat vitiligo in adults and children (11493).

POSSIBLY INEFFECTIVE

• Asthma. Taking picrorhiza orally for up to 12 weeks does not seem to help asthma symptoms or improve measurements of lung function (11858).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Chronic obstructive pulmonary disease (COPD). A small clinical study in patients with COPD and chronic cough shows that taking two capsules of a specific combination product (AKL1, AKL International Ltd.) containing picrorhiza ginkgo extract, and ginger twice daily for 8 weeks does not improve cough or other respiratory symptoms when compared with placebo (89702).
• Hepatitis. Preliminary clinical research suggests that picrorhiza, given orally for 2 weeks, might help acute viral hepatitis. It seems to improve symptoms such as anorexia, nausea, and malaise, as well as lower bilirubin and transaminase levels (11848). Picrorhiza has not been tested in patients with hepatitis B. More evidence is needed to rate picrorhiza for these uses.

(Read more about PICRORHIZA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Burns. Although there has been interest in using topical tree turmeric for burns, there is insufficient reliable information about the clinical effects of tree turmeric for this purpose.
• Diabetes. Oral tree turmeric has only been evaluated in combination with other ingredients for the management of type 1 and type 2 diabetes; its effect when used alone is unclear. Details: Clinical research in patients with type 2 diabetes shows that taking a specific combination product (Berberol, PharmExtracta) containing tree turmeric extract 1176 mg and milk thistle extract 210 mg improves some measures of diabetes control. A clinical study in patients with type 2 diabetes, obesity, and metabolic syndrome shows that taking this specific product daily for 12 months reduces glycated hemoglobin (HbA1c) by approximately 18% when compared to baseline. This reduction was significant when compared with the 5% reduction in the placebo group. Fasting blood glucose and insulin resistance were also improved, with a reduction in fasting blood glucose of approximately 25% for patients in the treatment group, compared to 10% in the placebo group (97624). Several other small clinical studies in adults with poorly controlled type 2 diabetes shows that taking this same product for 12 months improves HbA1c, fasting blood glucose, and insulin resistance when compared to baseline (96140,96141). A treatment duration of 3 months does not appear to be effective for improving fasting blood glucose levels in these patients; however, it does seem to improve HbA1c when compared with baseline (96141). This product has also been evaluated in patients with type 1 diabetes. A clinical study in patients with type 1 diabetes shows that taking this product with meals for 6 months reduces the amount of insulin needed to achieve adequate glycemic control by 14.5% and lowers fasting blood glucose levels by 10% when compared with placebo (96142).
• Hypercholesterolemia. Oral tree turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of four mostly low-quality clinical studies in hypercholesterolemic adults shows that taking a specific combination product (Berberol, PharmExtracta) containing tree turmeric extract 588 mg and milk thistle extract 105 mg twice daily for 3 months, along with diet and exercise, reduces levels of low-density lipoprotein (LDL) cholesterol by an average of 33 mg/dL when compared with diet and exercise alone (101158). These studies lasted for no more than 12 months and some studies allowed for inclusion of patients who required a reduction in statin dose due to adverse effects (95019,96140,101158). Taking this product does not appear to significantly lower triglyceride levels or increase high-density lipoprotein (HDL) cholesterol levels in most of these patients (95019,96140,101158). It is unclear if any effects are due to tree turmeric, milk thistle, or the combination. Other clinical research in adults with hypercholesterolemia shows that a similar product (Berberol K, PharmExtracta) containing tree turmeric extract of berberine 500 mg, milk thistle extract 105 mg, and monacolin K and KA 10 mg, taken once daily for 3 months along with diet and exercise, reduces levels of LDL cholesterol by about 28% when compared with diet and exercise alone (97625). It is possible that any benefit of this product is due to the monacolin content. Further, since this product is standardized to monacolin content, it is considered by the US Food and Drug Administration to be a new drug rather than a dietary supplement.
• Menorrhagia. Although there has been interest in using oral tree turmeric for menorrhagia, there is insufficient reliable information about the clinical effects of tree turmeric for this purpose.
• Trachoma. Although there has been interest in using oral tree turmeric for trachoma, there is insufficient reliable information about the clinical effects of tree turmeric for this purpose.
• Wound healing. Although there has been interest in using topical tree turmeric for wound healing, there is insufficient reliable information about the clinical effects of tree turmeric for this purpose. More evidence is needed to rate tree turmeric for these uses.

(Read more about TREE TURMERIC)

LIKELY SAFE ...when used orally and appropriately, short-term. Andrographis has been used with apparent safety in doses of up to 6 grams daily for up to 7 days. Andrographis extract has been used with apparent safety at doses of up to 340 mg daily for up to 12 months, 600 mg daily for up to 3 months, or 1200 mg daily for up to 8 weeks (2748,31220,31223,31231,91838,91839,101116). Andrographolide, a constituent of andrographis, has been used with apparent safety at a dose of 280 mg daily for 24 months (104821). A specific combination product containing andrographis extract 178-206 mg and eleuthero (Kan Jang, Swedish Herbal Institute) has been taken three times daily with apparent safety for up to 4-7 days (2744,2748,2773,2774,10441,10795,13016).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. Andrographis, in combination with other herbs, has been used with apparent safety in clinical trials at doses up to 48 mg daily in children 3-15 years of age for up to one month (12381,12382).

PREGNANCY: POSSIBLY UNSAFE
when used orally. Andrographis is thought to have abortifacient effects (12); avoid using.

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about ANDROGRAPHIS)

LIKELY UNSAFE ...when the unripe berries or foliage are used orally (4009,106095). There is insufficient reliable information available about the safety of ripe black nightshade berries when used orally or any part of the black nightshade plant when used topically.

PREGNANCY AND LACTATION: LIKELY UNSAFE
when used orally because of concerns it could be teratogenic (4009); avoid using.

(Read more about BLACK NIGHTSHADE)

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 used orally and appropriately. Picrorhiza seems to be safe when used for up to 1 year (11493,11848,11858).

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

(Read more about PICRORHIZA)

LIKELY SAFE ...when a specific product (Berberol, PharmExtracta) containing tree turmeric extract 588 mg and milk thistle extract 105 mg is used. This product has been safely used twice daily for up to 12 months (95019,96140,96141,96142,101158). There is insufficient reliable information available about the safety of other forms of tree turmeric when used orally or topically in medicinal amounts.

CHILDREN: LIKELY UNSAFE
when used orally in newborns. The berberine constituent of tree turmeric can cause kernicterus in newborns, particularly preterm neonates with hyperbilirubinemia (2589). There is insufficient reliable information available about the safety of tree turmeric in older children.

PREGNANCY: LIKELY UNSAFE
when used orally. The berberine constituent of tree turmeric is thought to cross the placenta and may cause harm to the fetus. Kernicterus has developed in newborn infants exposed to berberine (2589).

LACTATION: LIKELY UNSAFE
when used orally. The berberine constituent of tree turmeric and other harmful constituents can be transferred to the infant through breast milk (2589).

(Read more about TREE TURMERIC)

ACECLOFENAC Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, andrographis extract might increase the maximum concentration and decrease the area under the curve of aceclofenac. The clinical significance of these changes is unclear.  Details Animal research suggests that andrographis extract taken orally increases the maximum concentration and decreases the area under the curve of aceclofenac (112916).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, andrographis might increase the risk of bleeding when used with anticoagulant or antiplatelet drugs.  Details Animal and laboratory studies suggest that andrographis has antiplatelet effects (2758,2759).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, andrographis might increase the risk of hypotension when used with antihypertensive drugs.  Details Animal research suggests that andrographis has hypotensive effects (2755,2760).

CELECOXIB (Celebrex) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, andrographis extract might increase the maximum concentration and time to peak concentration of celecoxib. The clinical significance of these changes is unclear.  Details Animal research suggests that andrographis extract taken orally increases the maximum concentration and time to peak concentration of celecoxib but does not appear to impact the area under the curve (112916).

ETORICOXIB (Arcoxia) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, andrographis might decrease the absorption of etoricoxib, although the clinical significance is unclear.  Details Animal research shows that andrographis extract, or the constituent andrographolide, taken orally with etoricoxib decreases the bioavailability of etoricoxib. However, this reduced bioavailability is not correlated with a reduction in the anti-inflammatory effects of etoricoxib in arthritic mice models (91837). The clinical significance of this interaction is unclear.

GLIPIZIDE (Glucotrol) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, andrographis extract might increase the maximum concentration and area under the curve of glipizide; however, opposite effects are seen with the constituent, andrographolide. The clinical significance of this interaction is unclear.  Details Animal research suggests that andrographis extract taken orally with glipizide in diabetes-induced rats increases the maximum concentration and area under the curve of glipizide. However, the opposite effect is seen with the constituent, andrographolide, in which the maximum concentration and area under the curve are decreased when taken with glipizide (112917).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, andrographis might interfere with the effects of immunosuppressive drugs.  Details Laboratory research suggests that andrographolide has immunostimulant activity (2766).

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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.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, tree turmeric might have additive effects when used with anticoagulant and antiplatelet drugs and increase the risk of bleeding.  Details In vitro and animal research suggest that berberine, a constituent of tree turmeric, can inhibit platelet aggregation (33660,33694).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Theoretically, tree turmeric, taken alone or in combination with milk thistle, might increase the risk of hypoglycemia in patients taking antidiabetes drugs.  Details Clinical research shows that taking a product containing tree turmeric and milk thistle extracts can lower blood glucose levels, glycated hemoglobin (HbA1c), and insulin resistance in patients with type 2 diabetes, including those on antidiabetic agents (95019,96140,96141). Additionally, clinical research suggests that berberine, a constituent of tree turmeric, can lower blood glucose levels (20579,34247,34265,34282).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking tree turmeric along with antihypertensive drugs might have additive effects and increase the risk of hypotension.  Details Animal research suggests that berberine, a constituent of tree turmeric, can have hypotensive effects (33692,34308). Also, a meta-analysis of clinical research suggests that taking berberine in combination with amlodipine (Norvasc) can lower systolic and diastolic blood pressure when compared with taking amlodipine alone (91956).

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, use of tree turmeric along with CNS depressants might increase the risk of additive therapeutic and adverse effects.  Details Animal research suggests that berberine, a constituent of tree turmeric, can have sedative effects (13519,33650,33664,33692).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = A Berberine, a constituent of tree turmeric, can reduce metabolism of cyclosporine and increase serum levels.  Details Some clinical evidence suggests that berberine inhibits cytochrome P450 3A4 (CYP3A4), which metabolizes cyclosporine (13524,21112,34239).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, tree turmeric might increase the levels and clinical effects of drugs metabolized by CYP2C9.  Details Preliminary clinical evidence suggests that berberine, a constituent of tree turmeric, can inhibit CYP2C9 (34279).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, tree turmeric might increase the levels and clinical effects of drugs metabolized by CYP2D6.  Details In vitro research and preliminary clinical evidence suggest that berberine, a constituent of tree turmeric, can inhibit CYP2D6 (21117,34279,34297).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Theoretically, tree turmeric might increase the levels and clinical effects of drugs that are substrates of CYP3A4.  Details In vitro research and preliminary clinical evidence suggest that berberine, a constituent of tree turmeric, moderately inhibits CYP3A4 (13524,21114,34279,34297).

DEXTROMETHORPHAN (Robitussin DM, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, tree turmeric might increase levels of dextromethorphan and potentially increase the risk of adverse effects including drowsiness, confusion, and irritability.  Details Preliminary clinical research suggests that berberine, a constituent of tree turmeric, can inhibit cytochrome P450 2D6 (CYP2D6) activity and reduce the metabolism of dextromethorphan (34279).

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, tree turmeric might increase levels of midazolam and potentially increase the risk of adverse effects including sedation and respiratory depression.  Details Preliminary clinical evidence suggests that berberine, a constituent of tree turmeric, can inhibit cytochrome P450 3A4 (CYP3A4) activity and reduce metabolism of midazolam (34279).

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, tree turmeric might increase the sedative effects of pentobarbital.  Details Animal research suggests that berberine, a constituent of tree turmeric, can prolong pentobarbital-induced sleeping time (13519).

TACROLIMUS (Prograf) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = D Berberine, a constituent of tree turmeric, can inhibit metabolism of tacrolimus and increase plasma levels.  Details Some clinical evidence suggests that berberine inhibits cytochrome P450 3A4 (CYP3A4), which metabolizes tacrolimus (13524,21114,34279,34297,91954). In a 16-year-old patient with idiopathic nephrotic syndrome who was being treated with prednisone 40 mg/m2 and tacrolimus 6.5 mg twice daily, concomitant use of berberine, a constituent of tree turmeric, 200 mg three times daily increased plasma levels of tacrolimus from 8 to 22 ng/mL and increased serum creatinine levels from 0.7 to 1.2 mg/dL. Following a reduction of tacrolimus dosing to 3 mg daily, the blood concentration of tacrolimus decreased to 12 ng/mL and the serum concentration of creatinine decreased to 0.9 mg/dL (91954).

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General ...Orally, andrographis is generally well tolerated. Adverse effects are more likely when doses reach or exceed 5-10 mg/kg of andrographolide content and when treatment duration exceeds 14 days.
Most Common Adverse Effects:
Orally: Abdominal discomfort, altered taste, diarrhea, dizziness, fatigue, headache, nausea and vomiting, pruritus, rash, and urticaria.
Serious Adverse Effects (Rare):
Orally: Severe allergic reactions, including anaphylaxis.

Cardiovascular ...Orally, andrographis has been reported to cause vasculitis, edema, and increased sweating (12380,13016,91841).

Dermatologic ...Orally, andrographis has been frequently reported to cause maculopapular, erythematous rash, pruritus, and urticaria (31223,31222,31233,12380,31231,31220,13016,91838,91841,104821)(107783,112921). Andrographis consumption has also been reported to cause angioedema, exfoliative dermatitis, skin exfoliation, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, bullous eruption, fixed eruption, stomatitis, allergic purpura, flushing, and swelling (91841).
Parenterally, there have been reports of maculopapular rash, urticaria, pruritus, and flushing with the use of andrographolide derivative injections; about one-third of patients experienced skin or subcutaneous reactions (112921).

Gastrointestinal ...Orally, andrographis has been reported to cause nausea, vomiting, diarrhea, dyspepsia, flatulence, altered or metallic taste, and abdominal discomfort (6767,31213,2748,13016,31220,31222,91841,104821,107783,112921). Andrographis intake has also been reported to cause epigastric pain, ulcerative stomatitis, melena, dry mouth, and dry lips (31213,10795,13016,91841).
Parenterally, there have been reports of diarrhea, nausea, vomiting, and abdominal discomfort with the use of andrographolide derivative injections; over 40% of patients experienced gastrointestinal events (112921).

Genitourinary ...Orally, there is one case report of increased urinary frequency associated with andrographis use (91841)

Hematologic ...Orally, there is one case report of epistaxis (nosebleed) associated with andrographis use (31222).

Hepatic ...Orally, there is one case report of hepatitis associated with andrographis use (91841).

Immunologic ...Orally, andrographis has been reported to cause anaphylactic shock in 2 cases with determined causality, and 7 cases with probable causality. Anaphylactic shock developed in 5 minutes to one day after oral intake, and included symptoms such as hypotension, chest pain, urticaria, angioedema, wheezing, and tachycardia (91841). Additionally, andrographis intake has been associated with cases of eosinophilia and fever (91841,107783). High doses of the andrographolide constituent (5-10 mg/kg daily) have been associated with two cases of lymphadenopathy and three cases of lymph node pain (6767).
Parenterally, there have been 97 cases reporting severe or life-threatening anaphylaxis after andrographolide derivative injections, 3 of which resulted in death (112921).

Musculoskeletal ...Orally, andrographis has been associated with case reports of pain, muscle weakness, cramps, and paralysis (31220,91841,107783).

Neurologic/CNS ...Orally, andrographis has been reported to cause headache, fatigue, anorexia, somnolence, insomnia, lethargy, malaise, and drowsiness (2748,5784,6767,10795,12380,13016,31220,31213,31222,91841,107783). Headache and fatigue occurred more often with high doses of the andrographolide constituent (5-10 mg/kg daily) in one clinical trial (6767).

Pulmonary/Respiratory ...Orally, andrographis has been reported to cause dyspnea, coughing, bronchospasm, increased sputum, and nasal congestion (10795,13016,31213,91841,107783).

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General ...Orally or topically, a thorough evaluation of safety outcomes related to the medicinal use of black nightshade has not been conducted. However, the unripe berries and foliage of black nightshade can cause toxicity due to solanine content.

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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).

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General ...Orally, picrorhiza may cause vomiting, rash, anorexia, diarrhea, itching, and giddiness (11858).

Dermatologic ...Orally, picrorhiza may cause rash and itching (11858).

Gastrointestinal ...Orally, picrorhiza may cause vomiting, anorexia, and diarrhea (11858).

Neurologic/CNS ...Orally, picrorhiza may cause giddiness (11858).

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General ...Orally and topically, no adverse effects have been reported with the use of tree turmeric alone. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Gastrointestinal symptoms, especially nausea, with the use of a specific product containing tree turmeric and milk thistle (Berberol, PharmExtracta).

Gastrointestinal ...Orally, the most common adverse effects of a specific product (Berberol, PharmExtracta) containing tree turmeric and milk thistle extracts include gastrointestinal symptoms, especially nausea (95019,96140,96141,96142).

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