Fertility-Preg by L.A. Naturals

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Androgenic alopecia. Topical red clover has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in individuals with androgenic alopecia shows that topical application of a combination of red clover flower extract and acetyl tetrapeptide-3 increases the growth phase of hair production by 13% and decreases the resting phase of hair production by 29% when compared to baseline (19540). The validity of these findings is limited by the lack of a comparator group.
• Benign prostatic hyperplasia (BPH). Although there is interest in using oral red clover for BPH, there is insufficient reliable information about the clinical effects of red clover for this condition.
• Breast cancer-related hot flashes. It is unclear if oral red clover is beneficial for reducing hot flashes in patients who have had breast cancer. Details: A small clinical study in breast cancer patients with menopausal symptoms due to tamoxifen therapy shows that taking red clover extract (Promensil Forte) 80 mg daily for 24 months does not reduce menopausal symptoms, including hot flashes, sleep disturbance, and fatigue, any more than placebo (102901).
• Hyperlipidemia. It is unclear if oral red clover is beneficial in patients with hyperlipidemia; research is conflicting. Details: Most clinical trials in adult females with or without elevated cholesterol levels show that taking red clover extracts providing isoflavones 40-120 mg daily for 3 months to 1 year does not reduce total or low-density lipoprotein (LDL) cholesterol, or increase high-density lipoprotein (HDL) cholesterol, when compared with control (3375,8502,11089,11091,17091,19450,19543). However, a meta-analysis of 10 clinical trials in perimenopausal and postmenopausal patients with or without hyperlipidemia shows that red clover decreases total cholesterol by around 11 mg/dL, but does not affect LDL cholesterol, triglyceride, or HDL cholesterol levels, when compared with placebo (102840). This finding is limited by imprecision and inconsistency of the results and the fact that the benefit seems to be mostly attributed to two trials with a high risk of detection and performance bias. When this meta-analysis was repeated without those two trials, red clover supplementation for at least three months still shows a significant, albeit smaller, reduction in total cholesterol of around 4 mg/dL when compared with placebo among post-menopausal individuals. The meta-analysis also shows a small but statistically significant increase in HDL by approximately 1.5 mg/dL and no change in LDL or triglyceride levels (112145). Included studies were of moderate to high quality and lacked heterogeneity.
• Mastalgia. It is unclear if oral red clover is beneficial in patients with mastalgia. Details: One very small study in patients with cyclic mastalgia shows that taking red clover isoflavones (Promensil, Novogen) 40-80 mg daily reduces subjective ratings of breast pain and tenderness. Reductions in pain were 44% with 40 mg and 31% with 80 mg, compared with 13% for placebo (9552).
• Menopausal symptoms. It is unclear if oral red clover is beneficial for menopausal symptoms; research is conflicting and has notable methodological issues. Details: The most recent meta-analysis of 8 small clinical trials in patients with menopausal symptoms suggests that red clover reduces hot flash frequency by an average of 1.7 times when compared with control. The benefit tends to be greater in those with a higher frequency of hot flashes at baseline (5 or more) and when higher doses of red clover isoflavones are used (80 mg or more daily) (105694). However, this finding is limited by imprecision and inconsistency, as well as selective reporting bias in some of the included trials. An older meta-analysis of small, low-quality clinical studies in menopausal patients also suggests that red clover might improve psychological symptoms such as anxiety and depression when compared with control (91525). The most extensively studied product is a specific red clover supplement (Promensil or Melbrosin, Novogen). A meta-analysis of 5 small clinical studies assessing only Promensil shows that taking 80 mg daily for 12 weeks reduces hot flash frequency by 30% to 50%, or by about 3-4 hot flashes per day, when compared with placebo (96731). The validity of these findings is limited by imprecision, inconsistency, and publication bias. Notably, this meta-analysis and all included studies were funded by the supplement manufacturer (8925,10976,10991,17103,19545,96731). In contrast, studies with independent funding sources have not found a benefit with red clover isoflavones 40-120 mg daily for up to 12 months when compared with placebo (10975,17091,19549). Some research has also found benefit for menopausal symptoms when red clover is used in combination with other ingredients. Red clover has been used in combination with black cohosh, dong quai, milk thistle, American ginseng, and Vitex agnus-castus (Phyto-Female Complex) twice daily for 3 months (19552). Red clover isoflavones 37.1 mg have also been used in combination with a probiotic-rich liquid daily for 12 weeks (96730).
• Osteoarthritis. It is unclear if topical red clover is beneficial in patients with osteoarthritis. Details: Preliminary clinical research shows that applying 20 drops of a standardized extract of red clover aerial parts to the knee twice daily for 4 weeks, in addition to taking meloxicam orally, improves subjective measures of pain and function more than using meloxicam plus placebo. However, radiological and laboratory changes were not evaluated (102839).
• Osteoporosis. It is unclear if oral red clover is beneficial in patients with osteoporosis; research is conflicting. Details: One small clinical study in healthy postmenopausal patients shows that taking red clover providing isoflavones 57-85.5 mg daily for 6 months increases bone mineral density (BMD) of the proximal radius and ulna by 3% to 4% (10948). Another clinical study in females ages 49-65 years shows that taking a specific red clover extract (Promensil, Novogen) providing isoflavones 40 mg daily for one year does not increase BMD or bone mineral content (BMC) of the hip, but seems to slightly reduce the loss of lumbar spine BMD and BMC when compared with placebo (6127). However, other research has found no benefit. One clinical study in patients who are at least one year post-menopause and not taking bone preserving medications shows that taking a specific product containing enriched red clover isoflavones (Rimostil [formononetin enriched], Novagen) 50 mg daily for 2 years does not improve BMD of the spine, femoral neck, distal radius, or proximal radius when compared with placebo. However, this study may have been underpowered due to a high drop-out rate (91524). Another small clinical study in perimenopausal and postmenopausal adults shows that taking red clover flowering tops providing isoflavones 120 mg daily for one year does not seem to slow the loss of hip, femoral neck, or lumbar spine BMD when compared with placebo (17091). More evidence is needed to rate red clover for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Topical red raspberry leaf has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in females aged 30-65 years shows that applying a specific liquid (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) containing red raspberry leaf cell culture extract 0.0005%, vitamin C 20%, and vitamin E 1% to the face nightly for 8 weeks, in addition to regular facial skin products, improves skin color, elasticity, radiance, smoothness, and appearance of wrinkles when compared with regular facial skin products alone (102355).
• Cardiovascular disease (CVD). Although there has been interest in using oral red raspberry leaf for CVD, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Congestive heart failure (CHF). Although there has been interest in using oral red raspberry leaf for CHF, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Diabetes. Although there has been interest in using oral red raspberry leaf for diabetes, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Dysmenorrhea. Although there has been interest in using oral red raspberry leaf for dysmenorrhea, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Hypertension. Although there has been interest in using oral red raspberry leaf for hypertension, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Influenza. Although there has been interest in using oral red raspberry leaf for influenza, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Labor pain. Some research suggests that oral red raspberry leaf does not reduce analgesic use during labor. Details: Clinical research shows that taking red raspberry leaf 2.4 grams daily, beginning at 32 weeks' gestation and continuing until delivery, does not decrease the need for analgesics in the perinatal time period when compared with placebo (9796). A systematic review of retrospective studies also supports these findings, showing no improvement in perineal outcomes in patients consuming red raspberry leaf prior to labor (108005).
• Menorrhagia. Although there has been interest in using oral red raspberry leaf for menorrhagia, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Obesity. It is unclear if oral red raspberry fruit is beneficial in patients with obesity. Details: Preliminary clinical research in overweight and obese adults shows that consuming frozen red raspberry fruit 280 grams daily for 8 weeks does not reduce body mass index or waist circumference when compared with control (105873).
• Osteoarthritis. It is unclear if oral red raspberry leaf extract is beneficial for knee osteoarthritis. Details: A moderate-sized clinical study in patients with knee osteoarthritis shows that taking red raspberry leaf extract 200 or 400 mg once daily for 12 weeks reduces pain at the higher dose when measured by the visual analog scale, but does not improve physical performance, physical activity, walking distance, or Western Ontario McMaster osteoarthritis index (WOMAC) global score or pain, stiffness, and function subscores when compared with placebo (112127).
• Parturition. Some research suggests that oral red raspberry leaf does not shorten the duration of labor. Details: Clinical research shows that taking red raspberry leaf 2.4 grams daily, beginning at 32 weeks' gestation and continuing until delivery, does not reduce the length of labor when compared with placebo (108005). Traditionally, doses of up to 4 grams daily have been recommended for this purpose; however, doses greater than 2.4 grams daily have not been evaluated for safety or efficacy. Further high-quality research is needed to determine the optimal dose, duration, and formulation, if any, of red raspberry leaf for this purpose.
• Pharyngitis. Although there has been interest in using topical red raspberry leaf for pharyngitis, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Pregnancy-induced nausea and vomiting. Although there has been interest in using oral red raspberry leaf for pregnancy-induced nausea and vomiting, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Respiratory tract infections. Although there has been interest in using oral red raspberry leaf for respiratory tract infections, there is insufficient reliable information about the clinical effects of red raspberry for this purpose. More evidence is needed to rate red raspberry leaf for this use.

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POSSIBLY EFFECTIVE

• Diabetes. Oral stinging nettle seems to improve glycemic control in patients with diabetes. Details: A meta-analysis of 8 small heterogeneous clinical trials in adults with type 2 diabetes shows that taking stinging nettle 1.5-10 grams in divided doses daily for 8-12 weeks reduces fasting blood glucose (FBG) by 18 mg/dL when compared with placebo (102865). Glycated hemoglobin (HbA1c) was not improved, but the study durations were not adequate to detect an improvement in this measure. Despite positive results on FBG, taking stinging nettle does not seem to improve insulin secretion or measures of insulin sensitivity (91519,102865,108903). Another meta-analysis of 3 small clinical studies in adults with type 2 diabetes shows that taking stinging nettle reduces HbA1c by about 1.3% when compared with placebo. This analysis also suggests stinging nettle reduces post-prandial blood glucose by about 114 mg/dL; however, this is based on a single study. Stinging nettle did not improve fasting blood glucose or insulin resistance in this analysis (111503). The validity of these findings is limited by the low quality and heterogeneity of included studies, as well as unclear dosing. Furthermore, since most research has been conducted in Iran, it is unknown if these findings are generalizable to other geographic locations. Stinging nettle has also been used in combination with other natural medicines. One small clinical study in adults with type 2 diabetes shows that taking a product containing stinging nettle leaf extract 200 mg, milk thistle 200 mg, and Boswellia serrata gum 200 mg three times daily for 3 months reduces FBP by about 28 mg/dL and HbA1c by about 1.5%, compared with a smaller reduction in the placebo group (96742). It is unclear if this effect is due to stinging nettle, the other ingredients, or the combination.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). It is unclear if oral stinging nettle is beneficial for hay fever. Details: Taking stinging nettle leaf extract 300 mg 3-7 times daily at the first sign of hay fever symptoms seems to provide subjective improvement (7035). However, adding stinging nettle to conventional allergy medication might not provide any additional benefit. One small clinical study shows that adding stinging nettle tablets (Urtidin, Barij Essence Pharmaceutical Co.) 150 mg four times daily for 1 month to treatment with loratadine and nasal saline rinses does not improve symptoms of allergic rhinitis when compared with placebo with loratadine and nasal saline rinses (96743).
• Anemia. Although there is interest in using oral stinging nettle for anemia, there is insufficient reliable information about the clinical effects of stinging nettle for this condition.
• Asthma. Although there is interest in using oral stinging nettle for asthma, there is insufficient reliable information about the clinical effects of stinging nettle for this condition.
• Benign prostatic hyperplasia (BPH). It is unclear if oral stinging nettle is beneficial for BPH. Details: A meta-analysis of clinical research, including 5 clinical studies and 1,128 patients with BPH, shows that taking stinging nettle root extract 360-600 mg in divided doses daily for 2-12 months improves peak urinary flow rate and symptom scores while modestly reducing prostate volume when compared with control. However, the validity of these results is limited by significant heterogeneity due to the variability in the products used and the specific endpoints investigated (96744). In the largest clinical trial in the analysis, patients took stinging nettle root extract 120 mg three times daily for 6 months (76406). Stinging nettle has also been evaluated in combination products. Clinical research in patients with BPH shows that taking a specific combination product (PRO 160/120, Dr. Willmar Schwabe Pharmaceuticals) containing a specific extract of stinging nettle root (WS 1031) 120 mg plus a specific extract of saw palmetto fruit (WS 1473) 160 mg twice daily for 24-48 weeks seems to improve urinary tract symptoms when compared with control; the effect may last at least 48 weeks after treatment (15195,15551,76409). However, taking a different combination product does not seem to be beneficial. A small clinical study in patients with BPH shows that taking a product containing stinging nettle root extract 240 mg, saw palmetto, pumpkin seed oil, lemon bioflavonoid, and beta-carotene, three times daily for 6 months, does not improve symptoms of BPH (5093).
• Bleeding. Topical stinging nettle has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some preliminary clinical research shows that applying 4 mL of a specific product (Ankaferd blood stopper, Mefar Ilaç Sanayi A.S) containing alpinia, licorice, thyme, stinging nettle, and common grape vine to the affected area reduces bleeding, but does not improve the time for episiotomy repair, when compared with using saline (31010).
• Gingivitis. Stinging nettle in a mouthwash solution has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with moderate gingival inflammation suggests that using 10 mL of mouthwash solution containing a 1:1:1 mixture of stinging nettle, juniper, and yarrow twice daily for 3 months does not reduce plaque or bleeding when compared with control (76443). It is not clear if this effect is due to stinging nettle, the other ingredients, or the combination.
• Gout. Although there is interest in using oral stinging nettle for gout, there is insufficient reliable information about the clinical effects of stinging nettle for this condition.
• Gulf war syndrome. It is unclear if oral stinging nettle is beneficial for Gulf war syndrome. Details: A very small exploratory clinical trial in males with Gulf war syndrome shows that taking stinging nettle leaf (Nature's Way) 1305 mg in two divided doses daily for 30 days modestly improves symptom severity when compared with placebo (108311). The clinical relevance of this finding is limited by the use of an unvalidated scoring scale. Additionally, it appears that most patients had mild, unspecified symptoms at baseline; it is unclear if stinging nettle is beneficial for moderate to severe symptoms.
• Hyperandrogenism. It is unclear if oral stinging nettle is beneficial in patients with hyperandrogenism. Details: Preliminary clinical research in females with hyperandrogenism shows that taking dried extract of stinging nettle root 300-600 mg daily for approximately 4 months decreases total and free testosterone levels, but not menstrual cycle conditions, oily skin, or acne, when compared with taking spironolactone and cyproterone (91520).
• Insect bite. Oral stinging nettle has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that applying a homeopathic after-bite gel, containing stinging nettle, Echinacea, and marsh Labrador tea, on affected areas does not reduce erythema or itching after a mosquito bite when compared with placebo (89235).
• Kidney stones (nephrolithiasis). Although there is interest in using oral stinging nettle for kidney stones, there is insufficient reliable information about the clinical effects of stinging nettle for this condition.
• Myalgia. Although there is interest in using topical stinging nettle for myalgia, there is insufficient reliable information about the clinical effects of stinging nettle for this purpose.
• Osteoarthritis. Small clinical studies suggest that topical stinging nettle may modestly improve pain in patients with osteoarthritis. It is unclear if oral stinging nettle is beneficial. Details: Topically, stinging nettle leaf may have a counterirritant effect which may improve osteoarthritis pain in some patients. A small clinical study in patients ages 45-82 with osteoarthritis of the thumb shows that applying raw stinging nettle leaf to the thumb for 30 seconds daily for 1 week reduces pain and disability when compared with white dead nettle leaf control (12490). However, in another small clinical study in patients with knee osteoarthritis, topical application of raw stinging nettle leaf to the knee for 1 minute daily for 7 days does not seem to be more effective for reducing pain than applying a leaf from a related stingless nettle (76412). Non-raw stinging nettle has also been tried. In a small open-label study, a formulation of stinging nettle extract (Liquid PhytoCaps Nettle Leaf, Gaia Herbs) 13.33% compounded with lipobase oil-in-water emulsion and applied to the affected area twice daily for 2 weeks, modestly improves pain and function in patients with radiologically confirmed osteoarthritis when compared with baseline (76414). The validity of this finding is limited by the lack of a comparator group. Stinging nettle has also been evaluated orally, in combination with other ingredients. A clinical study in adults with knee osteoarthritis shows that taking a specific combination solution (Rosaxan, medAgil Gesundheitsgesellschaft mbH) containing stinging nettle extract 160 mg, rose hip puree 20 grams, devil's claw 108 mg, and vitamin D 200 IU daily for 12 weeks improves symptoms by an additional 28% and pain scores by an additional 33% when compared with placebo (96741). It is unclear if this effect is due to stinging nettle, the other ingredients, or the combination.
• Tinnitus. Oral stinging nettle has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with tinnitus shows that taking a specific product containing stinging nettle, tansy, and rose hip (Neurotec, Rose Pharmed), 100 mg orally daily for 3 months does not improve auditory thresholds when compared with placebo. However, the product improved some subjective symptoms scores, such as perceived loudness and severity scores (110512).
• Urinary tract infections (UTIs). Although there is interest in using oral stinging nettle for UTIs, there is insufficient reliable information about the clinical effects of stinging nettle for this condition. More evidence is needed to rate stinging nettle for these uses.

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There is insufficient reliable information available about the effectiveness of yellow dock.

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LIKELY SAFE ...when used orally in amounts commonly used in foods. Red clover has Generally Recognized As Safe (GRAS) status for use in foods in the US (4912,10372).

POSSIBLY SAFE ...when used orally and appropriately in supplemental amounts. Red clover extracts containing up to 80 mg isoflavones have been used with apparent safety in clinical studies lasting up to 2 years (3375,6127,8925,11089,11091,17091,19540,19556,91524,102901,102840). ...when used topically and appropriately. Red clover extracts have been used topically with apparent safety for up to 4 weeks (102839).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (4912).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in medicinal amounts. Red clover has estrogenic activity (19555); avoid using. There is insufficient reliable information available about the safety of the topical use of red clover during pregnancy and lactation.

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LIKELY SAFE ...when the fruit is used orally in amounts commonly found in foods (13622).

POSSIBLY SAFE ...when the fruit is used orally and appropriately in medicinal amounts (6481,9796). There is insufficient reliable information available about the safety of red raspberry leaf when used orally or topically.

PREGNANCY: LIKELY SAFE
when the fruit is used orally in amounts commonly found in foods (13622).

PREGNANCY: POSSIBLY SAFE
when red raspberry leaf is used orally and appropriately in medicinal amounts during late pregnancy under the supervision of a healthcare provider. Red raspberry leaf is used by nurse midwives to facilitate delivery. There is some evidence that red raspberry leaf in doses of up to 2.4 grams daily, beginning at 32 weeks' gestation and continued until delivery, can be safely used for this purpose (6481,9796). Make sure patients do not use red raspberry leaf without the guidance of a healthcare professional.

PREGNANCY: LIKELY UNSAFE
when red raspberry leaf is used orally in medicinal amounts throughout pregnancy or for self-treatment. Red raspberry leaf might have estrogenic effects (6180). These effects can adversely affect pregnancy. Tell pregnant patients not to use red raspberry leaf at any time during pregnancy without the close supervision of a healthcare provider.

LACTATION: LIKELY SAFE
when the fruit is used orally in amounts commonly found in foods (13622). There is insufficient reliable information available about the safety of red raspberry leaf; avoid using.

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POSSIBLY SAFE ...when used orally and appropriately. Stinging nettle root 360-600 mg has been used safely for up to 1 year (5093,11230,15195,76406,96744). ...when used topically and appropriately (12490).

PREGNANCY: LIKELY UNSAFE
when used orally due to possible abortifacient and uterine-stimulant effects (4,6,19).

LACTATION:
Insufficient reliable information available; avoid using.

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POSSIBLY SAFE ...when properly prepared and consumed in amounts commonly found in foods. Young leaves must be boiled to remove the oxalate content; death has occurred after consuming uncooked leaves (6,18).

POSSIBLY UNSAFE ...when the uncooked leaves are consumed. Young leaves must be boiled to remove the oxalate content; death has occurred after consuming uncooked leaves (6,18). There is insufficient reliable information available about the safety of properly prepared yellow dock when used orally in medicinal amounts.

PREGNANCY: POSSIBLY UNSAFE
when used orally; avoid using. Yellow dock contains anthraquinone glycosides; unstandardized laxatives are not desirable during pregnancy (4).

LACTATION: POSSIBLY UNSAFE
when used orally; avoid using. Anthraquinones are secreted into breast milk (4,5).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Although some laboratory research suggests that red clover may have anticoagulant and antiplatelet activity, clinical research has not shown this effect.  Details In vitro research suggests that genistein in red clover has antiplatelet effects, and historically, red clover was thought to have anticoagulant effects due to its coumarin content. However, some experts state that this is unlikely as most natural coumarins have not been shown to have anticoagulant effects, and their content in red clover is low (17091,19557,19558,19559). Additionally, some clinical research in postmenopausal patients found no effect on coagulation or prothrombin time with the use of red clover flowering tops 378 mg daily for 12 months or red clover isoflavone (Rimostil) 50 mg daily for 2 years (17091,91524).

CAFFEINE Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, soy might reduce the clearance of caffeine; however, a small clinical study found no effect.  Details Red clover contains genistein. Taking genistein 1 gram daily for 14 days seems to inhibit caffeine clearance and metabolism in healthy females (23582). However, this effect does not seem to occur with the lower amounts of genistein found in red clover. A clinical study in healthy postmenopausal individuals shows that taking red clover capsules standardized to contain 60 mg isoflavones twice daily for 14 days does not affect the pharmacokinetics of caffeine (105693).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, red clover might increase levels of drugs metabolized by CYP1A2; however, a small clinical study found no effect.  Details In vitro evidence shows that red clover inhibits CYP1A2 (12479). However, a clinical study in healthy postmenopausal individuals shows that taking red clover capsules standardized to contain 60 mg isoflavones twice daily for 14 days does not affect the pharmacokinetics of caffeine, a CYP1A2 probe substrate (105693).

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, red clover might increase the levels and clinical effects of drugs metabolized by CYP2C19.  Details In vitro evidence suggests that red clover weakly inhibits CYP2C19 (12479). This interaction has not been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, red clover might increase levels of drugs metabolized by CYP2C9; however, a small clinical study found no effect.  Details In vitro evidence suggests that red clover might inhibit CYP2C9 (12479). However, a clinical study in healthy postmenopausal individuals shows that taking red clover capsules standardized to contain 60 mg isoflavones twice daily for 14 days does not affect the pharmacokinetics of tolbutamide, a CYP2C9 probe substrate (105693).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, red clover might increase levels of drugs metabolized by CYP3A4; however, a small clinical study found no effect.  Details In vitro evidence shows that red clover might inhibit CYP3A4 isoenzymes (6450,12479). However, a clinical study in healthy postmenopausal individuals shows that taking red clover capsules standardized to contain 60 mg isoflavones twice daily for 14 days does not affect the pharmacokinetics of alprazolam, a CYP3A4 probe substrate (105693).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use of large amounts of red clover might interfere with estrogen therapy.  Details Red clover contains phytoestrogens which might have estrogenic activity in some people. Theoretically, red clover might compete for estrogen receptors and interfere with estrogen-containing drug therapy (4743,19560,19729).

METHOTREXATE (Trexall, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, red clover might increase the risk of methotrexate toxicity.  Details In a case report, a 52-year-old female receiving weekly methotrexate injections for psoriasis developed symptoms of methotrexate toxicity, including severe vomiting and epigastric pain, after three days of taking red clover 430 mg daily. Toxicity resolved after red clover was discontinued. However, no liver function tests or methotrexate levels were reported (91522).

TAMOXIFEN (Nolvadex) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, the phytoestrogens in red clover might interfere with tamoxifen.  Details In vitro and animal research suggests that genistein, a constituent of red clover, might antagonize the antitumor effects of tamoxifen (8192). However, there is some evidence from an animal study that red clover does not reduce the efficacy of tamoxifen (102901). Until more is known, tell patients taking tamoxifen to avoid red clover.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking red raspberry leaf with anticoagulant/antiplatelet drugs might increase the risk of bleeding.  Details In vitro research suggests that red raspberry leaf extract has antiplatelet activity and enhances the in vitro effects of the antiplatelet medication cangrelor (96300). This interaction has not been reported in humans.

INSULIN Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Red raspberry leaf might reduce glucose levels in patients being treated with insulin.  Details In one case report, a 38-year-old patient with gestational diabetes, whose blood glucose was being controlled with medical nutrition therapy and insulin, developed hypoglycemia after consuming two servings of raspberry leaf tea daily for 3 days beginning at 32 weeks' gestation. The patient required an insulin dose reduction. The hypoglycemia was considered to be probably related to use of red raspberry leaf tea (96299).

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, stinging nettle might have additive effects with antidiabetes drugs.  Details Clinical research shows that stinging nettle might decrease blood glucose levels in patients with diabetes (91519,102865).

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining stinging nettle with diuretic drugs may have additive effects.  Details Animal research suggests that the above ground parts and roots of stinging nettle may have a diuretic effect (1,4,11,76402).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, stinging nettle might reduce excretion and increase levels of lithium.  Details Animal research suggests that stinging nettle has diuretic and natriuretic properties, which could alter the excretion of lithium (76402). The dose of lithium might need to be decreased.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D There is some concern that stinging nettle might decrease the effects of anticoagulant drugs such as warfarin.  Details Stinging nettle contains a significant amount of vitamin K (19). When taken in large quantities, this might interfere with the activity of warfarin.

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DIGOXIN (Lanoxin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, yellow dock might increase the risk of digoxin toxicity when used long-term or in large amount.  Details When yellow dock is used chronically or in large amounts, hypokalemia may occur (4,19). This might increase the toxic effects of digoxin.

DIURETIC DRUGS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, yellow dock might increase the risk of hypokalemia when taken with diuretics.  Details When yellow dock is used chronically or in large amounts, hypokalemia may occur (4,19), and overuse of yellow dock might compound diuretic-induced potassium loss (19).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, the laxative effects of yellow dock might increase the effects of warfarin, including the risk of bleeding.  Details The anthraquinones in yellow dock have a mild stimulant laxative effect (4,6,12). Consuming excessive amounts can cause diarrhea (6). Diarrhea can increase the effects of warfarin, increase international normalized ratio (INR), and increase the risk of bleeding.

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General ...Orally and topically, red clover seems to be well tolerated.
Most Common Adverse Effects:
Orally: Myalgia, nausea, and vaginal spotting.

Dermatologic ...Orally, a specific red clover isoflavone product (Promensil) has been associated with mild cases of psoriasis and thrush, although a direct causal link has not been established (9552).

Gastrointestinal ...Orally, red clover has been reported to cause nausea (8194).

Genitourinary ...In human research, 80 mg, but not 40 mg, of a specific red clover isoflavone product (Promensil) increased the duration of menstrual cycles in patients with mastalgia (9552). Red clover has also been reported to cause vaginal spotting (8194).

Hematologic ...In one case report, a 53-year-old female had a spontaneous subarachnoid hemorrhage associated with the use of an herbal supplement containing red clover, dong quai, and eleuthero. It is not clear if this was due to red clover, another ingredient, the combination of ingredients, or other factors (70419). In another case report, a 55-year-old female with protein S deficiency and systemic lupus erythematosus (SLE) had temporary vision loss in the left eye from hemiretinal vein thrombosis 3 days after taking a combination phytoestrogen product containing red clover 250 mg, wild yam 276 mg, dong quai 100 mg, and black cohosh 250 mg (13155). It is unclear if red clover contributed to this event.

Musculoskeletal ...Orally, red clover has been reported to cause myalgia (8194).

Neurologic/CNS ...Orally, a specific red clover isoflavone product (Medoflavon) has been associated with headache, although with a similar frequency to placebo (19545).

Oncologic ...Due to potential estrogenic effects of red clover isoflavones, there has been some concern that red clover might increase the risk of estrogen-sensitive cancers such as breast cancer or uterine cancer. A meta-analysis of 8 clinical trials suggests that increased intake of red clover- and soy-derived isoflavones may modestly increase mammographic breast density in premenopausal, but not postmenopausal, adults when compared with placebo. However, in a sub-group analysis assessing only isolated red clover isoflavones, there was no change in breast density (70428). Furthermore, a 2015 review by the European Food Safety Authority (EFSA) reported no increase in risk of breast cancer in females taking isoflavone-containing supplements (91725). Similarly, no effect was found on endometrial thickness and histopathological changes in the uterus after up to 36 months of supplementation with 40-120 mg daily of isoflavones from red clover extract (91725).

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General ...Orally, red raspberry fruit is well tolerated. There is currently a limited amount of information on the adverse effects of red raspberry leaf.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal upset, and epigastric pain. However, these adverse effects do not commonly occur with typical doses.

Dermatologic ...A liquid containing red raspberry leaf cell culture extract 0. 0005%, vitamin C 20%, and vitamin E 1% (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) has been reported to cause mild tingling and skin tightness (102355). It is unclear if these effects are due to red raspberry leaf, the other ingredients, or the combination.

Gastrointestinal ...Orally, red raspberry may cause gastrointestinal upset, diarrhea, and epigastric pain (112127).

Pulmonary/Respiratory ...A case of occupational asthma due to the inhalation of red raspberry powder has been reported for a 35-year-old female. Symptoms included wheezing and shortness of breath (70370).

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General ...Orally, stinging nettle seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Constipation, diarrhea.
Topically: Contact with the raw plant causes itching, rash, and stinging.

Dermatologic ...Topically, fresh stinging nettle leaves and stalk can cause localized rash, itching, and stinging (12490,76399,76412,76414,76417,76428,76448,96746). Usually, short exposure to stinging nettle results in a transient urticarial reaction and a stinging sensation which may persist for more than 12 hours (76399,76414,76417,96746). In one report, a patient placed a fresh stinging nettle leaf on the tongue to suck out the sap of the leaf. Severe tongue edema, pain, and urticaria developed within 5 minutes. Symptoms continued for several hours after the leaf was removed (15197). In another case report, a young couple intoxicated with methamphetamine fell and laid in a stinging nettle bush for 20 minutes, after which urticaria and pain continued for 2-3 weeks, and a heightened sensitivity to cold persisted for several months (96746).

Endocrine ...A case of gynecomastia has been reported for a 33-year-old male who consumed stinging nettle tea 2 cups daily for one month prior to symptom onset. The condition subsided one month after discontinuing stinging nettle tea (76410).
There have been two cases of galactorrhea associated with the consumption of stinging nettle for one month (76410,108902). In one case, a 33-year-old female consuming stinging nettle tea showed high levels of estradiol and low levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH). The levels of these hormones normalized 6 weeks after discontinuing stinging nettle tea (76410). In the other case report describing a 30-year-old female self-treating with stinging nettle 500 mg daily, hormone levels were not reported; however, a mammogram showed scattered areas of fibroglandular density and benign-appearing calcifications. This patient had complete resolution of symptoms 1 week after discontinuation of stinging nettle (108902).

Gastrointestinal ...Orally, stinging nettle root can cause gastrointestinal complaints, including diarrhea and constipation (1,7,11230). Stinging nettle above ground parts may cause mild gastrointestinal discomfort when taken on an empty stomach (7035). Stinging nettle juice may cause diarrhea (1). One patient taking a combination product containing stinging nettle root extract and pygeum bark extract (Prostatonin, Pharmaton) experienced continual gastrointestinal pain and hyperperistalsis. It is not clear if this effect was due to stinging nettle or pygeum (70230).

Genitourinary ...There is a case report of decreased ejaculatory volume associated with an herbal blend product containing stinging nettle root extract, saw palmetto extract, pumpkin seed oil extract, lemon bioflavonoid extract, and beta-carotene (5093). It is unclear if this was due to stinging nettle, other ingredients, or the combination.

Hepatic ...A case of idiosyncratic drug-induced liver disease (DILI) is reported in a 36-year-old female who presented with abdominal pain after 1 month of taking an herbal liver detox tea containing stinging nettle and other ingredients. Remarkable laboratory values included elevated liver enzymes, alkaline phosphatase, and total bilirubin. The patient received a loading dose of N-acetylcysteine and was hospitalized for 12 days (112178). However, it is unclear if the adverse effect was due to the stinging nettle, other ingredients, or the combination.

Other ...Orally, stinging nettle root can cause sweating (1,7).

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General ...Orally, yellow dock seems to be well tolerated when properly prepared and consumed in food amounts. Consuming raw yellow dock leaves or rhizomes may be unsafe.
Serious Adverse Effects (Rare):
Orally: Raw leaves or rhizomes can cause hypocalcemia, kidney stones, and vomiting.

Cardiovascular ...Orally, yellow dock has been linked to ventricular fibrillation and death after ingestion of 500 grams (17). Oxalic acid, a constituent of yellow dock, reacts with calcium in plasma, forming insoluble calcium oxalate, which can cause hypocalcemia; the crystals may precipitate in the blood vessels and heart (12). Older or uncooked leaves should be avoided (6).

Dermatologic ...Orally, yellow dock can cause dermatitis when consumed in large amounts (4). Topically, contact with the plant may cause dermatitis in people sensitive to yellow dock (6).

Gastrointestinal ...Orally, vomiting may occur after ingestion of fresh rhizome (18). Consuming excessive amounts can cause diarrhea and nausea (6). Excessive use can also cause abdominal cramps and intestinal atrophy (4). There is one report of a death, preceded by vomiting and diarrhea, after ingestion of 500 grams of yellow dock (17). Older or uncooked leaves should be avoided (6).

Genitourinary ...Orally, yellow dock can cause polyuria when consumed in large amounts (6).

Hematologic ...Orally, in one case report, a 38-year-old female developed immune-mediated thrombocytopenia after consuming a "cleansing" tea containing unknown amounts of yellow dock and burdock. The patient presented with bruising, mild weakness, and fatigue, which started 2-3 days after consuming the tea, and was found to have a platelet count of 5,000 per mcL. Symptoms resolved after platelet transfusion and treatment with oral dexamethasone (108971). It is unclear if these effects were caused by yellow dock, burdock, the combination, or other contributing factors.

Hepatic ...Orally, yellow dock has been linked to liver failure and death after ingestion of 500 grams (17). Oxalic acid, a constituent of yellow dock, reacts with calcium in plasma, forming insoluble calcium oxalate, which can cause hypocalcemia; the crystals may precipitate in the liver (12). Older or uncooked leaves should be avoided (6).

Neurologic/CNS ...Orally, yellow dock has been linked to coma and death after ingestion of 500 grams (17). Older or uncooked leaves should be avoided (6).

Pulmonary/Respiratory ...Orally, yellow dock has been linked to respiratory depression and death after ingestion of 500 grams (17). Oxalic acid, a constituent of yellow dock, reacts with calcium in plasma, forming insoluble calcium oxalate, which can cause hypocalcemia; the crystals may precipitate in the lungs (12). Older or uncooked leaves should be avoided (6).

Renal ...Orally, yellow dock can cause polyuria when consumed in large amounts (6). There is one report of a death, preceded by kidney failure, after ingestion of 500 grams (17). Oxalic acid, a constituent of yellow dock, reacts with calcium in plasma, forming insoluble calcium oxalate, which can cause hypocalcemia; the crystals may precipitate in the kidneys. Individuals with a history of kidney stones should use yellow dock cautiously (12). Older or uncooked leaves should be avoided (6).

Other ...Orally, yellow dock can cause hypokalemia when taken in large amounts (4). There is one report of a death, preceded by severe metabolic acidosis, after ingestion of 500 grams of yellow dock (17). Oxalic acid, a constituent of yellow dock, reacts with calcium in plasma, forming insoluble calcium oxalate, which can cause hypocalcemia; the crystals may precipitate in the kidneys, blood vessels, heart, lungs, and liver (12). Older or uncooked leaves should be avoided (6).

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