Fem [Discontinued] by Loomis Enzymes

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atopic dermatitis (eczema). Although there is interest in using oral dong quai for atopic dermatitis, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Chronic kidney disease (CKD). There is limited evidence on the use of dong quai in patients with CKD. Details: A large propensity score-matched observational study over 15 years in Taiwanese adults with CKD suggests that taking dong quai is associated with a 5.1% risk of end-stage renal disease (ESRD) and 38% risk of overall mortality when compared with 7% and 56%, respectively, in controls. Higher cumulative doses (i.e., 15 grams or more) and longer duration of exposure (i.e., > 60 days) are also associated with fewer ESRD events (112362). However, the interpretation of these findings is limited by the lack of exact dosage information and retrospective study design.
• Coronary heart disease (CHD). Intravenous dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with CHD shows that injecting 20 mL of an intravenous solution containing dong quai, ginseng, and astragalus (Yi-qi Huo-xue Injection) daily for 2 weeks reduces the frequency and severity of angina episodes when compared with placebo. It also seems to increase exercise tolerance and improve left ventricular function when compared with placebo (33046). It is unclear if these benefits are due to dong quai, other ingredients, or the combination.
• Dysmenorrhea. Although there is interest in using oral dong quai for dysmenorrhea, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Hypertension. Although there is interest in using oral dong quai for hypertension, there is insufficient reliable information about the clinical effects of dong quai for this purpose.
• Idiopathic interstitial pneumonia. Oral dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of 17 studies conducted in China in patients with idiopathic interstitial pneumonia concludes that adding traditional Chinese medicine combinations containing dong quai root and astragalus root to treatment with conventional medicines improves pulmonary function index, six-minute walking distance, and the Borg scale of perceived exertion when compared with conventional treatment alone (103618). The included studies are of low quality, include a range of treatment durations from 1-12 months, and vary in the conventional medicines and Chinese herb combinations used. The doses of dong quai used were not stated.
• Infertility. Although there is interest in using oral dong quai for infertility, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Iron deficiency anemia. Although there is interest in using oral dong quai for iron deficiency anemia, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Menopausal symptoms. There is inconsistent and contradictory evidence about the effect of dong quai on menopausal symptoms. Benefits have only been seen when it is used in combination with other ingredients; its effect when used alone is unclear. Details: Some clinical research shows that taking dong quai, 1.5 grams three times daily for 24 weeks, does not affect menopausal symptoms (738). Other clinical research shows that dong quai improves menopausal symptoms when used in combination with other constituents. In one clinical trial, taking five chewable tablets of a specific combination of dong quai and chamomile (Climex) daily for 12 weeks reduced the frequency and severity of hot flushes when compared with placebo (48445). In another trial, taking a combination providing dong quai 75 mg, along with American ginseng, black cohosh, milk thistle, red clover, and vitex agnus-castus (Phyto-Female Complex) twice daily for 3 months reduces menopausal symptoms, including the number and intensity of hot flushes, the number of night sweats, and sleep quality (19552). Taking another combination product containing dong quai, burdock root, licorice root, motherwort, and Mexican wild yam root, 500 mg three times daily for 3 months, also reduces menopausal symptoms when compared with placebo (48522). It is unclear if the beneficial effects in these studies were due to dong quai, other ingredients, or a combination of ingredients.
• Migraine headache. Oral dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with menstrual migraine shows that taking a combination of soy isoflavones 60 mg, dong quai 100 mg, and black cohosh 50 mg daily for 24 weeks reduces the frequency of attacks when compared with placebo (35797). It is unclear if this effect is due to dong quai, other ingredients, or the combination.
• Osteoporosis. Although there is interest in using oral dong quai for osteoporosis, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Peptic ulcers. Although there is interest in using oral dong quai for peptic ulcers, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Premature ejaculation. Topical dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In one preliminary clinical trial in patients with premature ejaculation, a multi-ingredient cream preparation (SS Cream) containing dong quai, Panax ginseng root, Cistanches deserticola, Zanthoxyl species, Torlidis seed, clove flower, Asiasari root, cinnamon bark, and toad venom was applied to the glans penis 1 hour prior to intercourse and washed off immediately before intercourse. Patients using the cream had significantly improved ejaculatory latency when compared with placebo cream (2537). It is unclear if this effect is due to dong quai, other ingredients, or the combination.
• Premenstrual syndrome (PMS). Although there is interest in using oral dong quai for PMS, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Psoriasis. Although there is interest in using oral dong quai for psoriasis, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Pulmonary hypertension. Preliminary clinical research shows that intravenous dong quai may be effective in patients with pulmonary hypertension. Details: Some preliminary clinical research in patients with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension shows that intravenous administration of 250 mL of a solution containing dong quai 25%, once daily for 5-10 days, reduces pulmonary arterial pressure and pulmonary vascular resistance when compared to baseline (48438,48442,48443). The validity of these findings is limited by the lack of comparator groups.
• Rheumatoid arthritis (RA). Although there is interest in using oral dong quai for RA, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Stroke. Preliminary evidence does not support the use of intravenous dong quai for acute ischemic stroke. Details: Preliminary clinical research in patients with acute ischemic stroke shows that administering 200 mL of a solution containing dong quai 25% intravenously daily for 20 days does not improve neurological symptoms when compared with dextran-40 (48483). More evidence is needed to rate dong quai for these uses.

(Read more about DONG QUAI)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Celiac disease. Although there has been interest in using oral lipase for celiac disease, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Dyspepsia. It is unclear if oral lipase is beneficial for improving symptoms of postprandial distress syndrome. Details: A small clinical trial shows that taking a specific acid-resistant lipase (Amano Enzyme USA) 280 mg immediately before a high-fat meal does not reduce postprandial bloating and nausea when compared with placebo in individuals with postprandial distress syndrome (101900).
• Inflammatory bowel disease (IBD). Although there has been interest in using oral lipase for IBD, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Prematurity. It is unclear if adding a specific form of lipase, recombinant human bile salt-stimulated lipase (rhBSSL), to infant formula improves outcomes in premature infants. Some research suggests a potential increased risk for adverse effects. Details: Human breast milk contains rhBSSL, but it is inactivated when breast milk is pasteurized for donation. Clinical research in infants born before 32 weeks' gestation shows that adding rhBSSL as 8700 units per 100 mL formula or pasteurized breast milk, for 4 weeks does not increase growth velocity, body length, or head circumference over the next 12 months when compared with formula or pasteurized breast milk devoid of lipase. However, the infants who were small for gestational age (SGA), which made up approximately 15% of the study population, grew by an additional 1.9 grams/kg daily on average when compared with placebo (101940). More evidence is needed to rate lipase for these uses.

(Read more about LIPASE)

POSSIBLY EFFECTIVE

• Cachexia. Intravenous MCTs can provide calories in critically ill patients and patients with refractory cachexia, but do not seem to offer any advantages over long chain triglycerides. Details: Several small clinical studies in critically ill patients and patients with refractory cachexia secondary to cancer show that receiving parenteral nutrition with a 1:1 mixture of MCTs and long chain triglycerides is similarly effective to long chain triglycerides alone for improving metabolic parameters or nutritional status (2275,2276,93739).

POSSIBLY INEFFECTIVE

• HIV/AIDS-related wasting. Oral MCTs do not seem to promote weight gain or prevent weight loss in patients with HIV infection. Details: A large clinical study in patients with HIV infection shows that taking a peptide-based supplement containing MCTs (Peptamen Oral Complete Elemental Diet, Nestlé Clinical Nutrition) with multivitamins and minerals is no more effective than taking multivitamins and minerals alone for promoting weight gain or preventing weight loss (11730).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral MCTs are beneficial in patients with age-related cognitive decline. Details: A small, single-blind clinical study in older adults residing in a nursing home shows that taking MCTs 6 grams (a 3:1 mixture of caprylic acid:capric acid), with or without L-leucine 1.2 grams and vitamin D (cholecalciferol) 20 mcg, daily for up to 3 months increases mini-mental state exam (MMSE) scores by an average of 3.5 points, compared with a 0.7-point decline in those receiving a long chain triglyceride control. MMSE scores returned to baseline 1.5 months after discontinuation of MCT supplementation (105710).
• Alzheimer disease. Small clinical studies suggest that oral MCTs do not improve cognition in patients with Alzheimer disease or mild cognitive impairment. Details: A meta-analysis of small clinical studies in patients with Alzheimer disease or mild cognitive impairment shows that taking MCTs (as combinations of caprylic acid and capric acid) in doses of 20-56 grams or 22.5-165 mL daily for up to 6 months does not improve cognition when compared with placebo or baseline (103012).
• Athletic performance. It is unclear if oral MCTs are beneficial for endurance athletic performance. Details: A very small clinical study in 10 male recreational endurance runners shows that taking a ketone supplement containing MCTs and a salt form of beta-hydroxybutyrate 60 minutes prior to a run does not improve 5-kilometer run time when compared with placebo (107738). This study may have been inadequately powered to detect a difference between groups.
• Celiac disease. Although there has been interest in using oral MCTs for celiac disease, there is insufficient reliable information about the clinical effects of MCTs for this purpose.
• Chylothorax. It is unclear if oral MCTs improve time to resolution of spontaneous congenital chylothorax in neonates. Details: A small retrospective study in neonates with spontaneous congenital chylothorax shows that administering MCTs does not improve the time to resolution of chylothorax when compared with total parenteral nutrition (11729).
• Chyluria. Although there has been interest in using oral MCTs for chyluria, there is insufficient reliable information about the clinical effects of MCTs for this purpose.
• Cystic fibrosis. Although there has been interest in using oral MCTs for cystic fibrosis, there is insufficient reliable information about the clinical effects of MCTs for this purpose.
• Diabetes. Although there has been interest in using oral MCTs for diabetes, there is insufficient reliable information about the clinical effects of MCTs for this purpose.
• Epilepsy. It is unclear if oral MCTs are beneficial in adults and adolescents aged 12 years or older with drug-resistant epilepsy. Details: A small clinical study in adults and adolescents aged 12 years or older with drug-resistant epilepsy shows that adjunctive treatment with MCTs (Stepan Lipid Nutrition) as part of a non-ketogenic diet, 47-65 mL daily (about 35% of energy intake), or a maximally tolerated dose not exceeding 100 mL, for 12 weeks reduces median seizure frequency by 46% when compared with baseline (101967). The validity of this study is limited by its small sample size and the lack of a comparator group.
• Gallbladder disease. Although there has been interest in using oral MCTs for gallbladder disease, there is insufficient reliable information about the clinical effects of MCTs for this purpose.
• Hypertriglyceridemia. Oral MCTs might improve triglyceride levels and body weight in some patients with overweight and hypertriglyceridemia, but its effect in other populations is unclear. Details: Clinical research in patients with overweight and hypertriglyceridemia shows that taking 25-30 grams of an oil containing MCTs 13% daily for 8 weeks decreases triglyceride levels by 78 mg/dL when compared with consuming oil containing only long chain fats. Body weight, body fat, and waist circumference also decreased (93740). However, this benefit may be restricted to this specific population only. Some research in patients with obesity or patients with a normal body weight shows that taking 25-30 grams of an oil containing MCTs daily for 8 weeks does not lower triglyceride levels (93741).
• Obesity. Small clinical studies suggest that oral MCTs modestly improves weight loss; however, any effects may not be clinically relevant. Details: A meta-analysis of clinical research shows that taking MCTs decreases body weight by 0.5 kg, waist circumference by 1.5 cm, and hip circumference by 0.8 cm when compared with a control group not taking MCTs. Doses used in available research have ranged from 1-54 grams daily, or 1% to 24% of energy for 4-16 weeks (93735). Most research shows that at least 4 weeks is needed before effects are seen. The greatest benefit seems to occur in patients of Asian descent, males, and patients with higher body mass indices at baseline (93730,93731,93735,93736). While MCTs may improve weight loss in some patients, the effects are generally modest and may not be clinically relevant.
• Prematurity. It is unclear if oral or topical MCTs are beneficial in preterm infants. Details: A meta-analysis of small studies involving 136 otherwise healthy preterm infants receiving full enteral diets with formula as the predominant source of nutrition shows that administration of formulas containing at least 30% of fat by weight as MCTs (ranging in concentration from 6% to 80%) for at least 7 days does not affect short-term growth, including weight, length, and head circumference, when compared with formulas containing less than 30% of fat by weight as MCTs. Due to small study sizes, it is unclear whether either type of formula was better tolerated. The validity of this analysis is limited by the presence of unclear risk of potential bias in the included studies (105711). MCT oil has also been evaluated for the prevention of gastrointestinal Candida infections. A very small clinical study in preterm infants shows that adding MCT oil (Nestlé Health Science) 0.5 mL per ounce of formula or breast milk for 1 week reduces Candida colonization when compared with no MCT oil (101968). Topical use of MCT oil has also been evaluated for growth in preterm infants. A small clinical study in preterm infants weighing 1500-2000 grams shows that massage with MCT oil, consisting of tactile and kinesthetic stimulation, three times daily for 7 days increases weight gain when compared with no massage (107739). The validity of this finding is limited by unclear reporting. Also, it is unclear if this effect is due to MCT oil, massage, or the combination.
• Primary intestinal lymphangiectasia. It is unclear if oral MCTs are beneficial for the management of primary intestinal lymphangiectasia. Details: A review of 55 case reports suggests that taking MCTs as part of a low-fat, high-protein diet resolves symptoms in 63% of patients with primary intestinal lymphangiectasia, compared with 36% of patients receiving no treatment or other treatments such as diuretic therapy, albumin transfusions, resection of isolated segments of affected bowels, etc. Mortality is also reduced by 79% in patients treated with diet restrictions and MCTs when compared with those receiving no treatment or other treatments (93733).
• Sarcopenia. It is unclear if oral MCTs are beneficial in frail older adults. Details: A small clinical study in older adults residing in a nursing home shows that taking MCTs 6 grams, leucine 1.2 grams, and vitamin D (cholecalciferol) 20 mcg daily for 3 months increases body weight by 1.1 kg, right-hand grip strength by 13%, and peak expiratory flow by 28% when compared with baseline. These improvements are also significant when compared with patients receiving no supplementation (93729). In a second study in this same population conducted by the same research group, taking MCTs 6 grams, with or without leucine 1.2 grams and vitamin D (cholecalciferol) 20 mcg, daily for 3 months does not increase body weight or hand grip strength. There were small to moderate improvements in opening and closing the legs, repetitive swallowing, and measures of functional independence (101970). The validity of these findings is limited by the single-blind nature of the studies and the large number of endpoints. It is also unclear if any benefits are due to MCTs, other ingredients, or the combination.
• Short bowel syndrome. Although there has been interest in using oral MCTs for short bowel syndrome, there is insufficient reliable information about the clinical effects of MCTs for this purpose. More evidence is needed to rate MCTs for these uses.

(Read more about MEDIUM CHAIN TRIGLYCERIDES (MCTs))

Proteolytic enzymes represent a wide group of enzymes that are used alone or in combination. See specific monographs for effectiveness information.

(Read more about PROTEOLYTIC ENZYMES (PROTEASES))

POSSIBLY EFFECTIVE

• Mastalgia. Meta-analyses of small clinical studies show that vitex agnus-castus moderately reduces breast pain due to cyclic mastalgia. Details: Two small meta-analyses of low-to-moderate quality clinical studies in patients with cyclic mastalgia show that taking vitex agnus-castus moderately reduces breast pain when compared with placebo (101981,111753). The validity of these findings is limited by the heterogeneity of the included studies. Doses of vitex agnus-castus dried fruit extract range from 3.2-40 mg daily, for 2-6 months (90617,96250,101981,111753). Vitex agnus-castus is commonly used in proprietary products, alone or in combination with other herbs (Agnucaston/Cyclodynon, Bionorica AG, Femicur, Mastodynon, Bionorica AG, Monoselect Agnus, ZE 440) (13395).
• Premenstrual syndrome (PMS). Clinical research shows that vitex agnus-castus produces modest improvements in PMS symptoms. Details: Clinical research shows that taking vitex agnus-castus fruit extract orally for 2-6 menstrual cycles seems to reduce symptoms of PMS, especially breast pain or tenderness (mastalgia), edema, constipation, irritability, depressed mood, anxiety, anger, and headache (7055,7076,7078,7079,13394,15065,41483,41489,41490,41494,90619,101981). Doses of fruit extracts have varied from 3.5-40 mg daily, usually for 2-3 menstrual cycles (7055,7076,7078,7079,15065,41483,41489,41490,90619,96435). A meta-analysis of the available clinical research, including 17 studies involving 2,401 patients, shows that taking vitex agnus-castus is comparable to fluoxetine or oral contraceptives, and modestly more effective than placebo, for reducing the symptoms of PMS. A sub-group analysis indicates that efficacy is not impacted by the dose or form used, although the dried powdered berries appear to be ineffective. The low quality of the included studies and the high level of bias and heterogeneity limit the validity of these findings (96435). Another meta-analysis limited to three randomized controlled trials shows that taking vitex agnus-castus increases the likelihood of PMS symptom remission by 2.6-fold over placebo (101979). Some clinical studies have used a specific dried extract of vitex agnus-castus fruit (Agnolyt, Madaus AG) (7076). Other studies used a specific fruit extract known as Ze 440 (Prefemin, Zeller AG), which is standardized to casticin content (7078,90619). Additional studies have used the fruit extract BNO 1095 (Agnucaston/Cyclodynon, Bionorica AG) (15065,41483,41489,41490).

POSSIBLY INEFFECTIVE

• Fractures. Limited evidence suggests that vitex agnus-castus does not improve fracture healing rates. Details: Clinical research shows that taking a specific vitex agnus-castus dried fruit extract (Agnugol, Goldaru Pharmacy Company) 4 mg, alone or in combination with magnesium oxide (Nature Made Company) 250 mg, daily for 8 weeks does not improve long bone fracture healing when compared with placebo (90618).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there is interest in using oral vitex agnus-castus for acne, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Aging skin. Vitex agnus-castus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical trial in postmenopausal adults with wrinkles shows that taking one capsule orally daily of a combination of vitex agnus-castus 400 mg, evening primrose oil 500 mg, soy isoflavones 100 mg, and black cohosh 520 mg (Estosalus, Max Biocare Pty Ltd) for 12 weeks improves skin elasticity, skin smoothness, and wrinkle density scores when compared with placebo (109440).
• Amenorrhea. Although there is interest in using oral vitex agnus-castus for amenorrhea, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Anxiety. Although there is interest in using oral vitex agnus-castus for anxiety, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Benign prostatic hyperplasia (BPH). Although there is interest in using oral vitex agnus-castus for BPH, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Dementia. Although there is interest in using oral vitex agnus-castus for dementia, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Dysmenorrhea. It is unclear if oral vitex agnus-castus is beneficial in patients with dysmenorrhea. Details: Preliminary clinical research in patients with primary dysmenorrhea shows that taking a specific vitex agnus-castus extract (Agnucaston, Bionorica AG) daily for 3 months reduces pain, as measured on a visual analog scale, similarly to ethinyl estradiol 0.03 mg / drospirenone 3 mg (Yasmin) taken daily (104975).
• Fibrocystic breast disease. Although there is interest in using oral vitex agnus-castus for fibrocystic breast disease, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Hyperprolactinemia. Although there is interest in using oral vitex agnus-castus for hyperprolactinemia, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Infertility. It is unclear if oral vitex agnus-castus is beneficial for female infertility. Details: Preliminary clinical research in infertile females with oligomenorrhea or amenorrhea shows that taking homeopathic vitex agnus-castus (Phyto Hypophyson L, Steierl-Pharma GmbH) 50 drops orally three times daily for 3 months does not increase the chance of getting pregnant (41470). Also, one small clinical study in those with infertility due to secondary amenorrhea or luteal insufficiency shows that taking a vitex agnus-castus preparation (Mastodynon, Bionorica GmbH, Neumarkt/Opf.) 30 drops twice daily for at least 3 months does not increase the chance of pregnancy when compared with placebo, although the study was likely inadequately powered to detect a difference (7077).
• Insect repellent. Limited research suggests that topical vitex agnus-castus has insect repellent activity. Details: Preliminary clinical research shows that applying a carbon dioxide extract of vitex agnus-castus seeds seems to repel ticks and fleas for 6 hours, mosquitoes for 3-8 hours, and biting flies for 3 hours (13396). It is unclear how this compares with commonly used insect repellants.
• Insomnia. Although there is interest in using oral vitex agnus-castus for insomnia, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Lactation. Although there is interest in using oral vitex agnus-castus for stimulating lactation, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Menopausal symptoms. Clinical research suggests that vitex agnus-castus can relieve some menopausal symptoms; however, most research uses vitex agnus-castus in combination with other treatments. Details: Clinical research shows that taking vitex agnus-castus extract 15 mg twice daily for 8 weeks improves some menopausal symptoms, including anxiety and vasomotor dysfunction, by 76% and 88%, respectively, when compared with baseline. However, there was no effect on depression or sexual dysfunction (101980). Vitex agnus-castus has also been studied as a component of combination products. Preliminary clinical research shows that taking a combination of vitex agnus-castus, equivalent to 1000 mg dried fruit, black seed powder 500 mg, and citalopram 20 mg daily for 8 weeks reduces vasomotor, psychosocial, and physical symptoms of menopause when compared with citalopram alone (100325). Other preliminary clinical research shows that taking one capsule orally daily of a combination of vitex agnus-castus 400 mg, evening primrose oil 500 mg, soy isoflavones 100 mg, and black cohosh 520 mg (Estosalus, Max Biocare Pty Ltd) for 12 weeks moderately reduces the severity of hot flashes, sweating, sleep problems, depressed mood, and irritability when compared with placebo. There was no effect on plasma lipids, joint discomfort, anxiety, exhaustion, or sexual problems (105102). It is unclear if these effects are due to vitex agnus-castus, other ingredients, or the combination.
• Menorrhagia. It is unclear if oral vitex agnus-castus is beneficial in patients with menorrhagia. Details: A meta-analysis of two moderate quality clinical trials in patients who had heavy menstrual periods shows that taking vitex agnus-castus does not reduce menstrual bleeding over the next 1-2 menstrual cycles when compared with placebo (101982). However, preliminary clinical research in patients using an intrauterine device (IUD) shows that taking vitex agnus-castus three times daily for 8 days, starting on the first day of menstruation, and repeated for four consecutive menstrual cycles, reduces the amount of bleeding by approximately 48% when compared with baseline. This reduction was similar to the effects of mefenamic acid 250 mg daily after 4 months, although treatment with mefenamic acid was superior during the first three months (90620).
• Migraine headache. Although there is interest in using oral vitex agnus-castus for migraine headache, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Polycystic ovary syndrome (PCOS). Vitex agnus-castus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with oligomenorrhea due to PCOS shows that taking a traditional combination product (Aslagh) containing equivalent amounts of essential oils of vitex agnus-castus fruit, fennel, and wild carrot seeds orally daily for 3 months, either alone or in combination with metformin, improves rates of menstrual bleeding and menstrual cyclicity similarly to metformin alone. All three groups experienced a significant improvement from baseline. Aslagh was taken as two, 500-mg capsules twice daily, except during menses; metformin was titrated over one week to a dose of 500 mg three times daily (108974).
• Premenstrual dysphoric disorder (PMDD). Limited evidence suggests that vitex agnus-castus might improve symptoms of PMDD. Details: In a clinical trial, vitex agnus-castus 20-40 mg daily for 8 weeks was similar to fluoxetine 20-40 mg daily for relieving symptoms of PMDD. About 58% of patients responded to vitex agnus-castus, compared to about 68% of patients taking fluoxetine. Vitex agnus-castus was more effective for physical symptoms such as breast tenderness, swelling, cramps, and food cravings (12207,41493).
• Rheumatoid arthritis (RA). Although there is interest in using oral vitex agnus-castus for RA, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Sexual dysfunction. It is unclear if oral vitex agnus-castus is beneficial in patients with sexual dysfunction. Details: Preliminary clinical research in healthy females under 44 years of age with sexual dissatisfaction shows that taking a specific vitex agnus-castus product (Agnugol, Goldaru Herbal Pharmaceutical Company) 3.2-4.8 mg orally once daily for 16 weeks modestly improves scores of sexual satisfaction, function, arousal, and desire when compared with placebo (109437). Additionally, a moderate-sized clinical study in females 50-69 years old with sexual dysfunction conducted in Iran shows that taking vitex agnus-castus 40 drops daily for 8 weeks improves sexual dysfunction scores from mild dysfunction to no dysfunction at 6 and 8 weeks when compared with placebo but does not improve scores at 4 weeks (112361). More evidence is needed to rate the effectiveness of vitex agnus-castus for these uses.

(Read more about VITEX AGNUS-CASTUS)

POSSIBLY INEFFECTIVE

• Menopausal symptoms. Topical wild yam does not seem to improve menopausal symptoms. Details: Wild yam applied topically as a cream in menopausal patients for 3 months appears to be no better than placebo for relieving vasomotor symptoms, such as hot flashes and night sweats. It also does not appear to change serum follicle stimulating hormone (FSH), estradiol, or progesterone levels (10989).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cognitive function. It is unclear if oral wild yam is beneficial for improving cognitive function in healthy adults. Details: Preliminary clinical research in healthy adults shows that taking a specific wild yam extract (Diopower 15, Anti-Aging Pro Corporation) orally, 50 mg (containing diosgenin 8 mg) daily for 12 weeks, modestly improves overall measures of cognitive function and semantic fluency when compared with placebo (96724).
• Dysmenorrhea. Although there is interest in using oral or topical wild yam for dysmenorrhea, there is insufficient reliable information about the clinical effects of wild yam for this condition.
• Gallbladder disease. Although there is interest in using oral wild yam for gallbladder disease, there is insufficient reliable information about the clinical effects of wild yam for this condition.
• Infertility. Although there is interest in using oral or topical wild yam for infertility, there is insufficient reliable information about the clinical effects of wild yam for this condition.
• Osteoporosis. Although there is interest in using oral wild yam for osteoporosis, there is insufficient reliable information about the clinical effects of wild yam for this condition.
• Postmenopausal conditions. Although there is interest in using oral wild yam for postmenopausal conditions, there is insufficient reliable information about the clinical effects of wild yam for these conditions.
• Premenstrual syndrome (PMS). Although there is interest in using oral wild yam for PMS, there is insufficient reliable information about the clinical effects of wild yam for this condition.
• Rheumatoid arthritis (RA). Although there is interest in using oral wild yam for RA, there is insufficient reliable information about the clinical effects of wild yam for this condition.
• Sexual dysfunction. Although there is interest in using oral wild yam for sexual dysfunction, there is insufficient reliable information about the clinical effects of wild yam for this condition. More evidence is needed to rate wild yam for these uses.

(Read more about WILD YAM)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bleeding. Although there has been interest in using topical yucca for bleeding, there is insufficient reliable information about the clinical effects of yucca for this purpose.
• Dandruff. Although there has been interest in using topical yucca for dandruff, there is insufficient reliable information about the clinical effects of yucca for this purpose.
• Diabetes. Although there has been interest in using oral yucca for diabetes, there is insufficient reliable information about the clinical effects of yucca for this purpose.
• Hypercholesterolemia. Oral yucca has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with hypercholesterolemia shows that taking purified yucca extract in combination with quillaia extract orally three times daily for 4 weeks decreases total and low-density lipoprotein (LDL) cholesterol levels by more than 10% and 15%, respectively, when compared with baseline (86899). The validity of this finding is limited by the lack of statistical comparison to the placebo group.
• Hypertension. Although there has been interest in using oral yucca for hypertension, there is insufficient reliable information about the clinical effects of yucca for this purpose.
• Joint pain. Although there has been interest in using topical yucca for joint pain, there is insufficient reliable information about the clinical effects of yucca for this purpose.
• Migraine headache. Although there has been interest in using oral yucca for migraine headache, there is insufficient reliable information about the clinical effects of yucca for this purpose. More evidence is needed to rate yucca for these uses.

(Read more about YUCCA)

POSSIBLY SAFE ...when used orally and appropriately. Dong quai has been used with apparent safety in a dose of 4.5 grams daily for 24 weeks, or in combination with other ingredients in doses of up to 150 mg daily for up to 6 months (19552,35797). ...when used intravenously as a 25% solution, in a dose of 200-250 mL daily for up to 20 days (48438,48442,48443,48483).

POSSIBLY UNSAFE ...when used orally in large amounts, long-term. Theoretically, long-term use of large amounts of dong quai could be harmful. Dong quai contains several constituents such as bergapten, safrole, and isosafrole that are considered carcinogenic (7162). There is insufficient reliable information available about the safety of dong quai when used topically.

PREGNANCY: POSSIBLY UNSAFE
when used orally. Dong quai has uterine stimulant and relaxant effects (8142); theoretically, it could adversely affect pregnancy. Observational research has found that intake of An-Tai-Yin, an herbal combination product containing dong quai and parsley, during the first trimester is associated with an increased risk of congenital malformations of the musculoskeletal system, connective tissue, and eyes (15129).

LACTATION:
Insufficient reliable information available; avoid use.

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

CHILDREN: POSSIBLY UNSAFE
when recombinant human bile salt-stimulated lipase (rhBSSL) is used orally by premature infants. Adding rhBSSL to infant formula or pasteurized breast milk increases the risk for serious gastrointestinal adverse effects in premature infants (101940).

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

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LIKELY SAFE ...when used orally and appropriately (11726,11727,11728,11729,11730,93729). ...when used parenterally and appropriately (2275,2276,2278,11726,11727,11728,11729). There is insufficient reliable information available about the safety of MCTs when used topically.

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

(Read more about MEDIUM CHAIN TRIGLYCERIDES (MCTs))

POSSIBLY SAFE ...when used orally and appropriately. Various proteolytic enzymes have been safely used orally in clinical research (716,964,965,968,969,6252,6253,10622,11457,18281,18284) (91104,91105,91106,91111,96449). Side effects are typically mild to moderate and most often include gastrointestinal effects. See specific monographs for more detailed information related to the safety of individual proteolytic enzymes. ...when used topically and appropriately. Various proteolytic enzymes have been safely used topically in clinical research (67835,67843,67845,91113). Some proteolytic enzymes might cause allergic reactions when used topically. See specific monographs for more detailed information related to the safety of individual proteolytic enzymes.

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

(Read more about PROTEOLYTIC ENZYMES (PROTEASES))

LIKELY SAFE ...when the fruit extract is used orally and appropriately, short-term. Vitex agnus-castus fruit extract has been used safely in studies at doses up to 40 mg daily, for up to 3 months (7055,7076,7077,7078,7079,12207,13393,15065,90617,90618,96435). There is insufficient reliable information available about the safety of vitex agnus-castus seeds when used orally or topically.

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally. Theoretically, the hormonal effects of vitex agnus-castus might adversely affect pregnancy or lactation (10979,11456,13393,109439). Animal research shows that taking vitex agnus-castus fruit extract when planning to become pregnant or during pregnancy may increase the risk of infertility, low fetal body weight, abortion, and stillbirth (109439); avoid using.

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POSSIBLY SAFE ...when used orally. A dose of 50 mg (containing 8 mg diosgenin) has been used with apparent safety for 12 weeks (12,96724). ...when used topically. A wild yam cream has been used with apparent safety for 3 months (10989).

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

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LIKELY SAFE ...when used orally in amounts commonly found in foods. Specific species of yucca, including Mojave yucca (Yucca shidigera) and Joshua tree (Yucca brevifolia), have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912). There is insufficient reliable information available about the safety of yucca when used orally as medicine or when applied topically.

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

(Read more about YUCCA)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, dong quai may increase the risk of bleeding when used with anticoagulant or antiplatelet drugs; however, research is conflicting.  Details Animal studies suggest that dong quai has antithrombin activity and inhibits platelet aggregation due to its coumarin components (6048,10057,96137). Additionally, some case reports in humans suggest that dong quai can increase the anticoagulant effects of warfarin (3526,6048,23310,48439). However, clinical research in healthy adults shows that taking 1 gram of dong quai root daily for 3 weeks does not significantly inhibit platelet aggregation or cause bleeding (96137). Until more is known, use dong quai with caution in patients taking antiplatelet/anticoagulant drugs.

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, dong quai may reduce the effects of estrogens.  Details Dong quai has estrogenic effects (6180,7860,15108,15535,48459). Theoretically, concomitant use of large amounts of dong quai might interfere with hormone replacement therapy due to competition for estrogen receptors.

WARFARIN (Coumadin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Dong quai may increase the risk of bleeding when used with warfarin.  Details Case reports suggest that concomitant use of dong quai with warfarin can increase the anticoagulant effects of warfarin and increase the risk of bleeding (3526,6048,23310,48439). In one case, after 4 weeks of taking dong quai 565 mg once or twice daily, the international normalized ratio (INR) increased to 4.9. The INR normalized 4 weeks after discontinuation of dong quai (3526).

(Read more about DONG QUAI)

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(Read more about PROTEOLYTIC ENZYMES (PROTEASES))

ANTIPSYCHOTIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, vitex agnus-castus could interfere with the activity of antipsychotic drugs.  Details Vitex agnus-castus might interfere with the action of dopamine antagonists such as antipsychotic drugs due to its dopamine agonist effects (7014,7015).

CONTRACEPTIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, vitex agnus-castus could interfere with oral contraceptives.  Details Vitex agnus-castus might interfere with the efficacy of oral contraceptives due to possible hormone modulating activity (10979,11456).

DOPAMINE AGONISTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, vitex agnus-castus could interfere with dopamine agonists.  Details Vitex agnus-castus might potentiate the actions of dopaminergic agonists due to possible dopaminergic effects (10122).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, vitex agnus-castus could interfere with the activity of estrogens.  Details Vitex agnus-castus has hormone modulating activity that can interfere with the efficacy of hormone replacement therapy (10979,11456).

METOCLOPRAMIDE (Reglan) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, dopaminergic effects of vitex agnus-castus could interfere with metoclopramide.  Details Vitex agnus-castus might interfere with the action of dopamine antagonists such as metoclopramide due to its possible dopaminergic effects (7014,7015).

(Read more about VITEX AGNUS-CASTUS)

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, wild yam might increase or decrease the effects of estrogen.  Details Wild yam root shows estrogenic and anti-estrogenic effects in vitro (6180,70411,96723,96725). Theoretically, wild yam might interfere with hormone therapy.

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(Read more about YUCCA)

General ...Orally, dong quai is generally well-tolerated.
Most Common Adverse Effects:
Orally: Burping and flatulence.
Intravenously: Headache.

Cardiovascular ...Orally, dong quai might cause hypertension; according to one case report, a parent and breastfed infant experienced hypertension (195/85 mmHg and 115/69 mmHg, respectively) after the parent consumed a soup containing dong quai root (48428).

Dermatologic ...Dong quai contains psoralens that may cause photosensitivity and photodermatitis (10054,10057,48461).

Endocrine ...In a case report, a male developed gynecomastia after ingesting dong quai tablets (48504).

Gastrointestinal ...Orally, burping and gas may occur with dong quai (738).

Hematologic ...In one 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 three days after taking a phytoestrogen preparation containing dong quai 100 mg, black cohosh 250 mg, wild Mexican yam 276 mg, and red clover 250 mg (13155). It is unclear if dong quai contributed to this event.

Neurologic/CNS ...Dong quai given orally or by injection may be associated with headache (738,48438).

Oncologic ...Dong quai contains constituents that are carcinogenic; however, whether these constituents are present in concentrations large enough to cause cancer with long-term or high-dose use is unknown (7162).

Pulmonary/Respiratory ...A pharmacist experienced allergic asthma and rhinitis after occupational exposure to dong quai and other herbs (48435).

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General ...No adverse effects have been reported in adults. However, a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Gastrointestinal adverse effects, such as necrotizing enterocolitis, when recombinant human bile salt-stimulated lipase is used in premature infants.

Gastrointestinal ...Orally, when added to the formula or pasteurized breast milk consumed by premature infants, recombinant human bile salt-stimulated lipase (rhBSSL) can cause gastrointestinal adverse effects, including abdominal distension, flatulence, constipation, colic, abdominal pain, gastroenteritis, vomiting, regurgitation, and rectal bleeding (101940). Premature infants receiving rhBSSL also had a slightly higher rate of necrotizing enterocolitis (NEC) when compared with those receiving placebo. After review by a panel of experts, it was determined that the rate of confirmed or suspected NEC in infants consuming rhBSSL was 3.3%, compared with 0.5% in those receiving placebo. Although this rate of NEC is lower than the historical rate of occurrence in premature infants (11%), a possible increased risk for NEC cannot be ruled out (101940).

(Read more about LIPASE)

General ...Orally, MCTs can cause significant gastrointestinal upset, especially with higher doses.
Most Common Adverse Effects:
Abdominal discomfort, diarrhea, essential fatty acid deficiency, intestinal gas noises, irritability, nausea, reflux, vomiting. Gastrointestinal disturbances are thought to be associated with higher doses of MCT. Since MCTs are fats, excessive consumption can result in weight gain.

Cardiovascular ...There is some concern that MCTs may further increase the risk for hypertriglyceridemia in some preterm infants due to immature lipoprotein lipase activity in these infants. A case of extremely elevated triglyceride levels of 4,736 mg/dL and associated lipemia retinalis has been reported at 43 weeks post-menstrual age (PMA) for a preterm infant born at 30 weeks' gestational age. It was discovered that the baby had been receiving MCT supplements in addition to breast milk starting at 42 weeks' PMA. MCT supplements were discontinued. One month later triglycerides were reduced to 287 mg/dL, and the retinal vasculature had a normal hue. However, at 2-month follow-up, triglyceride levels were elevated to levels higher than normal for age despite MCT discontinuation. Investigators speculated that a genetic disorder of lipid metabolism may also have contributed to the elevated triglyceride levels in addition to use of MCTs (96330).

Gastrointestinal ...Orally, MCTs can cause significant gastrointestinal upset. Diarrhea is the most commonly reported side effect (11723,93737,93738,101967). Other reported side effects include vomiting, irritability, nausea, reflux, abdominal discomfort, intestinal gas noises, and essential fatty acid deficiency (11723,93738,101967). Taking MCTs with food can reduce these adverse effects (93737). Gastrointestinal disturbances are thought to be associated with higher doses of MCT, such as 85 grams (93731).

Other ...Excessive consumption of MCTs can result in weight gain. MCT oil contains 6-8.5 calories per gram. One tablespoon provides about 14 grams and about 115 calories (11724).

(Read more about MEDIUM CHAIN TRIGLYCERIDES (MCTs))

General ...Orally, proteolytic enzymes are generally well tolerated. See specific monographs for detailed safety information related to individual proteolytic enzymes.
Most Common Adverse Effects:
Orally: Gastrointestinal upset.
Serious Adverse Effects (Rare):
Topically: Allergic reactions.

Gastrointestinal ...Orally, some patients taking proteolytic enzymes may have gastrointestinal complaints (101517).

Immunologic ...Proteolytic enzymes are commonly found in laundry detergents and pre-spotter products. Rarely, protease specific IgE positive tests possibly related to these products have occurred. Exposure may be airborne or topical (102705). In addition, in case reports, occupational exposure to the airborne proteolytic enzyme pepsin has resulted in allergic rhinoconjunctivitis or asthma (102706,102707).

(Read more about PROTEOLYTIC ENZYMES (PROTEASES))

General ...Orally, vitex agnus-castus is generally well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, fatigue, headache, insomnia, irregular menstruation, nausea, skin irritation, stomach pain, vomiting.

Dermatologic ...Orally, skin conditions such as itching, irritation, urticaria, rash, acne, eczema, and hair loss have been reported (7055,7076,7078,7079,12207,13393,15065,90617,90619,101981).

Gastrointestinal ...Orally, gastrointestinal upset or pain, diarrhea, and nausea and vomiting, have been reported (7079,12207,13393,15065,90620,101981,101982). In one clinical trial, a single patient reported persistent gastroenteritis while taking vitex agnus-castus (7076). Orally, development of a bezoar resulting in colonic obstruction is described in a 63-year-old male who consumed an unknown amount of vitex agnus-castus seeds (111752).

Genitourinary ...Orally, irregular or prolonged menstrual bleeding has been reported (7055,7079,12207,13393,15065,41489,41490,95326).

Hematologic ...Orally, nosebleed has been reported in a single patient in a clinical trial (7079).

Immunologic ...Orally, multiple abscesses have been reported in a single patient (7055).

Neurologic/CNS ...Orally, headache, fatigue, and insomnia (7076,7078,12207,13393,13395,15065), confusion (90617), and vertigo (7079) have been reported.

Other ...Orally, weight gain has been reported (12207,13393,15065).

(Read more about VITEX AGNUS-CASTUS)

General ...Orally, wild yam is generally well tolerated.
Most Common Adverse Effects:
Orally: Fever, headache, upset stomach, and vomiting.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis.

Gastrointestinal ...Orally, wild yam can cause upset stomach and vomiting, especially at higher doses (12,86450).

Hematologic ...In one 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 wild yam 276 mg, dong quai 100 mg, red clover 250 mg, and black cohosh 250 mg (13155). It is unclear if wild yam contributed to this event.

Immunologic ...There are three case reports of anaphylaxis after ingestion of cooked wild yam (96722).

Neurologic/CNS ...Orally, wild yam can cause headache and fever, especially at higher doses (86450).

(Read more about WILD YAM)

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

Dermatologic ...Topically, yucca has been reported to cause phytodermatitis (68294). In one case report, an atopic gardener developed contact urticaria after occupational exposure to weeping fig, spathe flower, and yucca. Allergen skin tests were positive for all three plants (49961).

Gastrointestinal ...Orally, the saponins in yucca can be irritating to mucous membranes and might cause gastrointestinal irritation (7,4077).

Pulmonary/Respiratory ...Environmental exposure to yucca has been associated with allergic rhinitis in 59 patients who exhibited sensitization to yucca after allergen skin testing (86902).

(Read more about YUCCA)